J Clin Immunol (2016) 36:235–334

DOI 10.1007/s10875-016-0237-x

ABSTRACTS

2016 CIS Annual Meeting: Immune Deficiency & Dysregulation

North American Conference
Published online: 16 February 2016
# Springer Science+Business Media New York 2016

4189: DE NOVO X-LINKED CARD9 deficiency confers human susceptibility to inva-

AGAMMAGLOBULINEMIA sive fungal disease, including spontaneous central nervous
system candidiasis(sCNSc). We describe the clinical and
Mili Shum, Rauno Joks and Jack Moallem radiologic findings of sCNSc in a French-Canadian cohort,
to facilitate clinical recognition, and performed in-depth
Center for Allergy and Asthma Research, Department of analyses to further decipher the pathophysiology of
Medicine, SUNY Downstate Medical Center, Brooklyn, NY CARD9 deficiency.
In our series (n = 4), sCNSc had onset in adulthood
A 6-year-old boy with 2 days of headache and fever was diag- (median:38 years), often misinterpreted radiologically as
nosed with pneumococcal meningitis by CSF culture. He had brain malignancies; one had additional, novel features
recurrent otitis media, pyogenic skin infections, and sinusitis (endophthalmitis; osteomyelitis). CARD9 deficiency re-
since 10 months of age. Family history lacked significant in- sulted from a hypomorphic p.Y91H mutation and allelic
fections or early deaths. Laboratory investigation revealed ab- imbalance, established in this population via founder ef-
normally low levels of serum immunoglobulins and undetect- fects. We demonstrate a consistent cellular phenotype of
able antibody to rubella, mumps, and varicella. Flow cytometry impaired GM-CSF responses. The ability of CARD9 to
revealed absent B cells with normal T and NK cells. Genomic complex with BCL10 and MALT1 is intact, arguing
DNA analysis of Btk gene revealed a single base pair substitu- against its involvement in susceptibility to Candida.
tion in codon 606 on exon 18 resulting in a missense mutation. Instead, we show that the p.Y91H mutation impairs
Genomic DNA of his mother, father, and sister all demonstrat- complexing of CARD9 to RASGRF1, causing impaired
ed normal pattern indicating that they were not carriers of XLA. activation of NFkB and ERK in monocytes, and subse-
He was started on monthly IVIG and daily Bactrim without quent GM-CSF responses. Successful treatment of a sec-
recurrence of infections on 10-year follow-up. ond patient with adjunctive GM-CSF bolsters the clinical
X-linked agammaglobulinemia (XLA) is a rare disease char- relevance of these findings.
acterized by deficient immunoglobulin levels and absence of Hypomorphic CARD9 deficiency due to p.Y91H results in
circulating B cells due to mutation of Bruton tyrosine kinase adult-onset disease with variable penetrance and expressivity.
(Btk) gene on the X chromosome. XLA with normal maternal The CARD9/RASGRF1/ERK/GM-CSF axis appears central
Btk genotyping may occur due to de novo Btk mutations in to the pathophysiology of sCNSc.
15 % of cases or maternal gonadal chimerism with a likeli-
hood of less than 5 %. A high index of suspicion is essential 4204: FUNNY IMMUNOLOGY TO SAVE LIVES
for the diagnosis of XLA in a child without a family history of
infections and prompt treatment may prevent severe fatal Juan Carlos Aldave, MD
infections.
Allergy and Clinical Immunology, Hospital Nacional Edgardo
Rebagliati Martins, Lima, Peru
4200: IMPAIRED RASGRF1/ERK-MEDIATED
GM-CSF RESPONSE CHARACTERIZES CARD9 Introduction: Peru is a developing country with 30 million
DEFICIENCY IN FRENCH-CANADIANS people; we estimate 10,000 undiagnosed patients with
Primary Immunodeficiency (PI). A major obstacle for the di-
Donald C. Vinh, MD agnosis of these patients is the limited number of Clinical
Immunologists. Most Pregraduate Medical Programs in Peru
Infectious Disease Susceptibility Program, McGill University do not teach Immunology as a separate course, or they give
Health Centre - Research Institute, Montreal, QC, Canada Immunology instruction in a tedious way.
236 J Clin Immunol (2016) 36:235–334

Methods: It is necessary to convince Pregraduate Medical WBC and low immunoglobulin levels might be absent.
Students that Immunology is fantastic. An optimal way to Newborn TRECs screening would have helped in this tricky
achieve this goal in a low-resource setting is by teaching them presentation.
about the importance of the immune system and the impact of
immune defects using easy-to-remember material. This will en-
courage Medical Students to pursue a career in Immunology. 4214: COMPREHENSIVE CLINICAL
Long-term results will include an improvement in the diagnosis EVALUATION OF PRIMARY
and management of PI patients. IMMUNODEFICIENCY BY NEXT
Results: We have developed a book series entitled BFunny GENERATION SEQUENCING
Immunology to Save Lives^. It is composed of 9 books:
BThe Immunocytes^, BThe TH17 army against Candida^, Hui Yu, PhD1, Victor Wei Zhang, MD, PhD2, Asbjorg Stray-
BThe TH1 army against Mycobacteria^, BThe TH2 army Pedersen, MD, PhD3,4,5, Imelda Celine Hanson, MD3, Lisa R.
against worms^, BThe battle against Pneumococcus^, Forbes, MD3, M Teresa de la Morena, MD6, Elizabeth
BImmunocytes against cancer^, BT regs: controlling the im- Gorman, PhD1, Nancy J. Mendelsohn, MD7, Tamara C.
mune army^, BWhen immunocytes get sick^, and BWhen Pozos, MD PhD7, Ivan Chinn, MD3, Wojciech Krzysztof
immunocytes go crazy^. The early impact of our educational Wiszniewski, MD, PhD2, Sarah Kogan Nicholas, MD3,
material has been astonishing. Anne B Yates, MD8, Lindsey E Moore, DO8, Knut Erik
Conclusions: Our educational material can contribute to the Berge, MD, PhD5, Hanne Sorte5, Diana K. Bayer, DO9,
development of Immunology in other countries. Daifulah ALZahrani, MD10, Raif S. Geha, MD11, Ezra
Cohen, MD12, Yanming Feng, PhD1, Guoli Wang, PhD1,
Kaytee Bagley1, Jordan S. Orange, MD, PhD3, James R
4212: IS HYPERGAMMAGLOBULINEMIA Lupski, MD, PhD, DSc (hon)4, Jing Wang, MD2 and Lee-
POSSIBLE IN SCID? Jun C Wong, PhD2

1
Gustavo Soldateli, MD, Cristiane J. N. Santos, MD, Mayra Baylor Miraca Genetic Laboratories, Houston, TX,
2
de Barros Dorna, MD, Ana Paula B. Moschione Castro, MD, Department of Molecular and Human Genetics, Baylor
PhD, Antonio Carlos Pastorino, MD, PhD and Magda College of Medicine, Houston, TX,
3
Carneiro-Sampaio, MD, PhD Center for Human Immunobiology, Immunology Allergy
Rheumatology, Texas Children’s Hospital, Houston, TX,
4
Allergy and Immunology Unit - Department of Pediatrics, Baylor-Hopkins Center for Mendelian Genomics of the
Universidade de São Paulo, São Paulo, Brazil Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, TX,
5
Case report: 9 month-old male, born to non-consanguineous par- Norwegian National Newborn Screening, Oslo University
ents from a small town in Brazil. Older sibling died at 6 months Hospital, Oslo, Norway,
6
due to pneumonia. Referred to our hospital with recurrent fever, Department of Pediatrics, UT Southwestern Medical Center/
enlargement of right axillary lymph node and cough. He had a Children’s Medical Center Dallas, Dallas, TX,
7
medical history of multiple hospital admissions due to pneumo- Children’s Hospital & Clinics of Minnesota, Minneapolis, MN,
8
nia, failure to thrive and persistent BCG ulcer. Initial laboratory University of Mississippi Medical Center, Jackson, MS,
workup showed leukocytosis with lymphocytosis (23,940/mm3 9
Department of Pediatrics, Division of Pediatric Allergy/
and 17,240/mm3) and hypergammaglobulinemia (IgM 493, IgG Immunology and Pulmonology, University of Iowa Carver
3243 and IgA 437 mg/dL) with a monoclonal peak in the College of Medicine, Iowa City, IA,
10
gammaglobulin fraction of 0.6 g/dL. Immunophenotyping re- Department of Pediatrics, King Saud Bin Abdulaziz
vealed severe T cell lymphopenia (37/mm3) with elevated B cells University for Health Sciences, Jeddah, Saudi Arabia,
(2229/mm3), and NK cells (1209/mm3). Salmonella was isolated 11
Immunology Division, Department of Pediatrics, Boston
from stool, cytomegalovirus was detected by PCR in both bron- Children’s Hospital, Harvard Medical School, Boston, MA,
12
choalveolar lavage (BAL) and blood, and pneumocystis jirovecii Immunology Division, Boston Children’s Hospital, Harvard
in BAL. Empirical treatment was started for disseminated BCG- Medical School, Boston, MA
associated complications, ceftriaxone for Salmonella, co-
trimoxazole for P. jirovecii pneumonia and ganciclovir for Primary immunodeficiency diseases are inherited disorders of
CMV infection. Patient developed thrombocytopenia the immune system. The most severe form, severe combined
(1000/μL3) which improved after high-dose IV gamma globulin. immunodeficiency (SCID), presents with profound deficiencies
He is currently awaiting molecular diagnosis and HSCT. of T cells and/or B cells at the time of birth. If not treated
Although typically found in SCID patients, lymphopenia in promptly, affected patients usually do not live beyond infancy.
J Clin Immunol (2016) 36:235–334 237

Genetic heterogeneity of SCID frequently delays the diagnosis. history data. 21 % provided only QOL data. 77 % had
We developed an NGS-based multi-gene panel targeted for ever been hospitalized for infection and 58 % for bleed-
SCID in a clinical laboratory setting. The target gene capture/ ing. 17 % had autoimmunity. 11 % had cancer. Treatments
NGS assay provides an average read depth of 1000X. The high were SP (21 %), HCT (48 %), GT (4.5 %) or SC (26 %).
depth of coverage facilitates simultaneous detection of single PedsQL™ scores were 78 ± 17, consistent with clinically
nucleotide variants (SNVs) and exonic copy number variants important impairment. Scores did not differ significantly
(CNVs) in one comprehensive assessment. Exons with insuffi- between XLT and classic WAS. A trend favored
cient read depth (<20X) or high sequence homology are cytotherapy over SC for improved QOL.
complemented by PCR/Sanger sequencing. Analysis of more Our data show that patients with WAS have significantly de-
than 40 patient samples identified pathogenic variants involving creased QOL regardless of disease severity. HCT/GT may be
both SNVs and exonic CNVs, such as hemizygous changes in associated with improved QOL.
IL2RG; compound heterozygous changes in ATM, RAG1, and This abstract reflects the views of the authors and should not
CIITA; homozygous changes in DCLRE1C and IL7R; and a be construed to represent FDA’s views or policies.
heterozygous nonsense change in CHD7. High throughput deep
sequencing analysis greatly increases the diagnostic yield of pri-
mary immunodeficiency. Establishing a molecular diagnosis en- 4223: AUTOIMMUNE
ables early immune reconstitution through prompt therapeutic LYMPHOPROLIFERATIVE SYNDROME (ALPS)
intervention and guides management for improved long-term AND ALPS-RELATED SYNDROMES.
quality of life. DIFFERENT BIO-CLINICAL PROFILE AND
SIMILAR RESPONSE TO MMF AND
SIROLIMUS: A SINGLE CENTER EXPERIENCE
4215: QUALITY OF LIFE (QOL) IN PATIENTS
WITH WISKOTT-ALDRICH SYNDROME (WAS) Maurizio Miano 1 , Elena Palmisani 1 , Ilaria Caviglia 2 ,
Concetta Micalizzi1, Michaela Calvillo1, Paola Terranova1,
Rob Sokolic, MD1, Sumathi Iyengar, MD2, Christopher Tiziana Lanza1, Carlo Dufour1 and Francesca Fioredda1
Scalchunes, MPA3, Christina Mangurian, MD4, Michael
1
Albert, PD Dr.med.5, James W. Varni, PhD6 and Morton Clinical and Experimental Hematology Unit, IRCCS Istituto
Cowan, MD7 Giannina Gaslini, Genoa, Italy,
2
Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini,
1
Center for Biologics Evaluation and Research, Food and Genoa, Italy
Drug Administration, Silver Spring, MD,
2
Wiskott-Aldrich Foundation, Smyrna, GA, Clinical data on lymphoproliferative disorders are scarce. We
3
Immune Deficiency Foundation, Towson, MD, studied clinical features and treatment of patients with ALPS
4
Department of Psychiatry, University of California at San (32) and Related Syndromes (ARS, 33) defined as the presence
Francisco, San Francisco, CA, (5)University Children’s of Autoimmune Cytopenia (AC) and/or lymphoproliferation
Hospital, Munich, Germany, (LP) and at least one absolute/primary additional criterion for
6
Department of Pediatrics, Texas A&M University, College ALPS followed between 2001 and 2014. 41 pts (63 %) needed
Station, Texas, TX, therapy other than 1st line. LP, AC, and other autoimmunity
7
University of California San Francisco, San Francisco, CA had different incidence in both groups. All patients showed
similar response to MMF and Sirolimus. Median follow-up
QOL is critical in assessing outcomes of treatments for WAS was 3.3 years. Further studies are needed to identify the under-
including hematopoietic cell transplantation (HCT), gene ther- lying defects in ARS group, expecially in responding pts.
apy (GT), splenectomy (SP), and supportive care (SC). In a
cross-sectional international survey of WAS patients and/or n ALPS ARS p
their parents, we measured QOL using PedsQL™ 4.0 LP 51/65 32/32, 100 % 19/33, 58 % 0.01
Generic Core Scales, and correlated scores with clinical data. AC 51/65 22/32, 69 % 29/33, 88 % 0.07
A PedsQL™ score of 100 indicates the best possible QOL. Trilinear AC 7/51 7/22, 32 % 0/29, 0 % 0.01
Previous research has found children with post-HCT graft vs autoimmunity 18/65 13/32, 40 % 5/33, 15 % 0.02
host disease have a score of 75, children with no identified ITP* 16/51 4/32, 12 % 12/33, 36 % 0.07
illness have a score of 83 and children with cerebral palsy MMF 34/41 11/14, 79 % 6/11, 54 % ns
have a score of 51. Sirolimus 18/41 5/7, 71 % 7/9, 77 % ns
Data from 97 patients (24 XLT; 73 classic WAS) were
collected. 69 % provided complete QOL and medical *PLTs <30,000/mmc in ARS vs ALPS p = 0.01
238 J Clin Immunol (2016) 36:235–334

4228: IMMUNE DYSREGULATION, 4277: ELEVATED RISK OF PULMONARY

POLYENDOCRINOPATHY, ENTEROPATHY, VASCULAR DISEASE (PVD) WITH
X-LINKED SYNDROME (IPEX) ASSOCIATED PULMONARY HYPERTENSION (PH)
WITH NEUROLOGICAL PRESENTATION AND IN CHILDREN WITH PRIMARY
LATE DEVELOPMENT OF ACUTE MYELOID IMMUNODEFICIENCY (PID)
LEUKEMIA.

Mei-Sing Ong1,2,3, Marc D Natter1,2, Mary Mullen1,2 and

1,2,3 4 5
Mehdi Adeli , Heidi Sandige , Adiba Hamad and Eman Kenneth D Mandl1,2
Al-Muslemani5
1
Boston Children’s Hospital, Boston, MA,
2
Harvard Medical School, Boston, MA,
1 3
Hamad Medical Corporation, Hamad Medical Corporation, Macquarie University, Sydney, Australia
Doha, Qatar,
2
Allergy and Immunology, Sidra Medical and Research Background: PVD is a rare disease with high morbidity and
Center, Doha, Qatar, Doha, Qatar, mortality, particularly after progression to symptomatic PH.
3
Pediatrics, Weill Cornell Medical College in Qatar, Doha, We hypothesize that, as a result of immune-mediated patho-
Qatar, genesis, PH may disproportionately impact those with PID.
4
Sidra Medical and Research Center, Doha, Qatar, Sidra However, the co-occurrence of PH in PID remains poorly
Medical and Research Center, Doha, Qatar, Doha, characterized.
Qatar, Methods: Retrospective analysis of a U.S. health insur-
5
Pediatrics Department, Hamad Medical Corporation, ance claims database, with over 20 million patient-years
Doha, Qatar of exposure (6,941,722 subjects <18 years old, from years
2011 to 2013).
Results: 7542 (0.1 %) and 1346 (0.019 %) patients were
Abstract: IPEX syndrome (Immune dysregulation, diagnosed with PID and PH, respectively; 51 (0.7 %) pa-
polyendocrinopathy, enteropathy x-linked syndrome) is tients had PID and PH. The risk of PH in PID was mark-
characterized by autoimmune manifestations in multiple edly elevated (OR 36.3; 95 % CI 27.5–48.2; p < 0.0001).
organs. The patient presented at 22 months of age with Comorbidities recognized to be associated with PH and
decreased interactivity, anorexia with weight loss, and PID (e.g., congenital heart disease, connective tissue dis-
abnormal gait. He had regression of milestones includ- ease, interstitial lung disease and bronchiectasis) were
ing refusal to walk and talk, scattered erythematous present in 70 % of patients, but elevated risk of PH in
plaques and extreme pruritis localized the genital area, PID remained after accounting for these conditions (mul-
followed by a period of fevers without identified tivariate regression analysis OR 3.5; 95 % CI 2.6–4.9;
focus. Neurological symptoms slowly improved. p < 0.0001). A further subgroup analysis of children with-
Multidisciplinary workup found no endocrinopathies, out these recognized predisposing comorbidities also re-
enteropathy, neurological or infectious etiologies. vealed an increased risk of PH in PID (OR 2.3; 95 % CI
Elevated IgE and IgG 4, Normal IgM and IgA. 1.5–3.4; p < 0.0001).
Continued itching led to ulceration of the perineal area Conclusions: PID appears to be an independent risk factor for
and penile enlargement. Whole exome sequencing for the development of PH in this population-based analysis.
the diseases associated with elevated IgE revealed iso- Children with PID may benefit from enhanced surveillance
lated heterozygous mutation for the R397Q mutation in for PH.
the FOXP3 gene. Three and half years after initial pre-
sentation he developed AML . Mother is a carrier and he
has a brother with identical HLA typing for future bone 4281: FINDING A NEEDLE IN A HAYSTACK:
marrow transplant. NEW APPROACHES TO IDENTIFY
METHODS: Whole Exome Sequencing. DISEASE-CAUSING MUTATIONS IN PATIENTS’
CONCLUSION: IPEX presentation can be variable that HIGH-THROUGHPUT SEQUENCING DATA
this diagnosis should be considered in a male child with
potential autoimmune neurological dysfunction if associ-
ated with immune deregulation and localized pruritic Yuval Itan, PhD1, Lei Shang2, Shen-Ying Zhang, MD, PhD3,
skin rashes, AML should be considered in IPEX with Bertrand Boisson, PhD1, Laurent Abel4 and Jean-Laurent
Lymphadenopathy Casanova, MD, PhD1
J Clin Immunol (2016) 36:235–334 239

1
St-Giles Laboratory of Human Genetics of Infectious therapeutic strategies targeting aberrant methylation reverse
Diseases, Rockefeller University, New York, NY, gene silencing, and can be tailored to any specific genes in-
2
The Rockefeller University, New York, NY, volved for the recovery of cell differentiation and/or function.
3
St. Giles Laboratory of Human Genetics of Infectious Inhibitors of DNA methyltransferase (5-azacytidine) and his-
Diseases, The Rockefeller University, New York, NY, tone deacetylases (valproic acid) were used to treat bone mar-
4
Laboratory of Human Genetics of Infectious Diseases, row hematopoietic stem cells (HSCs) of CVID-affected and
Necker Branch, INSERM U1163, Necker Hospital for Sick healthy horses in order to reverse the aberrant epigenetic
Children, INSERM, Paris, France changes and rescue B cell lymphopoiesis. 5-azacytidine and
valproic acid treatment increased the percentage of HSCs
The exome of a patient with a rare Mendelian disease contains from both CVID-affected and healthy horses. In addition, 5-
about 20,000 variations, of which only one is disease-causing. azacytidine treatment did not affect normal B cell differentia-
Ascertaining whether a gene that harbors a variation may be tion. The in vitro generation of B cells from HSCs of CVID-
relevant to the disease being studied is key to testing as few affected horses is under pursue. Our overall goal is to correct
potential candidate mutant alleles as possible while not ex- aberrant epigenetic mechanisms in vitro for subsequent stud-
cluding the disease-causing allele(s). We developed three nov- ies of cure in vivo.
el gene-level approaches to estimate the relevance of a specific
gene to a disease. We first describe the human gene
connectome (HGC), the biological distance between any two 4287: WILD SYNDROME IS GATA2
human genes, used to prioritize candidate genes with genes DEFICIENCY: REPORT OF A NOVEL
that are known to be disease-causing. We then report gene MUTATION IN THE GATA2 GENE
damage index (GDI), a genome-wide, gene-level estimate of
accumulated mutational damage for human protein-coding Thomas G. Boyce, MD, MPH1, Michelle Van Hee, B.S.2,
genes. Genes that are frequently mutated in healthy individ- Susan A. Lagerstedt, BS3, Matthew J. Smith, BS3, Mrinal M.
uals are unlikely to cause rare diseases, and yet they contribute Patnaik, M.B.B.S. 4, Catherine C. Newman, M.D.5 and
to a large proportion of the next generation sequencing data Roshini Abraham, Ph.D.3
generated for any patient. We then present the mutation sig-
1
nificance cutoff (MSC): a benign/damaging threshold of sig- Pediatrics, Mayo Clinic, Rochester, MN,
2
nificance, specific for each human gene. With the MSC we Cellular & Molecular Immunol Lab, Dept. of Lab Medicine
improve discovery rate of new disease-causing alleles to & Pathology, Mayo Clinic, Rochester, MN,
3
98 %. Overall, we demonstrate that investigating a variation Department of Laboratory Medicine and Pathology, Mayo
in the context of the gene and the disease increases the dis- Clinic, Rochester, MN,
4
covery rate of disease-causing mutations. Hematology, Mayo Clinic, Rochester, MN,
5
Dermatology, Mayo Clinic, Rochester, MN

4285: REVERSING EPIGENETIC GENE An 18-year-old man presented with persistent warts and recent
SILENCING IN COMMON VARIABLE scrotal and penile edema. There were two prior episodes of
IMMUNODEFICIENCY streptococcal bacteremia with lymphangitis of the leg and a
history of recurrent molluscum contagiosum. An initial pre-
M. Julia B. Felippe, MedVet, MS, PhD, DACVIM, sumptive diagnosis of WILD syndrome (warts, depressed
Rebecca L. Tallmadge, PhD and Ute E. Schwab, PhD cell-mediated immunity, primary lymphedema, and
anogenital dysplasia) was made. Because of monocytopenia,
Department of Clinical Sciences, Cornell University College GATA2 deficiency was suspected. Lymphocyte subset quan-
of Veterinary Medicine, Ithaca, NY titation revealed B cell lymphopenia, mild CD4+ T cell lym-
phopenia, and normal NK cell count. Dendritic cell subsets
Our laboratory studies common variable immunodeficiency in were absent, consistent with dendritic cell, monocyte, B and
horses, which manifests with late-onset impaired B cell pro- NK lymphoid deficiency (DCML deficiency).
duction. Integrated analysis of transcriptome and quantitative GATA2 gene sequencing by NGS and Sanger methods re-
RT-PCR of RNA, and methylome and amplification of bisul- vealed a novel 354 bp deletion, c.1143+200_1198del
fite treated DNA of bone marrow of CVID-affected and con- ( N M _ 0 0 1 1 4 5 6 6 1 . 1 ) , c o n s i s t e n t w i t h G ATA 2
trol horses show that B cell differentiation is halted at the pre- haploinsufficiency. Bone marrow analysis showed no
pro B cell developmental transition. Higher methylation levels myelodysplasia and normal cytogenetics. A somatic ASXL1
of the enhancer region of the B cell gene PAX5 agrees with mutation was identified, which has been reported in associa-
lower gene expression in patients. Our hypothesis is that tion with GATA2 gene mutations.
240 J Clin Immunol (2016) 36:235–334

In summary, the phenotype of WILD syndrome (and DCML for DX-2930 than placebo. Dose-proportional increases in
deficiency) is consistent with GATA2 haploinsufficiency. DX-2930 concentration were observed; mean elimination
Immunological, genetic, and bone marrow analysis should half-life was ~2 weeks. 300 and 400 mg DX-2930 reduced
be performed in these patients. Hematopoietic stem cell trans- cleaved kininogen in HAE plasma to levels approaching that
plantation should be considered, especially in patients with the of subjects without HAE. From Day 8 to 50, in comparison to
ASXL1 mutation, which increases the potential for clonal my- placebo, the 300 mg group had a 100 % reduction
eloid transformation. (P < 0.00001) and the 400 mg group had an 88 % reduction
(P = 0.005) in attacks. DX-2930 was well tolerated at doses up
to 400 mg and a statistically significant finding of HAE attack
4289: DX-2930 IN PATIENTS WITH prevention was observed.
HEREDITARY ANGIOEDEMA—FINAL
RESULTS OF A PHASE 1b STUDY
4298: RUXOLITINIB AS A SALVAGE
1 2 3
Aleena Banerji , Paula Busse , Marc Riedl , William TREATMENT FOR A SEVERE REFRACTORY
Lumry4, Mark Davis-Lorton5, H. James Wedner6, Joshua INTERFERONOPATHY
Jacobs7, James Baker8, Jonathan A Bernstein9, Richard
Lockey10, Henry Li11, Timothy Craig12, Marco Cicardi13, Jean Jacques De Bruycker, MD1, Silvia Selleri, PhD1, Marie-
Ahmad Al-Ghazawi14, Carolyn Soo15, Ryan Iarrobino15, Elaine Métras, Pharm1, Guilhem Cros, MD2, Claire Saint-Cyr,
Dan Sexton15, Chris TenHoor15, Ryan Faucette15, Joseph MD2, Valérie Lamarre, MD1, Patricia Egerszegi, MD1, Julie
Biedenkapp15, Yung Chyung15 and Burt Adelman15 Barsalou, MD1, Aicha Merouani, MD1, Nathalie Alos, MD1,
Afshin Hatami, MD1, Marie-Paule Morin, MD1, Mélanie
1
Massachusetts General Hospital, Boston, MA, Vincent, MD1, Marie-Claude Miron, MD1, Vanessa Godin-
2
Mount Sinai Medical Center, Berthiaume, RN1, Marie-Claude Levasseur, RN1, Maude
3
University of California San Diego, Lemelin, RN1, Isabel Fernandez, PhD2, Françoise Le Deist,
4
AARA Research Center, MD PhD3, Pierre Lebon, MD4, Elie Haddad, MD PhD2,
5
Winthrop University Hospital, Raphaela Goldbach-Mansky, MD5 and Hélène Decaluwe,
6
Washington University School of Medicine, MD PhD1
7
Allergy and Asthma Clinical Research,
8 1
Baker Allergy, Asthma, and Dermatology, CHU Sainte-Justine, University of Montreal, Montreal, QC,
9
Division of Immunology, Allergy, & Rheumatology, College Canada,
2
of Medicine, University of Cincinnati, Cincinnati, OH, Department of Pediatrics, CHU Sainte-Justine, University of
10
University of South Florida, Montreal, Montreal, QC, Canada,
11 3
Institute for Allergy and Asthma, Department of Pediatrics, CHU Sainte-Justine, Montreal,
12
Penn State Hershey Medical Center, QC, Canada,
13 4
University of Milan, Hôpital Saint-Vincent de Paul-Cochin, Université Paris
14
Triumpharma, Descartes, Paris, France,
15 5
Dyax National Institute of Health, National Institute of Arthritis
and Musculoskeletal and Skin Diseases, Bethesda, MD
DX-2930 is an antibody inhibitor of plasma kallikrein (pKal)
in development for prevention of hereditary angioedema Type I interferonopathies are diseases characterized by an up-
(HAE) attacks. A phase 1b study was conducted to assess regulation of type I interferon (IFN) signaling. Here we report
the safety, tolerability, pharmacokinetics, pharmacodynamics the immunologic features and response to Ruxolitinib (an oral
(PD) and as an exploratory endpoint, efficacy of DX-2930 in Janus Kinase 1–2 inhibitor) in a 10-year old boy with an
subjects with HAE. In this double-blind study, 37 subjects extremely severe interferonopathy. This patient presented at
were randomized to receive 2 subcutaneous doses (14 days 3 months of age with purplish erythematous papules. Severe
apart) of 30, 100, 300 or 400 mg DX-2930 (n = 4, 4, 5, 11) or cutaneous lupus evolved over the years and consisted of de-
placebo (n = 13). PD effect was assessed using pKal activity bilitating vasculitic lesions leading to gangrenous necrosis,
assays. A primary efficacy assessment period of Day 8 to 50 and spontaneous amputations of extremities. He was refracto-
was prospectively selected based upon phase 1a PK modeling. ry to many immunosuppressive treatment regimens. Other
There were no discontinuations due to an AE, serious AEs, or features of his phenotype included persistently elevated acute
deaths in DX-2930-treated subjects. Most commonly reported phase reactants, severe failure to thrive, intracerebral calcifi-
treatment-emergent AEs (TEAEs) were HAE, injection site cations, extensive cutaneous calcinosis, osteolysis, multiple
pain, and headache. AE rates were not appreciably higher cutaneous and bone infections, recurrent fevers, hyperalgia,
J Clin Immunol (2016) 36:235–334 241

mild spasticity and alopecia. IFN alpha levels and interferon 4302: SIGNIFICANT IMMUNE
related gene expression were extremely elevated. Genetic test- ABNORMALITIES IN ASYMPTOMATIC LIG4
ing failed to confirm any known syndrome. Ruxolitinib was MUTATION CARRIERS
proposed as a salvage treatment. It was well tolerated and led
to dramatic clinical and biological response in a few months. Kerstin Felgentreff, MD1,2, Sachin N. Baxi, MD2, Yu Nee
Cutaneous improvements were remarkable with an almost Lee, PhD2, Kerry Dobbs, BS2, Lauren A. Henderson, MD2,
complete resolution of the vasculitic lesions. This case report Krisztian Csomos, PhD3, Erdyni N. Tsitsikov, PhD4, Mary Y.
describes a novel interferonopathy, and suggests a role for Armanios, MD5, Jolan E. Walter, MD PhD2,6 and Luigi D
JAK inhibitors in this group of diseases. Notarangelo, MD2,7

1
Department of Pediatrics and Adolescent Medicine,
4300: RITUXIMAB AS A SINGLE University Medical Center Ulm, University of Ulm, Ulm,
CHEMOTHERAPEUTIC AGENT FOR Germany,
2
TREATMENT OF GRANULOMATOUS Division of Immunology, Boston Children’s Hospital,
INTERSTITIAL LUNG DISEASE IN A YOUNG Harvard Medical School, Boston, MA,
3
WOMAN WITH COMMON VARIABLE Division of Pediatric Allergy/Immunology, Massachusetts
IMMUNODEFICIENCY General Hospital for Children, Boston, MA,
4
Department of Laboratory Medicine, Boston Children’s
Deena Pourang1, Thomas G Mahrer2, Shefali Samant1 and Hospital, Boston, MA,
Javed Sheikh1, 5
Departments of Oncology & Pathology, McKusick-Nathans
Institute of Genetic Medicine Johns Hopkins University
1
Allergy and Clinical Immunology, Kaiser Permanente Los School of Medicine, Baltimore, MD,
6
Angeles Medical Center, Los Angeles, CA Center for Immunology and Inflammatory Diseases,
2
Pulmonology, Kaiser Permanente Los Angeles Medical Massachusetts General Hospital, Harvard Medical School,
Center, Los Angeles, CA Boston, MA,
7
Harvard Stem Cell Institute, Harvard University, Cambridge,
Introduction: Granulomatous and lymphocytic interstitial MA
lung disease (GLILD) is a restrictive lung disease that
develops in a subset of patients with common variable Ligase 4 (LIG4) is a critical factor in the non-
immunodeficiency (CVID). There is no standardized homologous end-joining (NHEJ) DNA repair pathway
treatment for GLILD, though there have been reports that mandatory for V(D)J recombination. Genetic defects
combination chemotherapy with azathioprine and rituxi- in LIG4 cause a syndrome of short stature with mi-
mab results in improved symptoms, chest imaging and crocephaly, and variable degrees of pancytopenia,
pulmonary function testing. We report a case of successful combined immunodeficiency (CID) and developmental
treatment of GLILD with rituximab as a single agent in a delay.
patient with CVID. We identified biallelic LIG4 mutations in a 17y old girl
Case report: A 30 year-old woman presented with CVID with hypogammaglobulinemia, very low B cell counts
and biopsy-proven GLILD at the age of 20. Her CVID and microcephaly. Interestingly, two of her four siblings
was treated with subcutaneous immunoglobulin, and she carry the same mutations without a history of infections.
was started on infliximab therapy for the GLILD, but The 21 years old brother presented with normal IgG and
developed Mycobacterium terrae infection, treated with slightly decreased B cell numbers, whereas the 12 years
azithromycin, myambutol and rifampin. Infliximab thera- old sister had low IgG, almost absent B cells, and pan-
py was held, and patient’s respiratory symptoms wors- cytopenia. Radiosensitivity testing on T cells revealed
ened. There was concern that use of azathioprine may significantly decreased DNA repair capacity in the pa-
cause a worsening of mycobacterial infection, thus she tient and her sister, but a milder phenotype in the broth-
was started on rituximab alone for treatment of GLILD. er. By investigating T and B cell receptor repertoires
Her symptoms improved after 4 weeks of treatment and using next generation sequencing, we found significant
post-rituximab chest computed tomography showed skewing and shorter CDR3 lengths associated with de-
marked improvement. creased usage of N nucleotides in all siblings.
Conclusions: There are clinical situations in patients Importantly, V-D-J joins preferentially used by the pa-
with CVID and GLILD where T-cell sparing is desired, tients revealed an increased usage of microhomology-
and the use of rituximab could be considered as a single mediated end-joining, an alternative pathway to NHEJ
therapeutic agent. that does not require LIG4.
242 J Clin Immunol (2016) 36:235–334

LIG4-deficiency can be identified in asymptomatic individ- 4318: MANAGEMENT OF ADA-DEFICIENT

uals, who are at risk for manifestation of CID, bone marrow SCID PATIENT DURING PREGNANCY
failure or malignancies.
Marissa Shams, MD

4305: SPECIFIC ANTIBODY DEFICIENCY AND Department of Medicine, Emory University & The Emory
CHRONIC MUCOCUTANEOUS CANDIDIASIS Clinic, Atlanta, GA
IN STAT1 GAIN-OF-FUNCTION MUTATION
ADA-Deficient SCID (ADA-SCID) accounts for 15 % of
Jennifer Toh, MD1, Payal D Patel, MD2, Michelle Eisenfeld, SCID cases. Prior to the mid-1980s few children survived to
MD3, Rebecca Madan, MD4, Jenny Shliozberg, MD1, Arye puberty. As more therapies become available; patients are liv-
Rubinstein, MD, PhD5 and Steven M. Holland, MD6 ing longer. Few recommendations exist to direct the care of
pregnant patients with SCID. Knowledge detailing the man-
1
Division of Allergy and Immunology, Montefiore Medical agement of ADA-SCID patients during pregnancy is valuable
Center, Bronx, NY, to clinical immunologists.
2
Allergy Asthma Care, PC, A 27 years old female patient with ADA-SCID known to our
3
Asthma and Allergy Associates of Florida, academic practice was followed during 9 months of pregnan-
4
Division of Infectious Diseases, Albert Einstein College of cy. Prior to pregnancy; disease was well controlled with week-
Medicine, Bronx, NY, ly PEG-ADA injections. PEG-ADA was continued during
5
Pediatrics, Division of Allergy and Immunology, Albert pregnancy. Lymphocyte Enumeration, dAXP & Serum
Einstein College of Medicine and Montefiore Hospital, Immunoglobulins were assessed periodically.
Bronx, NY, As pregnancy progressed global lymphocyte decline oc-
6
Laboratory of Clinical Infectious Diseases, National Institute curred. Antibiotic prophylaxis was initiated at week 16.
of Allergy and Infectious Diseases, National Institutes of Pregnancy was complicated by the development of gestational
Health, Bethesda, MD hypertension. Anti-hypertensives were started.At week 33;
she was admitted to the hospital for Pre-Eclampsia after de-
Introduction: Signal transducer and activator of transcription tecting elevated liver enzymes and urinary protein. Baby was
1 (STAT1) gain-of-function (GOF) mutations cause impaired delivered on day 9 of admission. After delivery, baby was
dephosphorylation leading to decreased IL-17 producing T admitted to the NICU for 8 days for jaundice and temperature
cells and chronic mucocutaneous candidiasis (CMC). Other dysregulation.
infections such as bacterial pneumonias have also been seen. As treatment protocols for SCID improve, more immunolo-
We describe a boy with CMC and recurrent pneumonias who gists will manage patients during these critical 9 months. Few
was found to have a STAT1 GOF mutation. guidelines exist to detail the management of ADA-SCID pa-
Methods: Case description tients during pregnancy.
Results: A 12 year-old boy with CMC presented with recur-
rent Candida and Trichophyton tonsurans lesions of the left
eyelid and forehead that required surgical excisions and eyelid 4319: PRIMARY IMMUNODEFICIENCY
reconstruction. He also had recurrent S.aureus skin and soft EPIDEMIOLOGY IN CHILE EVALUATED
tissue infections. He was hospitalized 3 times for THROUGH ICD-10 CODED HOSPITAL
S. pneumoniae pneumonia with 1 episode complicated by ADMISSIONS
loculated, necrotizing pneumonia requiring chest tube drain-
age. Immune evaluation revealed normal lymphocyte subsets Cecilia Poli, M.D.1,2, Rodrigo Hoyos-Bachiloglu, M.D.3 and
with normal mitogenic responses, but absent antigenic re- Arturo Borzutzky, M.D.3,4
sponse to Candida. He had low IgG2 (66 mg/dl), IgG4
1
(<0.2 mg/dl), undetectable IgE (<1 mg/dl) with absent pneu- Department of Pediatrics, Faculty of Medicine, Universidad
mococcal titers after PCV13 and PPSV23 vaccinations. de Chile, Santiago, Chile,
2
Genetic analysis of CMC genes revealed a STAT1 GOF mu- Allergy, Immunology and Rheumatology Unit, Hospital Dr.
tation (c.1398C>A; p.S466R). He improved significantly on Roberto del Río, Santiago, Chile,
3
itraconazole prophylaxis and IVIG replacement for specific Department of Pediatric Infectious Diseases and
antibody deficiency. Immunology, Pontificia Universidad Católica de Chile,
Conclusion: STAT1 GOF have various presentations in addi- Santiago, Chile,
4
tion to CMC and can present as a CVID-like disease with Millennium Institute on Immunology and Immunotherapy,
extensive fungal and bacterial infections. Santiago, Chile
J Clin Immunol (2016) 36:235–334 243

Background: The epidemiology and admission trends of pri- (H3N2) infection. Laboratory criteria for hemaphagocytic
mary immunodeficiency (PID) in Chile are unknown. lymphohistiocytosis (HLH) were met. Peripheral blood
Methods: ICD10-coded PID admissions between 2001 and smears showed monocytes with microorganisms suspicious
2010 in Chile were reviewed using national hospital discharge for the dimorphic fungus Histoplasma capsulatum. Positive
databases. Results: During the study period, 5486 admissions blood cultures confirmed disseminated histoplasmosis. Bone
due to PID were registered. 58.5 % of patients were male and marrow biopsy showed yeast bodies and increased CD68+
66.3 % were <18 years. Median length of stay was 1 day histiocytes without hemophagocytosis, suggesting macro-
(range 1–403 days). Most frequent diagnoses were phage hyperactivation.
hypogammaglobulinemia (27.6 %), unspecified immunodefi- The child was treated with liposomal amphotericin followed
ciency (21.9 %), hemophagocytic lymphohystiocytosis by itraconazole. Immunosuppression included etoposide and
(18.3 %) and CVID (11.2 %). There was a significant increase corticosteroids. In opposition to past studies in HIV/AIDS
in PID admission rate and 1-day admissions during this period patients, improvement in antigen studies was very slow, with
(β = 0.2; P = 0.001 and β = 33; P ≤ 0.001, respectively), how- fungal antigenemia falling to below quantitation only after
ever no significant variation was found for >1 day admissions 4 months of therapy. His clinical course was complicated by
(β = 4.8 P = 0.18). The increasing trend in PID admission rate reactivation CMV disease and a recurrence of HLH.
was significant in patients with private, but not public insur- Hematopoietic stem cell transplantation was complicated by
ance (β = 0.53 P ≤ 0.001 vs. β = 0.08 P = 0.079, respectively). multi-organ system failure.
Conclusions: We report an increasing trend in PID admissions This case illustrates that disseminated histoplasmosis can
in Chile over a 10-year period. Increase is mainly due to short present in children immunosuppressed by maintenance che-
admissions, possibly accounting for improvements in IVIG motherapy for standard-risk leukemia. Histoplasmosis with an
access. Higher admission rates in patients with private insur- HLH / macrophage activation syndrome-like picture may
ance suggest socioeconomic disparities in access to treatment. progress more severely than cases seen in the literature.
The evaluation of ICD-10 coded admissions may prove a
useful tool to assess the epidemiology of PID in other coun-
tries worldwide. 4324: AN INFANT WITH FEVER, PYODERMA
GANGRENOSUM, OSTEITIS, SYNOVITIS AND
ORAL ULCERS: IMMUNOLOGY AND
4320: DISSEMINATED HISTOPLASMOSIS RHEUMATOLOGY COLLABORATION IN A
PRESENTING WITH A HEMOPHAGOCYTIC NOVEL AUTOINFLAMMATORY PHENOTYPE
LYMPHOHISTIOCYTOSIS / MACROPHAGE
ACTIVATION SYNDROME PHENOTYPE IN A Atoosa Kourosh, MD, MPH 1 , Anita Bharath, MD 2 ,
CHILD WITH PRE-B CELL ACUTE Nicholas Rider, DO3, Lisa Forbes, MD4 and Eyal Muscal,
LYMPHOBLASTIC LEUKEMIA MD, MS5

Karl O. A. Yu, M.D., Ph.D.1, Colleen B. Nash, M.D., 1

Department of Pediatrics, Section of Immunology, Allergy &
M.P.H.1, Michelle L. Nassin, M.D.2, Christine A. Carlos, Rheumatology, Baylor College of Medicine and Texas
M.D.3, Charles Van Slambrouck, M.D.4, Jason X. Cheng, Children’s Hospital, Houston, TX,
M.D., Ph.D.4, Jennifer McNeer, M.D., M.S.2 and Julia C. 2
Department of Pediatrics, Baylor College of Medicine and
Rosebush, D.O.1 Texas Childrens Hospital, Houston, TX,
3
Department of Pediatrics, Section of Immunology, Allergy &
1
Pediatrics (Infectious Diseases), Comer Children’s Hospital, Rheumatology, Baylor College of Medicine and Texas
University of Chicago, Chicago, IL, Children’s Hospital, Houston, TX,
2 4
Pediatrics (Hematology / Oncology / Stem Cell Department of Pediatrics, Section of Immunology, Allergy &
Transplantation), Comer Children’s Hospital, University of Immunology, Baylor College of Medicine and Texas
Chicago, Chicago, IL, Childrens Hospital, Houston, TX,
3 5
Pediatrics, Comer Children’s Hospital, University of Department of Pediatrics, Section of Immunology, Allergy
Chicago, Chicago, IL, and Rheumatology, Baylor College of Medicine and Texas
4
Pathology (Hematopathology), University of Chicago, Children’s Hospital, Houston, TX
Chicago, IL
A previously healthy 4 month old girl presented with ul-
Case Report: A 9 year old boy with standard risk pre B cell cerating rash, bloody diarrhea, aphthous-like oral ulcers,
acute lymphoblastic leukemia presented with cytopenias, fe- dehydration, and fever which progressed to severe anemia
ver and progressive transaminase elevation after influenza A and hypovolemic shock. CT showed multiple well-
244 J Clin Immunol (2016) 36:235–334

circumscribed splenic lesions and colitis. Skin biopsy con- Conclusions: PID are prevalent in Kuwait and show a pe-
firmed pyoderma gangrenosum and colonoscopy showed culiar pattern compared to patients from other geographic
lymphonodular hyperplasia with adenovirus infection. areas
Immunological evaluations revealed T cell and NK cell
lymphopenia, abnormal DHR, and elevation in sIL-2 and
IL-6. With supportive care and broad spectrum antibiotics, 4334: TARGETED GENE EDITING RESTORES
her immune abnormalities normalized and she was REGULATED CD40L EXPRESSION AND
discharged. She re-presented with fever and left ankle ar- FUNCTION IN X-HIGM T CELLS.
thritis. Multi-focal osteitis and tenosynovitis were noted on
MRI. Whole Exome Sequencing revealed a single NOD2 Nicholas W. Hubbard1, David Hagin, MD PhD2, Karen M.
variant in the proband and her healthy father. Due to an Sommer, PhD, Yumei Song, PhD1, Courtnee Clough, Iram F
autoinflammatory phenotype suggestive of IL-1 pathway Khan, PhD, David J. Rawlings, MD 4 , Andrew M.
dysregulation, but inconsistent with reported NOD2 phe- Scharenberg, MD5 and Troy R. Torgerson, MD PhD6,7
notypes, we initiated IL-1 blockade (anakinra) with good
1
clinical response. This case illustrates the complicated evo- Center for Immunity and Immunotherapies and the Program
lution of autoinflammatory disease and the importance of a for Cell and Gene Therapy, Seattle Children’s Research
multi-disciplinary approach. Institute, Seattle, WA,
2
Allergy and Immunology, University of Washington / Seattle
Children’s Hospital, Seattle, WA,
3
4325: REPORT FROM THE KUWAIT NATIONAL Seattle Children’s Research Institute, Seattle, WA,
4
PRIMARY IMMUNODEFICIENCY DISORDERS Center for Immunity and Immunotherapies and the Program
REGISTRY (2004–2015) for Cell and Gene Therapy, Seattle Children’s Research
Institute and University of Washington Medical Center,
Waleed Al-Herz, MD Seattle, WA,
5
Department of Pediatrics, University of Washington, Seattle,
Pediatric Department, Faculty of Medicine, Kuwait WA,
6
University, Kuwait, Kuwait Center for Immunity and Immunotherapies, Seattle
Children’s Research Institute, Seattle, WA
Aim: To present an updated report from Kuwait National
Primary Immunodeficiency Registry (KNPIDR) for the peri- Loss of CD40L expression or function results in X-Linked
od of 2004–2015 Hyper-IgM Syndrome (X-HIGM), characterized by recurrent
Method: All patients registered in KNPIDR during the study infections due to impaired immunoglobulin class-switching
period are presented and were classified according to the 2015 and somatic hypermutation. Previous attempts using retroviral
IUIS classification gene transfer to correct murine CD40L expression restored
Results: A total of 264 patients (142 males and 122 fe- immune function; however, treated mice developed lympho-
males) were registered during the study period. The distri- proliferative disease, likely due to viral-promoter dependent
bution of these patients showed the following: immunode- constitutive CD40L expression, highlighting the importance
ficiencies affecting cellular and humoral immunity (30 %), of preserving endogenous gene regulation. Here we report
combined immunodeficiencies with associated or efficient, on-target, homology directed repair editing of the
syndromic features (22 %), predominantly antibody defi- CD40LG locus in primary human T cells using a combination
ciencies (21 %), diseases of immune dysregulation (15 %), of a TALEN-induced double-strand break and a donor tem-
congenital defects of phagocyte number, function or both plate delivered by recombinant Adeno-Associated Virus.
(7 %), defects in intrinsic and innate immunity (0.3 %), HDR mediated insertion of a transgene within Exon 1 allowed
autoinflammatory disorders (0.7 %) and complement defi- expression to be regulated by endogenous CD40LG promoter/
ciencies (4 %). The average annual incidence rate for the enhancer elements. Expression of the transgene paralleled that
study period of (S)CID in children was 13.01/100,000, of endogenous CD40L in unedited T cells, both at rest and in
with an estimated occurrence of 1/7500 live births. response to stimulation. The use of this method to edit X-
Parental consanguinity and family history of PID were re- HIGM patient T cells restored normal expression of CD40L
ported in 77 % and 49 % of the patients, respectively. and CD40-muIg binding, and rescued IgG class switching of
Molecular diagnosis was reached in 53 % of the patients naïve B-cells in vitro. These results demonstrate the feasibility
and there were 4 novel PID-causing genes identified. IVIG of engineered nuclease-directed gene repair to restore endog-
was used in 52 % of the patients and there were 69 deaths enously regulated CD40L, and the potential for its use in T cell
(26 %) during the study period therapy for X-HIGM syndrome.
J Clin Immunol (2016) 36:235–334 245

4335: IMPROVEMENT IN TREATMENT immunodeficiency(PID) with impaired specific Ab responses

SATISFACTION AMONG PRIMARY (n = 31) and patients with a possible PID (n = 22), some that
IMMUNODEFICIENCY PATIENTS ON AN were on Ab replacement therapy. Results: 100 % of healthy
INVESTIGATIONAL 20 % SUBCUTANEOUS controls and 16/22 patients with a possible PID developed
IMMUNOGLOBULIN THERAPY specific Abs following immunization, while only 2/31 pa-
tients with a known PID generated an Ab response to S. typhi
Lisa Meckley, PhD1, Diane Ito, MA1, Xingdi Hu, PhD1 and immunization with ViPS. Commercially available Ig prepara-
Leman Yel, MD2 tions were tested and did not contain detectable S. typhi Abs.
8/10 patients with suspected PID receiving Ig replacement
1
HEOR, Baxalta US Inc, Cambridge, MA, therapy did develop S. typhi titers. Conclusion:
2
Clinical Science, Immunology, Baxalta US Inc, Cambridge, Measurement of specific Abs following administration of the
MA polysaccharide ViPS vaccine is useful in distinguishing PID
patients from controls and suspected PID patients on Ig
Subcutaneous immunoglobulin therapy (IGSC) offers an op- replacement.
portunity for patients with primary immunodeficiencies (PI) to
self-infuse at home, potentially reducing treatment burden and
improving satisfaction. This study assessed overall patient ex- 4337: PATIENT AND PHYSICIAN BELIEFS
perience and treatment satisfaction (TS) with an investigation- REGARDING IMMUNOGLOBULIN THERAPY
al 20 % subcutaneous IG therapy (IGSC20%). TS was ROUTE OF ADMINISTRATION
assessed within a phase 2/3 prospective study
(NCT01218438) of subjects with PI (n = 68) who were treated M. Chris Runken, PharmD1, Dan Wasserman2 and Deborah
with intravenous IG (IGIV) for 3 months followed by the Gelinas, MD1
investigational IGSC20% for a 12 month period. TS was
1
assessed at the end of each treatment period using the Grifols, Research Triangle Park, NC,
2
Treatment Satisfaction with Medication (TSQM-9) and Life KJT Group, Inc., Honeoye Falls, NY
Quality Index (LQI) instruments. Subjects reported significant
improvement on LQI Treatment Interference (p Objectives: This study assessed preferences for Intravenous
(IV) and Subcutaneous (SC) administration of
Immunoglobulin (IG) among patients with Primary
4336: THE USE OF SALMONELLA TYPHI Immunodeficiency (PIDD) and physicians who manage
VACCINE TO DIAGNOSE ANTIBODY PIDD patients.
DEFICIENCY Methods: This was an IRB approved online survey of 100
Allergists/Immunologists and 152 patients. Preference for
Mary T. Bausch-Jurken, PhD1, Katherine A. Gonzaga, MD, route of administration (RoA) was determined using a 100
Nancy Elms, D1, Mary Hintermeyer, RN/CPNP, Stephen point visual analog scale.
Gauld, PhD, James W Verbsky, MD/PhD3 and John M Results: Among patients RoA preference is fairly evenly
Routes, MD4 split (47 % prefer SCIG; 42 % prefer IVIG) whereas 57 %
of physicians believe patients prefer SCIG and only 30 %
1
Pediatrics, Medical College of Wisconsin, Milwaukee, WI, IVIG. Patients strongly preferred their current RoA. For
2
Department of Pediatrics, Division of Rheumatology, patients who had a preference it was strong (76 %). Top
Medical College of Wisconsin, Milwaukee, WI, reasons for patient IVIg preference include decreased infu-
3
Department of Allergy and Clinical Immunology, Medical sion frequency and for SCIG decreased side effects. 71 %
College of Wisconsin, Milwaukee, WI of physicians recommend a specific RoA to patients.
Among patients preferring SCIG, 86 % expressed their
Background: The measurement of specific antibody (Ab) re- HCP recommended it; only 67 % of patients preferring
sponses following immunization with the pneumococcal IVIG felt their HCP recommended it. Physician and patient
(Pncc) vaccine in diagnosing Ab deficiency has limitations, perception about the decision maker differs with 84 % of
including prior exposure to the Pncc vaccine, controversy in physicians reporting decisions were joint decisions vs.
interpreting Pncc titer results, and the presence of Pncc Abs in 47 % of patients.
replacement Ig therapy. Methods: Pre and post vaccination Conclusions: Patients exhibit stronger route of administration
titers following immunization with the killed S. typhi vaccine preferences than recognized by physicians. Preferences are
(ViPS) were measured by ELISA, in healthy controls (n = 21), split between SCIG and IVIG. Underlying patient preferences
patients previously diagnosed with a known primary should be explored.
246 J Clin Immunol (2016) 36:235–334

1
4338: FLOW CYTOMETRY-BASED Clinical Genetics Unit, Hospital das Clinicas da
RADIOSENSITIVITY ASSAY: APPLICATION IN Universidade de São Paulo, Sao Paulo, Brazil,
2
PATIENT WITH HETEROZYGOUS ATM Translational Research Laboratory, Instituto de Medicina
MUTATION AND CLINICAL ATAXIA Integral Prof. Fernando Figueira, Recife, Brazil,
3
TELANGIECTASIA PHENOTYPE Clinical Immunology, IMIP - Instituto de Medicina Integral
Prof. Fernando Figueira, Recife, Brazil,
Jay J. Jin, MD, PhD1, Matthew J. Smith, BS2, Susan A. 4
Department of Pediatrics, Universidade de São Paulo, São
Lagerstedt, BS2, Margot A. Cousin, PhD3, Nicole J. Boczek, Paulo, Brazil
PhD3, Eric W. Klee, PhD3, Avni Y. Joshi, MD, MSc1 and
Roshini S. Abraham, PhD2 INTRODUCTION: Chronic granulomatous disease (CGD)
is a primary immunodeficiency characterized by recurrent
1
Division of Allergic Diseases, Mayo Clinic, Rochester, MN, life-threatening infections as well as autoinflammatory and au-
2
Department of Laboratory Medicine and Pathology, Mayo toimmune diseases. METHODS: To report the evaluation of
Clinic, Rochester, MN, the cellular immune response of a CGD patient who developed
3
Center for Individualized Medicine, Mayo Clinic, Rochester, autoimmune hypothyroidism. RESULTS: The patient showed
MN normal levels of total T cells (1873 cells/mm3, 50th–90th per-
centile), TCD8+ (416 cells/mm3, 10th–50th percentile), TCD4+
A female infant with T cell lymphopenia on NBS-SCID, on (1166 cells/mm3, 50th–90th percentile). Low absolute levels of
follow-up also showed B cell lymphopenia with NK lympho- NK cells (86 cells/mm3, 10th percentile). Normal levels of total
cytosis. The proportion of CD45RA+4+ T cells was normal at B lymphocytes (465 cells/mm3, 10th–50th percentile). Low
67 % but thymic function was impaired though not absent levels of memory B cells (8.58 %) compared to a healthy con-
(TREC and CD4RTE). T cell function (PHA, anti-CD3) was trol (44.39 %). High relative values of total NKT cells (7.61 %)
normal. Spectratyping revealed normal T cell repertoire diver- and iNKT cells (0.7 %) compared to a healthy control (2.58 and
sity. Genetic testing for 18 SCID-related genes was negative. 0.2 %, respectively). CONCLUSION: Although infections
She had candidal dermatitis managed with fluconazole. T cell and granuloma formation are indubitably the most common
lymphopenia was progressive with multiple URI at 7 months manifestations in CGD patients, there is a significant subset
and elevated AFP (77 ng/mL; <6.0 ng/mL). Currently at of CGD patients who experience a broad variety of autoim-
15 months, she has symptoms of ataxia without telangiectasia. mune diseases. We presented for the first time in the literature
Targeted NGS followed by WES of infant and parents revealed the role of NKT cells on development of autoimmune disorders
a heterozygous ATM variant (c.3245_3247delinsTGAT) in in CGD patients and that, therefore, will contribute to a better
exon 22 in patient and father. Father is clinically and im- understanding of the mechanisms involved in the cellular im-
munologically asymptomatic. A second pathogenic variant mune response of autoimmune diseases.
was not observed in ATM. A flow-based radiosensitivity
assay was used to evaluate ATM and H2AX phosphoryla-
tion in T and B cells. Autophosphorylation of ATM 4341: INCREASED INCIDENCE OF FATIGUE IN
(S1981) was observed in parents but not in infant. PRIMARY IMMUNODEFICIENCY DISORDERS,
Phosphorylation of H2AX was normal. The clinical and PREVALENCE AND ASSOCIATIONS WITHIN
immunological phenotype in the patient suggests loss of THE USIDNET REGISTRY.
function of the second allele. RNA-seq and Methyl-seq
are being employed to determine if an intronic variant is Joud Hajjar, MD1,2, Danielle Guffey, MS3, Charles Minard,
causing exon skipping or if epigenetic silencing through PhD3 and Jordan S. Orange, MD, PhD1
DNA methylation is causing loss of expression.
1
Section of Immunology, Allergy and Rheum, Baylor College
of Medicine, Houston, TX,
2
4340: HIGH LEVELS OF NKT CELLS IN Texas Children’s Hospital, Houston, TX,
3
CHRONIC GRANULOMATOUS DISEASE Dan L. Duncan Institute for Clinical and Translational
ASSOCIATED WITH HASHIMOTOXS Research, Baylor College of Medicine, Houston, TX
THYROIDITIS: A CASE REPORT
Introduction: Primary Immunodeficiency (PI) patients often
Diogo C Soares, MD1, Francisco S Albuquerque Filho2, Ana report fatigue, yet it has not been studied in PI. Fatigue affects
Carla Augusto Moura Falcão, MD3, Jailson B Correia, MD, 6–7.5 % of healthy adults. The goal of this study was to esti-
PhD 2 , Leuridan C Torres, PhD 2 and Magda Carneiro- mate the prevalence of fatigue in PI and investigate its asso-
Sampaio, MD, PhD4 ciated factors.
J Clin Immunol (2016) 36:235–334 247

Methods: β1- and β2-adrenoceptor subtypes. Activators of PKA, but

We performed a query of 2537 PI patients registered in not Epac system, enhanced VEGF release, and this effect
USIDNET to determine responses to the field Bfatigue^ in was abolished by KT 5720 and Rp-cAMPS—both selective
the core registry. Demographics, immune phenotype and co- PKA inhibitors. These results show that β1- and β2-, but not
morbid conditions were compared between fatigued and non- β3-adrenoceptors, mediate cAMP-dependent enhancement of
fatigued patients to identify relevant associations. T-test, Chi- VEGF release in LPS-primed differentiated human U937
square, Fisher’s exact and Wilcoxon rank sum tests were used macrophages, and that PKA, not Epac, was the downstream
to compare the 2 groups. effector of cAMP activity.
Results: This study was funded by Kuwait University grant # YM
Fatigue prevalence was 16.9 % (95 % CI: 15.5–18.5). 79 % of 14/09.
fatigued patients had Primary Antibody Deficiency (PAD).
Fatigue was reported in 24.3 % (95 % CI: 22.1–26.7) of PAD
4347: CLINICAL CHARACTERIZATION OF
patients, compared to 7.8 % (95 % CI: 6.3–9.55) of non-PAD.
CHILDREN WITH RECURRENT INFECTIONS
Prevalence of fatigue was the highest in CVID (p < 0.001).
AT HOSPITAL UNIVERSITARIO HERNANDO
Fatigued patients were more likely to be females, not on IVIG,
MONCALEANO PERDOMO FROM 2014 TO 2015
had higher BMI, higher rate of autoimmunity, hepatomegaly
IN NEIVA, COLOMBIA
and granulomas, and lower Absolute Lymphocyte, CD3, CD4,
and CD8 counts compared to non-fatigued (p < 0.005-<0.001).
Jairo Antonio Rodríguez Rodríguez, MD, PhD and José
Conclusion:
Santiago Cortés Guzmán
Our findings suggest that fatigue is over-represented in PI
patients. Prospective studies to estimate prevalence, risk fac-
Faculty of Health Sciences, Universidad Surcolombiana,
tors and fatigue etiology in PI are warranted, so therapeutic
Neiva, Colombia
interventions can be conceived.
Recurrent infections are an important awareness of pediatri-
cians to detect primary immunodeficiencies (PID). The Jeffrey
4343: CHARACTERIZATION OF
Modell Foundation has promoted 10 warning signs to detect
BETA-ADRENOCEPTOR-MEDIATED
PID, among them, recurrent pneumonia, otitis, sinus infec-
ENHANCEMENT OF VASCULAR
tions, fungal infections are included. There is lack of epidemi-
ENDOTHELIAL GROWTH FACTOR RELEASE
ological data on PID in our region, and despite relevance of
IN ACTIVATED HUMAN MACROPHAGES
this condition timely diagnosis is deficient, that is the reason
why we pretend to analyze the frequency of PID in children
Charles I. Ezeamuzie, PhD
who attended to the Hospital Universitario Hernando
Moncaleano Perdomo in Neiva, Colombia from January
Sara N. El-Zohairy, MSc and Mabayoje A. Oriowo, PhD,
2014 to December 2015. Our main goal is to characterize
Dept of Pharmacology & Toxicology, Faculty of Medicine,
clinically and immunologically pediatric patients affected by
Kuwait University, Kuwait City, Kuwait
recurrent infections. From near 214 children who consulted
during the chosen period, 36 fulfilled criteria for PID. As
This study characterized the signaling pathway involved in the
expected humoral deficiency was the main defect found,
enhancement of vascular endothelial growth factor (VEGF)
followed by combined cellular and humoral defects and final-
release by β-adrenoceptor agonists in human macrophages.
ly some cellular defects. We hope this report will improve
Human U937 cells differentiated into macrophages were
timely diagnosis of this group of patients in our region.
primed with LPS in the absence or presence of β-
adrenoceptor agonists and antagonists. The VEGF released
and the intracellular cAMP generated were assayed by 4348: HYPER IgM SYNDROME: A REPORT
ELISA. Isoprenaline, procaterol and salbutamol FROM THE USIDNET REGISTRY
concentration-dependently enhanced the release of VEGF in-
duced by LPS in U937 macrophagess. They also increased Emily A. Leven1, Hans D. Ochs, MD2, Paul R. Scholl3,
intracellular cAMP levels in these cells. BRL 37344, a selec- Rebecca H. Buckley, MD4, Ramsay L. Fuleihan, MD5, Raif
tive β3-adrenoceptor agonist, did not enhance VEGF release. S. Geha, MD6, Coleen K. Cunningham7, Francisco Bonilla,
Propranolol, ICI 118551 and atenolol all produced a parallel MD PhD8, Mary Ellen Conley9, Ronald M. Ferdman10, Vivian
rightward shift of the isoprenaline dose–response curve. The – Hernandez-Trujillo, MD11, Jennifer M. Puck, MD12, Kathleen
logKB values were 8.12 ± 0.17, 8.03 ± 0.05 and 7.23 ± 0.05, Sullivan, MD, PhD13, Patrick Maffucci, BA14, Manish
respective, respectively, indicating clear involvement of both Ramesh15 and Charlotte Cunningham-Rundles, MD, PhD14
248 J Clin Immunol (2016) 36:235–334

1
Icahn School of Medicine at Mount Sinai, New York, NY, Conclusions: Analysis of the USIDNET Registry provides
2
Department of Pediatrics, University of Washington School data on common clinical features of this rare syndrome,
of Medicine, Seattle, WA, and in contrast with previously published data, demon-
3
Boehringer Ingelheim Pharmaceuticals, strates longer survival times and reduced incidence of
4
Division of Allergy and Immunology, Duke University respiratory tract complications and gastrointestinal
School of Medicine, Durham, NC, diseases.
5
Division of Allergy and Immunology and Jeffrey Modell
Diagnostic Center for Primary Immunodeficiencies,
Department of Pediatrics and Department of Pathology, 4359: OCULAR INFLAMMATIONS IN PATIENTS
Children’s Memorial Hospital, Northwestern University WITH INFLAMMATORY BOWEL DISEASE IN
Feinberg School of Medicine, Chicago, IL, KOREA: A PROSPECTIVE SINGLE CENTER
6
Immunology Division, Department of Pediatrics, Boston CROSS SECTIONAL STUDY
Children’s Hospital, Harvard Medical School, Boston, MA,
7
Department of Pediatrics, Duke University Medical Center, Hye Jin Lee, MD
Durham, NC,
8
Childrens Hospital Boston, Boston, MA, Department of Ophthalmology, Jeju National University
9
St. Giles Laboratory of Human Genetics of Infectious School of Medicine, Jeju-si, Korea, The Republic of
Diseases, Rockefeller Branch, The Rockefeller University,
New York City, NY, Inflammatory bowel disease (IBD) including Crohn¡¯s
10
Division of Clinical Immunology and Allergy, Department disease (CD) and ulcerative colitis (UC) has been report-
of Pediatrics, Children’s Hospital Los Angeles, University of ed to be associated with various ocular inflammations.
Southern California, However, there is little report about ophthalmologic com-
11
Allergy/ Immunology, Miami Children’s Hospital, plications in IBD patients of Korea. The aim of this study
Miami, FL, is to evaluate the prevalence of ocular inflammation with
12
Pediatrics, University of California San Francisco, San IBD. A total of 61 patients were examined between
Francisco, CA, May 2013 and October 2014. Full ophthalmologic exam-
13
Children’s Hospital of Philadelphia, Philadelphia, PA, inations were performed. The number of CD patients was
14
Division of Clinical Immunology, Department of 36 (59.0 %) and UC 25 (41.0 %). Mean age of the pa-
Medicine, Icahn School of Medicine at Mount Sinai, tients was 34¡¾16 years (range 13–77 years) and disease
New York, NY, duration was 45.3¡¾23.9 months (range 2–264 months).
15
Montefiore Medical Center, New York City, NY CD patients exhibited; rates of remission (63.9 %), mild
(27.8 %), moderate (8.3 %), and severe activity (0 %).
Purpose: The United States Immune Deficiency Network UC patients showed; remission (52.0 %), mild (16.0 %),
(USIDNET) patient registry was used to characterize clinical moderate (28.0 %), and severe activity (4.0 %). The most
presentation, genetic mutations, immunologic phenotypes and common inflammation was blepharitis in 15 (CD 7, UC
treatment practices in a large number of patients with Hyper 8) patients. Iritis was diagnosed 3 (CD 2, UC 1),
IgM Syndrome (HIGM). episcleritis in 1 (CD), iritis with optic disc swelling in 1
Methods: The USIDNET Registry was queried for all HIGM (CD) and serous retinal detachment in 1 patient (UC).
patient data collected from Oct. 1992 to July 2015. The most common ocular inflammation is blepharitis in
Results: 52 physicians entered data for 145 HIGM patients IBD patients. Significant vision harming ocular inflam-
(131 male); 2072 patient years were analyzed. Median age at mations such as uveitis and serous retinal detachment
entry was 12 years (2 months–62 years). Causal mutations occurred in 5.6 % of CD and 4.0 % of UC patients.
were recorded in 72 subjects; 68 were in CD40L. 5 % had Inflammatory eye diseases are much common so evalua-
autosomal recessive HIGM. 58 subjects (40 %) had normal tion of the eyes should be a routine component in IBD
serum IgM and 22 (15 %) had normal IgA. 91 % of patients patients.
reported infection. Pulmonary, ear, and sinus infections were
most common. Pneumocystis jiroveci was reported in 42 %
and Cryptosporidium in 6 %. 41 % had neutropenia. 78 % 4361: GASTROINTESTINAL PRESENTATIONS
experienced non-infectious complications: chronic diarrhea IN PATIENTS WITH CVID
(n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8). 16
patients underwent transplantation (13 hematopoietic marrow/ Edith Schussler, MD1, Ramsay L Fuleihan, MD2, Kathleen
stem cell, 3 solid organ). 13 were known to have died (median Sullivan, MD, PhD3 and Charlotte Cunningham-Rundles,
age = 14 years). MD, PhD4
J Clin Immunol (2016) 36:235–334 249

1
Division of Allergy & Immunology, Icahn School of PIK3R1 splice site mutations result in hyperactive PI3K sig-
Medicine at Mount Sinai, New York, NY, naling associated with recurrent sinopulmonary and viral in-
2
Division of Allergy & Immunology and Jeffrey Modell fections, lymphoproliferation, hypogammaglobulinemia and
Diagnostic Center for Primary Immunodeficiencies, Ann & increased lymphoma risk. 4/8 reported patients with PIK3R1
Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, mutations presented a Hyper IgM syndrome (HIGM) pheno-
3
Children’s Hospital of Philadelphia, Philadelphia, PA, type. We present a not previously described pediatric patient
4
Division of Clinical Immunology, Department of Medicine, with PIK3R1 mutation.
Icahn School of Medicine at Mount Sinai, New York, NY A 2-year-old Spanish girl, born to non-consanguineous
healthy parents, presented with a suppurative cervical lymph-
Rational: Gastrointestinal symptoms are common in CVID adenopathy due to S. pneumonia requiring intravenous antibi-
patients and often severe. We report clinical characteristics otics and repetitive surgical drainage. Immunology work-up
of CVID patients registered in USIDNET. showed low IgG (7 mg/dl) and IgA (2 mg/dl) and raised IgM
Methods: The USIDNET Registry was queried for informa- (769 mg/dl), reduced class-switched memory B cells and ele-
tion about CVID related GI disease. vated transitional B cells. Autosomal recessive HIGM was
Results: 413/889 (46 %)CVID patients in the USIDNET reg- suspected and IVIG substitution initiated with poor clinical
istry have had a GI condition 55 % were female and 45 %, response. PIK3R1 mutation (G>A chr5:67589663) was de-
male. Mean age at diagnosis of CVID was 26.3 years. tected and sirolimus therapy (2 mg/m2/24 h/vo) led to a de-
Immunoglobulins were (mg/dl): IgG mean 735, median 1134, crease of lymphadenopathies but onset of recurrent aphthous
range 7–2640, IgA mean 53.4, median 27, range 0–716, IgM stomatitis and was stopped.
mean 66.1, median 37, range 0–1210. These conditions includ- PI3K mutations should be included in the differential diagno-
ed GE reflux (176), diarrhea (228), abdominal pain (114), IBD sis of HIGM. Whilst an increased infection risk has been de-
(34), constipation (55), colitis/enteritis (38), liver function ab- scribed, this is the first case of a S. pneumonia adenitis.
normality (27), malabsorption (24), hepatomegaly(22), celiac Selective p110δ inhibitors, such as GS-1101, may provide a
disease (11), eosinophilic esophagitis (18), cirrhosis (10), auto- more specific and less harmful approach for children with this
immune hepatitis (3), appendicitis (10), aphthous ulcers (7), kind of mutations compared to sirolimus, a mTOR inhibitor.
protein losing enteropathy (3), intestinal nodular lymphoid hy-
perplasia (5), fistula (5), obstruction (4), gall bladder disease
(5), gall stones (3), eosinophilic enteritis (3), perianal ulceration 4364: THE WIDE PHENOTYPICAL SPECTRUM
(2), steatosis (1). 25 patients had received TPN. 67 also had OF GAIN OF FUNCTION (GOF) MUTATIONS IN
another autoimmune condition. There were 15 lymphomas, 4 THE p110ä CATALYTIC SUBUNIT OF THE
leukemias and 11 other cancers reported in these subjects. PHOSPHATIDYLINOSITOL-3-OH (PIK3CD):
Conclusion: Common and rarer inflammatory GI manifesta- ONE CENTER’S EXPERIENCE
tions occur in CVID and targeted interventions may be needed.
Joel Louis Gallagher, MD1, James W Verbsky, MD/PhD2,
Heather Hartman, MD1, Mary K Hintermeyer, APNP3, Julie
4363: STREPTOCOCCUS PNEUMONIA Niemela, PhD 4 , Jennifer L Stoddard, BS 5 , Sergio D.
ADENITIS AND HYPER IgM SYNDROME IN A Rosenzweig, MD, PhD5 and John M Routes, MD1
1
CHILD WITH PIK3R1 MUTATION Department of Allergy and Clinical Immunology, Medical
College of Wisconsin, Milwaukee, WI,
Peter Olbrich, MD1,2, Berta Sanchez3, Jose Manuel Lucena 2
Department of Pediatrics, Division of Rheumatology,
Soto 3 , Paula Sanchez Moreno 1 , Marta Melon 1 , Marta Medical College of Wisconsin, Milwaukee, WI,
Benavides Nieto1, Concepcion Alvarez del Vayo Benito4, 3
Allergy and Clinical Immunology, Children’s Hospital of
Paola Cura Daball 5 , Anne Rensing-Ehl 5 , Carsten Wisconsin, Milwaukee, WI,
Speckmann, MD5, Stephan Ehl, MD5 and Olaf Neth1 4
Department of Laboratory Medicine, NIH, Bethesda, MD,
5
Immunology Service, Department of Laboratory Medicine,
1
Pediatric Infectious Diseases and Immunodeficiency, National Institutes of Health, Bethesda, MD
Hospital Universitario Virgen del Rocio, Seville, Spain,
2
Pediatric Infectious Diseases and Immunopathology, Seville, Background: GOF mutations in PIK3CD cause increased
Spain, susceptibility to sinopulmonary infections, lymphoprolif-
3
Immunology, Hospital Universitario Virgen del Rocio, eration, and malignancies. These mutations result in in-
4
Pharmacy, Hospital Universitario Virgen del Rocio, creased phosphorylation of AKT, leading to enhanced
5
Center of Chronic Immunodeficiency, University Freiburg mTOR activity, and T cell lymphopenia with memory T
Medical Center, Freiburg, Germany cell skewing. Immunoglobulins show an elevated IgM
250 J Clin Immunol (2016) 36:235–334

with a variable IgG. Management focuses on IgG re- families with rare syndromic and non-syndromic
placement. Methods: A chart review was performed on immunodeficiency.
eight patients with confirmed PIK3CD (c.3061G>A,
p.E1021K). Results: All patients had recurrent
sinopulmonary infections. Vaccine responses were non- 4369: SUCCESSFUL HAPLO-IDENTICAL STEM
protective, especially against polysaccharide antigens. CELL TRANSPLANTATION FOR
IgG and IgA levels were highly variable (70–1550 mg/ REFRACTORY EPSTEIN-BARR
dL and VIRUS-INDUCED HLH IN A BOY WITH XLP
DUE TO A DELETION IN EXON 1 OF SH2D1A

4365: CLINCIAL UTILITY OF WHOLE EXOME Barbara Bosch, MD1, Benoît Florkin, MD2, Gwendoline
SEQUENCING IN CLINICAL DIAGNOSES OF Lepiece, MD2, Leen Moens, PhD3, Heidi Schaballie, MD1,
SYNDROMIC AND NON-SYNDROMIC Marleen Renard, MD, PhD4, Anniek Corveleyn5 and Isabelle
IMMUNODEFICIENCY DISORDERS IN Meyts, MD, PhD1
PEDIATRIC PATIENTS
1
Childhood Immunology, University Hospitals Leuven,
1 2 3
Alexander Valencia, PHD , Xinjian Wang, PHD , Chao Wei , Leuven, Belgium,
Abhinav Mathur4, James Denton4, Subba Indugula5, Ammar 2
CHR de la CITADELLE, Liège, Belgium,
Husami6, Jenice Brown4 and Kejian Zhang, MD1 3
Microbiology and Immunology, KU Leuven, Leuven,
Belgium,
1 4
Human Genetics, Cincinnati Children’s Hospital, Cincinnati, Division of Pediatric Oncology and Hematology, University
OH, Hospitals Leuven, Leuven, Belgium,
2 5
Huaman Genetics, Cincinnati, OH, Laboratory for Molecular Diagnosis, Center for Human
3
Cincinnati Children’s Hospital, Cincinnati, OH, Genetics, Universy Hospital Leuven, Leuven, Belgium
4
Cincinnati, OH,
5
Human Genetics, Cincinnati, OH, Familial hemophagocytic lymphohistiocytosis (fHLH) is a
6
Division of Human Genetics, Cincinnati Children’s Hospital rare, life-threatening syndrome of uncontrolled inflammation;
Medical Center hematopoietic stem cell transplantation (HSCT) is its sole
cure.
The Next-generation sequencing, a high-throughput se- A boy presented at 16 months with fulminant HLH, se-
quencing technologies, have facilitated the discoveries of vere central involvement including bilateral retinal necro-
many novel genetic causes in recent years. As part of the sis and leukomalacia and respiratory failure requiring me-
clinical validation and testing, we tested 48 patients in 44 chanical ventilation. Peripheral blood EBV PCR was
unrelated families with unknown immunodeficiency disor- log9.
ders by clinical whole exome sequencing. Most of these Stabilization was obtained with the HLH 2004 protocol,
patients have been through extensive clinical work up and rituximab and alemtuzumab, a regimen continued until
resulted in no definitely clinical diagnoses. We developed a HSCT. In the absence of a matched unrelated / cord blood
bioinformatics analysis suite that includes commercially donor, haplo-identical alpha-beta T cell depleted (αβ T−)
available software and in-house developed computational HSCT with the mother as a donor was performed. Post
tools. Clinical relevant variants were confirmed by Sanger HSCT, donor chimerism was complete but persistent lym-
sequencing. In addition, a series of quality measurements phopenia failed to protect the boy from relapse HLH and
were implemented to meet the CLIA and CAP requirement central activation. He was treated with VP16, dexameth-
for clinical testing. asone plus intrathecal rituximab, methotrexate and hydro-
From this study, we established clinical genetic diagnoses in cortisone. A CD34+ selected boost was given at day
19 (40 %) patients, of which 7 (37 %) have autosomal reces- +174. This resulted in EBV clearance at day +248, in-
sive disorders and 11 (58 %) are autosomal dominantly crease in lymphocytes and slow yet up till now incom-
inherited and 4 (8 %) follow X-linked inheritance pattern. plete neurological improvement.
More than half of the mutations have not been previously We found decreased SAP expression and NK cell degran-
described in peer reviewed literatures and more than 30 % of ulation suggestive of a mutation in SH2D1A, causative of
the mutations are de novo (not found in parents). X-linked lymphoproliferative syndrome, a PID with ful-
In conclusion, with a robust analyses pipeline and afford- minant mononucleosis, EBV-driven HLH, lymphoma and
able sequencing cost, direct exome sequencing provides a dysgammaglobulinemia. The mother is carrier of the
clinically useful tool for clinical genetic diagnoses in deletion.
J Clin Immunol (2016) 36:235–334 251

1
4370: A COMPLEX CASE OF HYPER IgM Research Center for Immunodeficiencies, Pediatrics Center
IMMUNODEFICIENCY AND LATE of Excellence, Children’s Medical Center, Tehran University
PRESENTATION OF ATAXIA of Medical Sciences, Tehran, Iran, Tehran, Iran (Islamic
TELANGIECTASIA WITHOUT NEUROLOGIC Republic of),
2
SIGNS Research Center for Immunodeficiencies, Pediatrics Center
of Excellence, Children’s Medical Center, Tehran University
Ashmi Doshi, MD1, Sergio D. Rosenzweig, MD, PhD2 and of Medical Sciences, Tehran, Iran, Tehran, Iran (Islamic
Stephanie Leonard, MD1 Republic of),
3
Pediatrics Clinic and Institute for Molecular Medicine A.
1
Division of Allergy, Immunology, and Rheumatology, Nocivelli, Department of Clinical and Experimental
University of California, San Diego; Rady Childrens’ Sciences, University of Brescia, Spedali Civili, Brescia,
Hospital, San Diego, CA, Italy, Brescia, Italy,
2 4
Immunology Service, Department of Laboratory Medicine, Department of Molecular and Traslational Medicine,
National Institutes of Health, Bethesda, MD A.Nocivelli Institute of Molecular Medicine, Dept. of
Pathology, University of Brescia,
5
Introduction: In Ataxia-Telangiectasia (AT), ATM gene Department of Pediatrics, 17th Shahrivar Children’s
mutations result in defective DNA repair. We present a Hospital, Guilan University of Medical Sciences, Rasht,
complex case of Hyper-IgM syndrome (HIGM) later diag- Iran, Rasht, Iran (Islamic Republic of),
6
nosed with AT. Department of Immunology and Hematology, Zahedan
Case Report: A 3 years old female with a history of failure Medical, Sciences University, Zahedan, Iran., Zahedan, Iran
to thrive, recurrent sino-pulmonary infections and bronchi- (Islamic Republic of),
7
ectasis was found to have IgM 1966, IgG 26, and IgA Pediatric Respiratory Diseases Research Center, National
40 mg/dL. Work-up revealed non-protective specific anti- Research Institute of Tuberculosis and Lung Diseases,
body titers, absent isohemagluttinins, and decreased mito- Shahid Beheshti University of Medical Sciences, Tehran,
gen and antigen proliferation. Clinical course included Iran., Tehran, Iran (Islamic Republic of)
nonspecific hepatitis, splenomegaly, lymphadenopathy,
and thrombocytopenia. HIGM genetic work-up was nega- Gentoype-Phenotype Correlatoin in Iranian Congenital
tive, however at age 6 she was found to have a homozy- Agammaglobulinemia Cohort
gous ATM gene mutation (c.2250 G>A) with elevated al- Abstract:
pha-fetaprotein. Parents and brother were heterozygous Objectives: Early B-cell development impairment results
carriers. Detailed exam revealed oculocutaneous telangiec- from severe decreased in numbers and function of B-cells.
tasias and café au lait lesions, and an in depth neurological Mutations in the gene encoding for Bruton’s-tyrosine-kinase
evaluation found subtle gait ataxia. Her status has declined (BTK) and the components of the pre-B-cell receptor complex
with persistent hypoxia and additional findings of erythe- or downstream signaling molecules have been related to this
ma nodosum, bone marrow cells with 9p21 deletion, and defect in patients with agammaglobulinemia.
benign paraspinal tumors. Methods: Iranian patients with congenital agammaglobu-
Discussion: This AT patient with a complex constellation of linemia were included and the correlation between
symptoms presented initially with immunodeficiency not neu- disease-causing mutations and parameters such as clinical
rologic signs as is unusual. and immunologic phenotypes were evaluated in available
Conclusion: AT is a progressive disease with radiosensitivity patients.
and a risk for malignancy. It is imperative to include AT in the Results: Out of 87 patients, a molecular investigation was
differential of HIGM. performed on 51 patients leading to identification of 39 cases
with BTK (1 novel mutation), 5 cases of μ-heavy chain (3
novel mutations) and 1 case of Igα-deficiencies.
4372: GENTOYPE-PHENOTYPE Conclusion: Although there is no comprehensive correla-
CORRELATOIN IN IRANIAN CONGENITAL tion between type of responsible BTKmutation and severity
AGAMMAGLOBULINEMIA COHORT of clinical phenotype, our data suggest that BTK-deficient
and autosomal recessive agammaglobulinemia patients dif-
Asghar Aghamohammadi, MD, PhD1, Hassan fer significantly regard ing clinical/imm unologic
Abolhassani2, Massimiliano Vitali3, Vassilios Lougaris3, characteristics.
Silvia Giliani4, Nima Parvaneh2, Leyla Parvaneh2, Taher Keywords: Bruton’s tyrosine kinase, X-linked agammaglob-
Cheraghi5, Hosseinali Khazaei6, Fatemeh Kiaei2, Seyed ulinemia, Autosomal recessive agammaglobulinemia,
Alireza Mahdaviani7 and Alessandro Plebani3 Genotype-phenotype correlation, Long-term cohort
252 J Clin Immunol (2016) 36:235–334

1
4373: IPEX… ARE ALL FEMALE CARRIERS Research Center for Immunodeficiencies, Pediatrics Center
HEALTHY? of Excellence, Children’s Medical Center, Tehran University
of Medical Sciences, Tehran, Iran, Tehran, Iran (Islamic
Barbara Bosch, MD 1, Steven Dockx, MD2 , Stuart G. Republic of),
Tangye3, Isabelle Meyts, MD, PhD1 and Leen Moens, PhD4 2
Research Center for Immunodeficiencies, Pediatrics Center
of Excellence, Children’s Medical Center, Tehran University
1
Childhood Immunology, University Hospitals Leuven, of Medical Sciences, Tehran, Iran, Tehran, Iran (Islamic
Leuven, Belgium, Republic of)
2
AZ Sint Dimpna, Geel, Belgium,
3
Immunology Division, Garvan Institute of Medical Objectives: The most common primary antibody deficiency
Research, Darlinghurst, Australia, is Selective immunoglobulin A deficiency (SIgAD). A great
4
Microbiology and Immunology, KU Leuven, Leuven, risk of coexistent autoimmune disorders has been reported in
Belgium patients with SIgAD as compared to healthy individuals. We
aimed to investigate specific clinical or immunological find-
CD4(+)CD25(+)CD127(-)FoxP3(+) regulatory T (Treg) cells ings linked with potential associations of autoimmunity and
are key to the maintenance of self-tolerance and to the preven- SIgAD.
tion of autoimmunity. Genetic deficiency of FoxP3 causes Methods: Comprehensive clinical and laboratory examina-
immuno-dysregulation, polyendocrinopathy, enteropathy, X- tions were performed in 57 symptomatic SIgAD patients reg-
linked (IPEX) syndrome. istered in Iranian national database to find the history or
It has been hypothesized that the lack of symptoms in female sign/symptoms of autoimmunity.
IPEX carriers can be explained by the presence of normally Results: Approximately 30 % of studied SIgAD patients suf-
functional Tregs (Tommasini CEI 2002). fer from autoimmune disorders (9 males and 8 females).
We previously diagnosed 2 boys with IPEX syndrome Autoimmune thyroiditis and hemolytic anemia (3 cases each)
due to c.1190 G>A in exon 11 leading to p.R397Q. The were the most frequent manifestations. Family history of au-
mother is carrier of the mutation; at the age of 33 she toimmunity was positive in 10 patients. Long follow-up
presented with rectal bleeding and passage of mucus. (p = 0.003), high serum level of IgM (p = 0.01), low regulatory
Biopsy showed fulminant ulcerohaemorrhagic T-cell count (p = 0.03), and reduced class-switched memory
rectocolitis with crypt abscesses and rectal aphts. She B-cell count (p = 0.01) were associated with autoimmune pre-
was diagnosed with auto-immune colitis, a common sentation in SIgAD patients. Progression of SIgAD to more
finding in IPEX. profound humoral antibody deficiency were reported in most-
RT-PCR showed no skewed X-inactivation of the muta- ly 25 % of cases with autoimmunity (p = 0.006).
tion in leukocytes. Immune phenotyping however re- Conclusion: Autoimmune cytopenia should be considered as
vealed reduced Treg counts. She also had considerably a characteristic factor for prediction of severe clinical mani-
decreased FoxP3 mean fluorescence intensity (1580 ver- festations in patients with SIgAD.
sus 2219.2 ± 361.3 in controls) and a significantly reduced
relative Treg frequency (Tregs 0.63 % of CD3(+)cells
versus 2.00 ± 0.55 in controls). The low percentage of 4376: CHARACTERIZATION AND
Tregs with reduced FoxP3 expression may account for SUCCESSFUL TREATMENT OF A NOVEL
the phenotype. AUTOSOMAL DOMINANT IMMUNE
In conclusion: we found reduced Treg numbers with re- DYSREGULATORY SYNDROME CAUSED BY A
duced FoxP3 expression in a IPEX carrier with JAK1 GAIN-OF-FUNCTION MUTATION
rectocolitis. This may be the first report on a symptomatic
IPEX carrier. Stuart E. Turvey, Kate L. Del Bel, Robert J. Ragotte, Aabida
Saferali and Margaret L. McKinnon

4374: CLINICAL AND IMMUNOLOGIC BC Children’s Hospital and Child & Family Research
PROFILES OF SELECTIVE IgA DEFICIENCY Institute, Vancouver, BC, Canada
ASSOCIATED WITH AUTOIMMUNE
MANIFESTATIONS Introduction: Janus Kinase 1 (JAK1) plays an essential,
non-redundant role in the JAK/STAT signaling cascade, a
Mohammad Hossein Asgardoon1, Behdad Gharib1, Hassan key pathway in the control of hematopoiesis and immune
Abolhassani1, Nima Rezaei1 and Asghar Aghamohammadi, function. Significant progress has been made in elucidat-
MD, PhD2 ing the role of JAK1, but gaps in our knowledge still
J Clin Immunol (2016) 36:235–334 253

persist. Loss-of-function mutations in Jak1 are perinatal Acute GVHD occurred in 10 patients (precipitated by inter-
lethal in mice, while somatic gain-of-function mutations ventions for mixed chimerism in 7). Seven patients died 1–
have been linked to T-cell acute lymphoblastic leukemia. 12 months after transplant with infections (n = 5) or hemor-
Results: We describe the first known patients with a rhage (n = 2).
germ-line gain-of-function mutation in JAK1. The clinical T cell recovery was achieved in 80 % of patients at last
phenotype includes severe atopic dermatitis, markedly el- follow up (1–6 years). The median CD4+ and CD8+ T cell
evated blood eosinophil counts with eosinophilic infiltra- counts were 1619 (range 260–2265) and 750 (239–2203)
tion of the liver and gastrointestinal tract, cells/μL. B cell recovery was achieved in 46 % of patients
hepatosplenomegaly, autoimmunity, and failure to thrive. with a median CD19+ B cell count of 284 (136–2335)
Functional analysis established the gain-of-function phe- cells/uL.
notype caused by the mutation and in vitro studies dem- Conclusion:
onstrated that the enhanced signaling could be controlled Alem, Flu, Mel RIC HSCT results in favorable immune re-
by ruxolitinib, an approved JAK1/2 inhibitor. Informed by covery in many patients and provides a curative approach for
these experimental data, the patients were treated with SCID patients.
ruxolitinib with remarkable improvement in a variety of
clinical end-points, including hematological profiles and
growth parameters. Conclusions: Our characterization of 4379: MONOGENIC PRIMARY IMMUNE
a human JAK1 gain-of-function mutation defines a novel DEFICIENCIES IDENDIFIED IN A
human immune dysregulatory condition which can be ef- PEDIATRIC-ONSET CVID COHORT, IS THERE
fectively controlled with ruxolitinib. A PREDICTIVE MARKER?

Elif Karakoc-Aydiner, Ayca Kiykim, MD2, Ercan Nain, MD,

4378: IMMUNE RECONSTITUTION IN SCID Melissa Kacmaz, Ismail Ogulur, Safa Baris, MD3, Ahmet
PATIENTS AFTER ALEMTUZUMAB, Ozen, MD, Isil Barlan, MD and Mustafa Bakir, MD4
FLUDARABINE, AND MELPHALAN REDUCED
1
INTENSITY CONDITIONING ALLOGENETIC Immunology, Marmara University,
2
HSCT. Immunology, Marmara University, Istanbul, Turkey,
3
Pediatric Allergy&Immunology, Marmara University School
Manar M Abdalgani, M.B.B.S1 and Rebecca Marsh, MD2, of Medicine, Istanbul, Turkey

1
Immunology/BMT, Cincinnati Children’s Hospital Medical Background: CVID is a heterogeneous predominantly anti-
Center, Buffalo, NY, body deficiency. Recently, various novel genetic variations
2
Division of Bone Marrow Transplantation and Immune were reported in CVID cohorts. We report 2 of each CD19,
Deficiency, Cincinnati Children’s Hospital Medical Center, LRBA, PI3K, ICF, and 1 BTK deficiencies identified in a
Cincinnati, OH pediatric and adult CVID cohort. Materials and Methods:
Fourty-six patients (13F,33M) were enrolled with a median
Introduction: age of 19 years (min:4, max:59 years) and parental consan-
There is limited information regarding immune reconstitution guinity of 46 %. Clinical and laboratory data were retrospec-
in SCID patients treated with alemtuzumab, fludarabine, and tively collected from medical records. Results: CVID patients
melphalan (Alem, Flu, Mel) reduced intensity conditioning (Group I) and monogenic PIDs identified in CVID cohort
(RIC) allogeneic HSCT. Here we describe immune reconsti- (Group II) were similar for gender, height, weight, current
tution in 29 SCID patients. age, follow-up duration, consanguinity, family history and
Methods: PID warning signs. Group II had significantly younger age
We conducted a retrospective study of all SCID patients at onset (median: 8.5 months) and diagnosis (median:
transplanted with Alem, Flu, Mel at our center. T cell recovery 60 months) (p = 0.05 and p = 0.024; respectively). Group II
was defined as a CD3+ count and mitogen stimulated prolif- showed lower levels of IgE (median: 1 KU/L, p = 0.008), B
eration >80 % of the normal ranges. B cell recovery was cell counts (median: 28/mm3, p = 0.007), percentage (median:
defined as IVIG independence and protective vaccine titers 1 %, p = 0.003) and unclass-switched B cell counts (median:
and/or CD19 count >70 % of the normal range. 4/mm3, p = 0.014). Additionally, lymphoproliferation, auto-
Results: immunity, diarrhea were found to be similar among 2 groups.
29 SCID patients were transplanted between 2005 and 2013. Moreover, baseline FVC (median: 60 %, p = 0.024) was lower
Donors were matched at 8/8 (n = 17), 7/8 (n = 8) or 6/8 (n = 4) in Group II. Conclusion: Early-onset at infancy, remarkably
HLA alleles. Mixed chimerism developed in 14 patients. low B cells and IgE, and severely affected PFTs at
254 J Clin Immunol (2016) 36:235–334

1
presentation were found to be associated with a monogenic Immunology, Marmara University,
2
PID among our CVID cohort. Pediatric Allergy&Immunology, Necmettin Erbakan
University Meram School of Medicine, Konya,
Turkey,
4380: HIGHER LEVELS OF COMPLEMENT C3 3
Pediatric Infectious Diseases, Istanbul University
AND C4 WERE OBSERVED IN PATIENTS WITH
School of Medicine, Istanbul, Turkey,
IRFR AND ES AFTER HAPLOIDENTICAL 4
Immunology, Marmara University, Istanbul, Turkey,
ALLOGENEIC STEM CELL 5
Pediatric Allergy&Immunology, Marmara University
TRANSPLANTATION
School of Medicine, Istanbul, Turkey
Yao Chen, Feng-rong Wang, Jing-zhi Wang, Xiao-jun Huang
Background: Serum IgE levels and blood eosinophil
and Lan-ping Xu
counts are both elevated in atopic diseases and primary
immune deficiencies (PID). Current study aimed to find a
Peking University People’s Hospital, Peking University
cut-off value to discriminate these two disease groups.
Institute of Hematology, Peking University Institute of
Materials and Methods: Patients (n = 259, median age
Hematology, Beijing, China
7 years (min:0-max:17 years)) with asthma and rhinitis
(n = 101), asthma (n = 67), IgE mediated cowÕs milk al-
Purpose: Differentiation between infectious and nonin-
lergy (n = 44), atopic dermatitis (n = 31), rhinitis (n = 16),
fectious fever remains a diagnostic challenge in patients
HIES (n = 40), CGD (n = 16) were enrolled. Age, IgE
with profound neutropenia during the first 3 weeks after
levels, eosinophil counts and sensitizations were recorded.
the infusion of haploidentical stem cell. Noninfectious
Sensitivity, specificity, negative (NPV) and positive pre-
febrile reactions during these periods include infusion-
dictive values (PPV) and ROC analyses were performed.
related febrile reaction and engraftment syndrome. Thus,
Results: PID patients had significantly higher IgE (medi-
this observational and single-center study was conducted
an: 2542 vs 265 KU/L) and eosinophil levels (median:
to evaluate the potential diagnostic role of CRP, com-
1000 vs 400 /mm3) compared to atopic patients
plement C3 and C4 in noninfectious febrile reactions
(p2500KU/L and eosinophil >1500/mm3 should be eval-
(group I), infectious group (group II) and Control group
uated as HIES unless proven otherwise.
(group III).
Methods: Enrolled 96 patients included 45 noninfectious fe-
brile reactions, 15 infectious fever, and 36 no fever patients.
4384: TREATMENT OPTIONS IN A PATIENT
Results: Both of C3 and C4 levels were significantly
WITH DELAYED DIAGNOSIS OF XLT
higher (p < 0.001) in group I as compared with group III
(median of C3: 1.32 vs. 1.18 g/L; median of C4: 0.27 vs.
Mirinda Gillespie, ScM, MD 1, Jenni Yoon, MD 2 and
0.24 g/L). CRP from group II, was significantly highest
Jennifer W. Leiding, MD3
with median value of 86.9 (range: 27–190) mg/L. AUC-
ROC in the diagnosis of group I versus other two groups 1
Office of Medical Education, All Children’s Hospital Johns
were 0.70 for C3 (p = 0.001) and 0.636 for C4 (p = 0.023).
Hopkins Medicine, St. Petersburg, FL,
C3 and C4 level above 1.275 and 0.264 g/L had a sensi- 2
Division of Allergy and Immunology, University of South
tivity of 60.0 and 52.3 % and specificity of 72.2 and
Florida, St. Petersburg, FL,
63.9 % to predict noninfectious febrile reactions, 3
University of South Florida, Tampa, FL
respectively.
Conclusions: C3 and C4 can rapidly differentiate noninfec-
INTRODUCTION
tious febrile reactions from infectious etiology.
X-linked thrombocytopenia (XLT) is a mild form of Wiskott-
Aldrich syndrome (WAS). Conservatively managed patients
4381: DO CUT-OFF VALUES OF IgE AND have normal life expectancy but often experience severe com-
EOSINOPHIL LEVELS HELP DISCRIMINATE plications. Therapeutic options are limited and convey signif-
HYPERIGE SYNDROME FROM ATOPIC icant risk. Herein, we describe the complexities surrounding
DISEASES? treatment for XLT.
CASE
Elif Karakoc-Aydiner, Ayca Kiykim, MD2, Ezgi G Yuce, Ezgi The patient is a 19 y/o male with immune thrombocyto-
Baris, Ercan Nain, MD, Sevgi Keles3, Hacer Akturk4, Ahmet penic purpura (ITP) who required splenectomy at age
Ozen, MD, Safa Baris, MD5, Mustafa Bakir, MD6 and Isil 3 years after failing medical management. He had no
Barlan, MD major infections. At age 18 years, after 2 maternal male
J Clin Immunol (2016) 36:235–334 255

cousins developed ITP, a mutation affecting WAS protein Objective: To evaluate the clinical efficacy of rapidly gener-
(T116C) was diagnosed. Antibiotic prophylaxis was re- ated VSTs for treatment of CMV, EBV, and adenovirus in
started and IVIG initiated. Since, he has developed a patients with PID before or after HSCT.
classic malar rash and positive direct Coombs and Methods: VSTs were cultured from HSCT or third-party
ANA. HSCT evaluation has identified matched unrelated donors via a rapid protocol, and were tested for specificity
donors. Discussions are ongoing concerning the best and non-alloreactivity via IFNg γ ELISpot and 51Cr cyto-
therapy. toxicity assay. Patients were followed for 45 days follow-
CONCLUSIONS ing infusion for toxicities and for up to 21 months for
XLT treatment includes conservative management, cura- antiviral response.
tive HSCT or gene therapy. Antibiotic prophylaxis may Results: Nine patients with PID have been infused with
offer limited protection. HSCT is effective, has a high VST at doses ranging from 5 to 20 × 10E6/m2. Two pa-
survival rate, and may appeal to those experiencing com- tients received VST infusion prior to HSCT. Antiviral
plications. However, HSCT risks include GvHD, infec- responses were seen against CMV in 4 of 5 patients,
tion, and in XLT, splenectomy is a major risk factor for EBV in 2 of 3, and adenovirus in 1 of 2. Median time
death from sepsis. Donor availability can present an addi- to >50 % drop in viral PCR was 28 days. Antiviral T-
tional challenge, and so gene therapy may be an option. cell activity against targeted viruses was detectable by
This case highlights the intricacy of treatment selection in IFNγ ELIspot in 5 of 9 patients after infusion. Two
XLT. patients developed grade I–II GVHD, but no VST-
related > grade III toxicities occurred within the
45 day toxicity monitoring.
4385: ADOPTIVE T CELL IMMUNOTHERAPY Conclusions: VST appear to be effective and safe for control
FOR TREATMENT OF VIRAL INFECTIONS IN of viral infections in PID patients.
PRIMARY IMMUNODEFICIENCY

Michael D. Keller, MD1, Patrick J Hanley, PhD2, Sarah 4386: DIAGNOSIS OF CVID: RESULTS FROM
McCormack, BA2, Haili Lang, MS2, Cecilia Barese, MD A JOINT CID & ESID MEMBERSHIP SURVEY
PhD2, Allistair Abraham, MD2, David Jacobsohn, MD3,
Evelio Perez-Albuerne, MD3, Kirsten M Williams, MD2, Javeed Akhter, MD1, Cheryl Lefaiver, PhD, RN2, Klaus
Roberta H Adams, MD 4 , Orly R Klein, MD 5 , Amy Warnatz3 and Christopher Scalchunes, MPA4
Keating, MD6, Nancy J Bunin, MD 7 and Catherine M
Bollard, MD2 1
Pediatrics, Advocate Hope Children’s Hospital, Oak
Lawn, IL,
1 2
Division of Allergy / Immunology, Children’s National Advocate Center Pediatric Research, Advocate
Health System, Washington, DC, Children’s Hospital, Oak Lawn, IL,
2 3
Center for Cancer and Immunology Research, Children’s Centre for Chronic Immunodeficiency, Freiburg,
National Medical Center, Washington, DC, Germany,
3 4
Blood and Marrow Transplantation, Children’s National Immune Deficiency Foundation, Towson, MD
Medical Center, Washington, DC,
4
Hematology/Oncology, Phoenix Children’s Hospital, The criteria used to diagnose common variable immune
Phoenix, AZ, deficiency (CVID) continue to evolve. In a recent
5
Pediatric Blood and Bone Marrow Transplant Program, Immune Deficiency Foundation survey, we evaluated the
Division of Hematology/Oncology, Johns Hopkins practice of allergists/immunologists in regard to CVID
Hospital, Baltimore, MD, diagnosis. Responses were compared between ESID and
6
Children’s Hospital Colorado, Aurora, CO, CIS members. There were a total of 227 responses (ESID
7
University of Pennsylvania and Children’s Hospital of response rate = 17 %; CIS response rate = 14 %). All had
Philadelphia, Philadelphia, PA treated a patient with CVID or hypogammaglobulinemia
and 97 % were currently treating patients with one of
Background: Adoptive immunotherapy using virus-specific these disorders. Respondents most commonly ordered
T-lymphocytes (VSTs) has been successful in restoring anti- quantitative serum IGs but there was variation in the
viral immunity after hematopoietic stem cell transplantation use of IgG subclass and vaccine antibody titers. There
(HSCT), including in patients with primary immunodeficien- were significant differences in tests used by CIS versus
cy (PID). Current protocols permit production of VSTs in 10– ESID members. Respondents were not consistently using
12 days. widely recognized diagnostic criteria. Increased and
256 J Clin Immunol (2016) 36:235–334

broader distribution of diagnostic guidelines for CVID are demonstrates that Chronic Granulomatous Disease (CGD)
needed. can be confused with Still’s disease and that screening for
CGD should be considered in these patients.
Tests: Diagnosis of CVID
CIS Member ESID Member 4390: IMMUNE RESPONSE TO VACCINATION
n = 83 (%) n = 144 (%)
IN VERY EARLY ONSET INFLAMMATORY
Quant IGs (G A&M) 83 (100) 143 (99)
BOWEL DISEASE
IgG Subclass* 21 (25) 82 (57)
Anti-Tetnus Titer* 77 (93) 107 (74) Huyen-Tran Nguyen, M.D.1 and Patricia C Fulkerson, MD,
Anti-Strep Pneumoniae Titer* 82 (99) 99 (69) PhD2
Anti-Haemophilus Influenza Titer* 48 (58) 43 (30)
Isohemagglutin Titer* 22 (27) 77 (54) 1
Allergy & Immunology, Cincinnati Children’s Medical
Hospital Center, Cincinnati, OH,
* p value < 0.01 2
Allergy & Immunology, Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH

Very early onset inflammatory bowel disease (VEOIBD) can

4388: AN UNUSUAL PRESENTATION OF
be associated with abnormal innate immunity, which can be
CHRONIC GRANULOMATOUS DISEASE
further compounded by the use of immunosuppressive medi-
cations for treatment. Despite recommendations that IBD pa-
Jutte E. van der Werff ten Bosch, MD, PhD1, Machiel van
tients, even those on immunosuppressive medications, receive
den Akker, MD 2 , Annieta Goossens, MD 3 and Xavier
inactivated vaccines, this patient population often remains un-
Bossuyt, MD, PhD4
der-vaccinated. Uncertainty about the immunogenicity is one
1 of the most common reasons for poor vaccination rates in IBD
Pediatrics, UZ Brussel, Brussels, Belgium,
2 patients. Studies have shown that adults with IBD, particularly
Pediatrics, Universitair ziekenhuis Brussel, Brussels,
those on immunosuppressive therapies, have decreased re-
Belgium,
3 sponse to pneumococcal and influenza vaccines, yet protec-
Department of Pathology, Universitair Ziekenhuis Brussel,
tive serum levels are still observed. Pediatric studies on the
Brussels, Belgium,
4 vaccine response in VEOIBD patients are limited. We present
Microbiology and Immunology, KU Leuven, Leuven,
a case of VEOIBD and his immune response to vaccination
Belgium
following onset of therapies. Our patient is a now 19-month-
old, who was diagnosed with VEOIBD after presenting with
A 2 years old boy presented with oligoarticular arthritis and a
chronic, frequent stooling, up to 20 times per day.
low grade fever. Inflammatory parameters were high. A work
Immunology and genetic work-up has been non-diagnostic
up showed discrete hepatosplenomegaly and intra abdominal
thus far. His current therapies include infliximab and low-
lymphadenopathies. No infectious agent could be identified.
dose systemic corticosteroids. Prior to initiation of immuno-
Blood work showed markedly elevated granulocytes, espe-
suppressive therapies, he completed only his 4-month immu-
cially eosinophils. A lymphnode biopsy showed small granu-
nizations. Further studies of vaccine response in VEOIBD are
loma’s and a remarkable eosinophilic infiltrate. A cytokine
needed to develop an immunization plan to minimize the risk
profile showed an elevation of IL18, suggesting Still’s disease
of vaccine-preventable disease.
and this diagnosis was withheld. Treatment with corticoste-
roids was initiated, leading to a prompt improvement. The
child relapsed twice, and was treated with anti IL-6 4392: EFFECT OF BMI AND BASELINE IgG
(Tocilizumab) with a good response. Throughout the LEVELS ON IMMUNOGLOBULIN THERAPY
18 months episode described above, the child had 1 pneumo- DOSING IN PRIMARY IMMUNE DEFICIENCY
nia and a few ear infections. Besides, he had an episode of PATIENTS TREATED IN THE HOME: DATA
CMV infection. When the patient presented with high fever FROM THE IDEAL PATIENT REGISTRY
and multiple abscesses in the liver, CGD was suspected. The
rhodamine staining was abnormal and genetic analysis re- Sean Kearns, Ph.D1, Loretta Kristofek, RN1, Bill Bolgar,
vealed a mutation in the CYBB gene (101 G>A). This case PharmD1 and Luqman Seidu, M.D.2
demonstrates that CGD can be the underlying pathology in
1
children with Still’s disease and that pediatricians should be IDEaL Patient Registry, Coram Clinical Trials, Denver, CO,
2
aware of this and screen for this disorder. This case Omni Allergy Immunology and Asthma, Atlanta, GA
J Clin Immunol (2016) 36:235–334 257

BACKGROUND chart review was undertaken at Mayo Clinic, Rochester,

There are a variety of factors that influence immunoglobulin MN.
(Ig) dosing for patients with primary immune deficiencies RESULTS: 26 cases were included in this study that had
(PID). Data from the IDEaL Patient Registry, which collects radiologic evidence of GLILD. 17/26 (65 %) of the cases
long term data on patient’s receiving Ig in the home, was had co-existent splenomegaly with lower IgA levels
analyzed. We looked at the distribution of BMI’s, as well as (P = 0.04) and monocyte counts (P = 0.04) as compared to
baseline serum IgG levels to see if that affected dosing. GLILD subjects without splenomegaly. Subjects with low
METHODS IgA (<13 mg/dL) also had expansion of CD21dim B cells
Patients of Coram CVS Specialty Infusion whose physicians (P = 0.007). Age at diagnosis was a significant predictor of
were participating in the registry were consented using an IRB lower FEV1/FVC ratio seen in cases (p = 0.04), but not in
approved informed consent. Data was collected from nursing controls. As compared with the controls, cases with GLILD
and pharmacy standard of care forms. showed expansion of CD21dim B cells (P = 0.017) and were
RESULTS nearly 3.5 times more likely to have complete IgA deficiency
The average BMI of the population examined was 29.5 (P = 0.02).
(N = 310, range 17–67). For patients on SCIg we noted a sig- CONCLUSION: These data suggest that serum IgA and ex-
nificant difference between the doses in mg/kg/week received pansion of CD21 dim B cells may be useful to identify a group
between those with a normal BMI, those who were over- of patients at high risk for development of GLILD.
weight (P = 0.0056), and those that were obese (P = 0.0061). FUTURE DIRECTION: We propose to create a prediction
For IVIg we did not find any significant difference in the model for CVID subjects using the above parameters to help
doses between the normal BMI group and those that were segregate CVID patients that may warrant additional investi-
overweight or obese. We found a significant difference in gations for GLILD.
patient dosing depending on initial IgG levels, in patients re-
ceiving SCIg (P = 0.01) but not in IVIg patients. (P > 0.08).
CONCLUSIONS 4399: ALTERED PHOSPHORYLATION
We found significant differences between doses in SCIg pa- KINETICS, CELLULAR LOCATION AND
tients depending on their BMI as well as their initial IgG TRANSCRIPTIONAL ACTIVITY OF A STAT3
levels. We did not see any significant difference in the IVIg GOF MUTATION IN THE DNA BINDING
populations in terms of dosing based on BMI or initial IgG DOMAIN
levels.
Tiphanie P. Vogel, MD, PhD1, Nermina Saucier, MS2 and
Megan A. Cooper, MD, PhD3
4396: IgA DEFICIENCY PREDICTS THE
1
ASSOCIATION OF SPLENOMEGALY AND Pediatrics, Division of Rheumatology, and Internal
GRANULOMATOUS LYMPHOCYTIC Medicine, Division of Rheumatology, Washington
INTERSTITIAL LUNG DISEASE (GLILD) IN University in St. Louis, Saint Louis, MO,
2
CVID SUBJECTS Pediatrics, Division of Rheumatology, Washington
University in St. Louis, Saint Louis, MO,
Stella Hartono1, Megan S Motosue, MD2, Shakila Khan, 3
Pediatrics, Division of Rheumatology, and Pathology and
MD1, Vilmarie Rodriguez, MD3, Thomas G. Boyce, MD, Immunology, Washington University in St. Louis, St. Louis,
MPH3 and Avni Y. Joshi, MD, MSc4 MO

1
Rochester, MN, Germline, gain-of-function (GOF) mutations in STAT3
2
Allergic Disease, Mayo Clinic, Rochester, MN, cause multi-organ autoimmunity. Mechanisms by which
3
Pediatrics, Mayo Clinic, Rochester, MN, GOF mutations impact downstream roles of STAT3 have
4
Mayo Clinic, Rochester, MN not been determined. We investigated STAT3 activation
using cells engineered with hetero- and homozygous mu-
BACKGROUND: A subset of CVID patients develops gran- tations in the DNA binding domain (G421R), modeling a
ulomatous lymphocytic interstitial lung disease (GLILD), GOF patient. De-phosphorylation of G421R is delayed in
which is associated with early mortality. We sought to deter- a dose-dependent manner in response to multiple cyto-
mine if clinical and/or laboratory parameters may correlate kines. Cellular fractionation experiments reveal the
with GLILD development and progression. prolonged phospho-G421R is retained in the nucleus.
METHODS: A retrospective nested case (CVID subjects Removing the capacity for WT STAT3 to be phosphory-
with GLILD)-control (CVID subjects without GLILD) lated at Y705 (WT_Y705F) nearly abrogates its
258 J Clin Immunol (2016) 36:235–334

transcriptional activity. However, while G421R_Y705F T follicular helper (Tfh) cells are a specialised CD4+ T cell
has diminished transcriptional activity compared to subset that function to induce B-cell activation, differentiation
G421R, its activity remains higher than WT. Removal of and Ab production. As such, Tfh cells underpin T-dependent
the ability of WT STAT3 to be phosphorylated at S727 humoral immunity and the success of most vaccines. We have
(WT_S727A) has no effect on its transcriptional activity. previously shown IL-12 can induce some characteristics of
By contrast, transcriptional activity of G421R_S727A is Tfh cells. We have now extended this work to determine the
reduced compared to G421R, although still above WT. IL- molecular requirements for generating human Tfh cells. By
6 stimulation leads to an increase in un-phosphorylated examining patients with monogenic mutations in STAT3,
G421R compared to WT. Interestingly, unlike WT STAT1, IL21/R, IL10R, IFNGR1/2, IL12RB1, CD40LG,
STAT3, un-phosphorylated G421R is detectable in the nu- NEMO, ICOS or BTK we reveal a reduction in circulating
cleus in the resting state. Our data suggests that G421R Tfh (cTfh) cells in patients with loss-of-function (LOF) muta-
enhances STAT3 activity through classical and non- tions in STAT3, IL10R, CD40LG, NEMO, ICOS or BTK.
canonical aspects. Future work will elucidate additional Furthermore, LOF mutations in STAT3 or IL21/R, or gain-of-
mechanisms of G421R GOF, as well as other STAT3 function mutations in STAT1, skewed cTfh cell differentiation
GOF mutations. towards a CXCR3+ Th1-type, characterised by overexpres-
sion of IFNg and PD-1. Together with data showing increased
serum Ig in patients with defects in IFNg-mediated immunity,
4400: HUMAN T FOLLICULAR HELPER CELLS this study identifies an inhibitory role for IFNg in restraining
IN PRIMARY IMMUNODEFICIENCY: Tfh-cell induced B-cell differentiation. In summary, specific
QUALITY JUST AS IMPORTANT AS QUANTITY mutations can differentially affect the quantity and the quality
of the Tfh cells generated, both of which can impact T-
Cindy S. Ma, PhD1, Natalie Wong, B Sc2, Geetha Rao3, dependent humoral immune responses. Furthermore, these
Danielle T Avery4, Klaus Warnatz5, Masao Kobayashi6, findings highlight limitations in assessing Tfh cell function
Steven M Holland, MD 7 , Satoshi Okada 8 , Jacinta based purely on frequencies of CD4+CXCR5+ T cells.
Bustamante9 , Stephanie Boisson-Dupuis, PhD 10 , Jean-
Laurent Casanova, MD, PhD11, Gulbu Uzel, MD12 and
Stuart G. Tangye13 4401: PROLONGED SURVIVAL AFTER INITIAL
TRANSPLANTATION IN AN ADOLESCENT
1
Immunology Division, Garvan Institute of Medical WITH T CELL-ASSOCIATED SEVERE
Research, darlinghurst, Australia, CHRONIC ACTIVE EPSTEIN-BARR VIRUS
2
Immunology Program, Garvan Institute of Medical INFECTION
Research, Sydney, NS, Australia,
3
Garvan Institute, darlinghurst, Australia, Niraj C Patel, MD1 and Michael J Eckrich, MD2
4
Darlinghurst, Australia,
5 1
Centre for Chronic Immunodeficiency, Freiburg, Germany, Pediatrics, Carolinas Medical Center, Charlotte, NC,
6 2
Hiroshima, Japan, Pediatrics, Division of Bone and Marrow Transplantation,
7
Laboratory of Clinical Infectious Diseases, National Institute Carolinas Medical Center, Charlotte, NC
of Allergy and Infectious Diseases/NIH, Bethesda, MD,
8
St-Giles Laboratory of Human Genetics of Infectious Rationale: Severe chronic active Epstein-Barr virus
Diseases, Rockefeller University, New York, NY, (SCAEBV) infection is characterized by chronic EBV vi-
9
Laboratory of Human Genetics of Infectious Diseases, remia and histologic evidence of organ invasion. EBV in-
Institut National de la Sante et de la Recherche Medicale, fection of T lymphocytes has the poorest survival despite
Paris, France, attempts with hematopoietic stem cell transplantation
10
St. Giles Laboratory of Human Genetics of (HSCT).
Infectious Diseases, The Rockefeller University, New Methods: We report a case of T-cell associated SCAEBV
York, NY, infection who received HSCT twice.
11
St Giles Laboratory of Human Genetics of Results: A 17-year old Hispanic male with EBV-related acute
Infectious Diseases, The Rockefeller University, New interstitial nephritis and hepatitis was diagnosed with
York, New York, USA, SCAEBV. He underwent cytoreduction with bortezomib and
12
Laboratory of Clinical Infectious Diseases, NIAID/ ganciclovir prior to receiving reduced intensity conditioning
NIH, Bethesda, MD, (RIC) with fludarabine, cyclophosphamide and 200 cGy TBI
13
Immunology Division, Garvan Institute of Medical (Flu/Cy/TBI) with lung shielding followed by a 10/10
Research, Darlinghurst, Australia matched-unrelated donor HSCT. He developed graft failure
J Clin Immunol (2016) 36:235–334 259

and low level serum EBV reactivation. A T/NK cell lympho- cells (n = 3), low IFN-γ production (n = 6), and reduced IL-
ma nasal type in the lungs was resected and a second trans- 17A production (n = 6).
plant was performed using Campath and Flu/Cy/TBI 400 cGy Combined use of percentage of cTfh cells and intracellular
with peripheral blood stem cells from the same unrelated do- IFN-y/IL-17A production is an useful tool for identification
nor. Post-HSCT he had 100 % donor engraftment with unde- and discrimination of patients (>2y) with STAT1 GOF and
tectable serum EBV. He is currently doing well, surviving STAT3 LOF mutations.
>180 days after transplant without evidence of graft-versus-
host disease.
Conclusions: T-cell associated SCAEBV is fatal unless treat- 4403: A CASE REPORT OF A PATIENT
ed, and mortality rate is high despite curative attempts with DIAGNOSED WITH A CYTOTOXIC T
HSCT. RIC followed by a second HSCT resulted in engraft- LYMPHOCYTE ANTIGEN–4
ment and undetectable serum EBV. HAPLOINSUFFICIENCY AND TREATED WITH
ALLOGENEIC BONE MARROW
TRANSPLANTATION
4402: CTFH CELLS AS DISCRIMINATOR
BETWEEN PATIENTS WITH STAT1 AND STAT3 Payal Amul Patel, MD1, Arvind Srinath, MD1, Hey Chong,
MUTATIONS MD2 and Randy Windreich, MD3

Leen Moens, PhD1, Heidi Schaballie, MD2, Glynis Frans, 1

Pediatric Gastroenterology, Children’s Hospital of
MPharm1, Barbara Bosch, MD2, Rik Schrijvers, MD, PhD3, Pittsburgh, Pittsburgh, PA,
Anniek Corveleyn4, Xavier Bossuyt, MD, PhD1 and Isabelle 2
ALLERGY AND IMMUNOLOGY, CHILDREN’S
Meyts, MD, PhD2 HOSPITAL OF PITTSBURGH, PITTSBURGH, PA,
3
Division of Blood and Marrow Transplantation and Cellular
1
Microbiology and Immunology, KU Leuven, Leuven, Therapies, Pediatric Hematology/Oncology, Children’s
Belgium, Hospital of Pittsburgh, Pittsburgh, PA
2
Childhood Immunology, University Hospitals Leuven,
Leuven, Belgium, Cytotoxic T lymphocyte antigen-4 (CTLA-4) deficiency can
3
Laboratory of Clinical Immunology, KU Leuven, Leuven, disrupt immune tolerance and is characterized by autoimmu-
Belgium, nity, recurrent infections, hypogammaglobulinemia, lympho-
4
Laboratory for Molecular Diagnosis, Center for Human proliferation, and enteropathy. We describe a patient with a
Genetics, Universy Hospital Leuven, Leuven, Belgium novel CTLA-4 mutation who was treated with allogeneic
matched unrelated-donor bone marrow transplantation (allo-
Chronic mucocutaneous candidiasis and MUD BMT).
hyperimmunoglobulinaemia E syndrome are rare PIDs, both Patient is a 19 year old female with menorrhagia found to
characterized by defective T helper 17 (Th17). This Th17 be pancytopenic. Workup revealed aplastic anemia, vita-
defect is mainly caused by STAT1 gain of function (GOF) min B12 deficiency, hypogammaglobulinemia, and low T
mutations and STAT3 loss of function (LOF) mutations, re- cells, NK cells, and near absent B cells. Serial bone mar-
spectively (Liu L. 2011, Ma C. 2008). Moreover, a significant row (BM) studies revealed progressive aplasia but persis-
reduction of circulating T follicular helper cells (cTfh) was tent lymphoid aggregates. Endoscopy found patchy villous
observed in patients with mutations in STAT3 (Ma C. 2012). atrophy but negative celiac testing. Biopsy of lung nodules
The percentage of CD4+CD45RA−CXCR5+ cTfh of pa- showed lymphocytic pneumonitis. Due to progressive BM
tients (n = 70) or controls (n = 15) were determinate by failure, she received an allo-MUD BMT prior to comple-
flow cytometry (FC). Simultaneous, PBMCs were stimu- tion of whole exome sequencing (WES). BM evaluations
lated with S. aureus enterotoxin B. IL-17A and IFN-γ post-BMT showed improved cellularity with trilineage he-
production was measured. STAT1 and STAT3 were matopoiesis and 100 % donor chimerism. She remains
sequenced. lymphopenic while on immunosuppression for mild upper
Four patients with low percentage of cTfh cells, an decreased gastrointestinal graft versus host disease. WES revealed
IL-17A but a normal IFN-γ production had heterozygous heterozygous c.515C>A (p.S172X) mutation in the
STAT3 mutations. Whereas three patient with normal cTfh CTLA-4 gene.
cells but decreased IFN-γ and abolished IL-17A production This is the first known BMT for CTLA-4 haploinsufficiency,
had heterozygous STAT1 mutations. On the other hand, STAT1 with stable engraftment and resolution of pancytopenia. More
and STAT3 were WT in eight individuals younger than 2 years studies are warranted on the long-term outcomes of BMT in
of age. Although they showed decreased percentage of cTfh these patients.
260 J Clin Immunol (2016) 36:235–334

4408: LATIN AMERICAN SOCIETY FOR normal NK cell counts. The proliferation response to PHA
IMMUNODEFICIENCY (LASID) was essentially absent, and the response to PWM was de-
REGISTRY—RESULT OF TWO DECADES creased but detectable. The diagnosis of T- B+ NK+ SCID is
OF WORK. indicated. Chromosomal microarray was negative for
DiGeorge syndrome but did reveal 51 Mb of regions of ho-
Latin American Immunodeficiencies Lasid mozygosity. 15 OMIM genes associated with 27 AR condi-
tions are within the LOH regions, including IL7R gene.
Latin American for Immunodeficiencies, Sao Paulo, Brazil Genomic DNA of the patient was sequenced with next gener-
ation sequencing technology. A list of primary immunodefi-
The first manuscript from LAGID registry was published in ciency genes including SCID genes was analyzed. A novel
1998 when 8 countries participated with a total of 1428 pa- significant homozygous splicing site substitution in IL-7R
tients (JClinImmunol,1998). The following publication was gene was revealed (707-2A>G). This variant is located in
done with data from 12 countries with 3321 patients the acceptor splice site of intron 5 and likely results in skip
(JClinImmunol,2007). Official LASID registry started in of exon 6. Exon 6 encodes for transmembrane domain of
2009 using ESID software. In the first year, 26 reference cen- IL7RA (CD127) protein. Flow cytometry confirmed that the
ters inserted 600 patients identified and it was followed by lymphocyte surface expression of IL7RA was dramatically
1000 and >2000 cases out of 40 centers in 2010 and 2011, reduced in this patient. T cell depleted haploidentical
respectively. The number of patients reached over 5000 pa- (maternal) PBSCT was performed at 6 weeks of age with
tients in 2014 out of 95 reference centers from 14 countries. 100 % T cell engraftment and the child is currently doing well.
Currently there are 108 reference centers with over 6200 reg-
istered patients. Argentina (36 %) and Brasil (22 %) claim 58,
44 % of the total registered patients followed by Mexico 4410: POST-TRANSPLANT HEALTH-RELATED
(19 %) and Colombia (15 %). Guatemala, Paraguai, QUALITY OF LIFE FOR DIFFERENT SEVERE
Republica Dominicana and Venezuela are the countries with COMBINED IMMUNODEFICIENCY
fewest numbers of registered patients (1, 2, 3, and 5 respec- GENOTYPES
tively). Regarding the number of reference centers, Brazil,
Mexico and Argentina have the highest numbers (42, 29 and Intan Juliana Abd Hamid 1,2 , Mary Slatter 3 , Fiona
11 respectively) and all the other countries have less than 10, McKendrick4, Mark S. Pearce5 and Andrew R. Gennery6
and 7 of these have only 1. Antibody deficiencies were pre-
1
dominant with 58 and 53 % in 1998 and 2007 respectively and Institute of Cellular Medicine, Newcastle University,
continues to be with 53 % of all registered cases. Currently, Newcastle upon Tyne, United Kingdom of Great Britain and
LASID registry is the second PID database in the world and Northern Ireland,
2
provides an important source of PID data in Latin America. Regenerative Medicine Cluster, Institut Perubatan &
Pergigian Termaju, USM, Kepala Batas, Malaysia,
3
Department of Paediatric Immunology, Newcastle upon
4409: NOVEL IL7R MUTATION IN A T-B+NK+ Tyne Hospital NHS Foundation Trust, UK,
4
SCID INFANT Department of Health Psychology, Newcastle & North
Tyneside NHS Trust, Newcastle, United Kingdom of Great
Yenhui Chang, MD, PhD1, Panida Sriaroon, MD2, Gabi Jervis, Britain and Northern Ireland,
MS, CGC1, Jingda Shi, PhD1, Maxine Sutcliffe, PhD1, Alexsandra 5
Institute of Health & Society, Newcastle University, Newcastle,
Petrovic, MD3 and Jennifer W. Leiding, MD2 United Kingdom of Great Britain and Northern Ireland,
6
Department of Paediatric Immunology, Newcastle upon Tyne
1
Pathology and Laboratory Medicine, All Children’s Hospital/ Hospitals, Newcastle upon Tyne, UK, United Kingdom
Johns Hopkins Medicine, St. Petersburg, FL,
2
Pediatrics, Division of Allergy, Immunology, and Quality of life (QoL) data post-HSCT for SCID are scarce: 1
Rheumatology, University of South Florida, St. Petersburg, FL, study reported poor function compared to healthy controls(1).
3
Hematology/ Oncology, All Children’s Hospital, St. We assessed QoL of SCID survivors according to genetic
Petersburg, FL diagnosis. Patients >2 years post-HSCT answered the
PedsQL Generic Core Scales v4.0 questionnaires. 59/88
An 8 day old female of Guatemalan parents presented with (67 %) responded. Older patients answered questionnaires,
zero TRECs picked by the newborn screening program of the parents answered for younger patients. Median time post-
State of Florida. Laboratory testing results showed extremely HSCT was 11 years, range 2–27. Responder according to
low T cells numbers, normal B cell and IgM levels, and SCID genotypes were IL2RG/JAK3 (20/31 65 %), IL-7Ra
J Clin Immunol (2016) 36:235–334 261

(10/14 71 %), Adenosine Deaminase (ADA)(12/16 75 %), Common variable immune deficiency (CVID) presents
Artemis (5/7 71 %) and RAG1/2 (6/9 67 %). Mean scores unique diagnostic and treatment challenges. We report a
were compared with published UK norm. ADA patients had 13-year-old boy who presented with recurrent
significantly lower QoL except in the emotional domain, all sinopulmonary infections beginning at age four.
other SCID types were normal. Parents of IL2RG/JAK3 SCID Diagnostic evaluation identified marked
reported significantly lower QoL in 3 domains, parents of hypogammaglobulinemia and very low B cells with nor-
ADA SCID in 5 domains. QoL scores were normal for IL- mal T cell number and function. BTK gene and protein
7Ra and Artemis SCID. RAG1/2 SCID reported significantly testing were normal. He was diagnosed as CVID and man-
lower QoL in 1 domain. (Table). We found most SCID geno- aged with intravenous immunoglobulin with significant
types reported normal Qol. Parameters examined were normal improvement in his clinical status. At 15-years of age he
except in those with ADA SCID and those on immunoglobu- developed lymphadenopathy and was diagnosed with
lin therapy. 1. Titman P et al. Blood 2008;112:3907 Hodgkin’s lymphoma. Further testing revealed progression
to combined immunodeficiency with decreases in both B
and T cell populations. He achieved complete remission of
4411: DETECTION OF ANTI-GLUTAMIC ACID
his lymphoma following chemotherapy and proceeded to
DECARBOXYLASE (GAD) ANTIBODIES IN
allogeneic stem cell transplantation. Whole exome se-
IMMUNOGLOBULIN PRODUCTS
quencing identified compound heterozygous mutations in
RAG1. Mutation c.2487_2488delGAinsTT causes a frame
Tukisa D. Smith, MD, MS and Charlotte Cunningham-
shift that creates a truncated protein with complete loss of
Rundles, MD, PhD
RAG1 activity. The novel mutation c.335G>A (p.R112H)
occurs at an evolutionarily conserved position. Using an in
Division of Clinical Immunology, Department of Medicine,
vitro model, we show that the R112H mutation causes
Icahn School of Medicine at Mount Sinai, New York, NY
markedly reduced RAG1 activity (35 % of wild-type).
Our findings expand the phenotypic spectrum of RAG1
Serum Anti-glutamic acid decarboxylase (GAD) antibodies
mutations and demonstrate that exome sequencing may
are highly specific for Stiff-person syndrome (SPS). Two pa-
expedite definitive diagnosis and treatment of patients with
tients with immunodeficiency receiving intravenous immuno-
CVID.
globulin therapy (Gammagard and Gammunex, respectively)
had detectable anti-GAD antibodies (160.0 and 103.8 IU/ml,
respectively) and SPS was suspected. This diagnosis was sup-
4413: HEPATOSPLENIC CANDIDIDASIS FROM
ported by Electromyography (EMG) findings. To examine
INTERFERON GAMMA PATHWAY DEFECT
potential passive transfer, we tested anti-GAD antibodies in
4 patients with X-linked Agammaglobulinemia (XLA) receiv-
Sharada Ravikumar, Mar Soe Win, Joan Lim, Jessamine Goh
ing immunoglobulin therapy. All of which were positive (3.1–
and Louis Chai
89.0 IU/ml). Our data suggests that passive transfer of anti-
GAD antibody in immunoglobulin products may confound
National University Health System, Singapore, Singapore
the use of this diagnostic test.
Background Hepatosplenic candidiasis is seen exclusively
4412: A HYPOMORPHIC MUTATION IN RAG1 in patients with underlying hematologic malignancies who
PRESENTING AS COMMON VARIABLE are recovering from neutropenia. The underlying patho-
IMMUNE DEFICIENCY AND LYMPHOMA physiology and optimal treatment remain to be
ascertained. We describe here a previously well non-
Erin Leanne Reigh, MD, MS1, Cecelia Calhoun, Lynn S. hematologic patient with the disease. Method The patient
White, Marisa Vineyard, Avraham Beigelman, Melanie was a 42 years old Asian female who was investigated for
Fields, Marwan Shinawi, Megan A. Cooper, MD, PhD3 and fever. There was no family history of immunodeficiency
Jeffrey J. Bednarski, MD, PhD4 or consanguinity. Besides routine hematological, bio-
chemical and radiological investigations, the patient’s im-
1
Allergy/Immunology, Washington University, Saint Louis, mune response assessed through ELISA cytokine mea-
MO, surement, flow cytometry and phagocytosis killing assay.
2
Pediatrics, Division of Rheumatology, and Pathology and Result The patient’s blood count had 15.1 × 109/L white
Immunology, Washington University in St. Louis, St. Louis, MO, blood cells with no cytopenia. Computed tomography
3
Pediatrics, Division of Hematology and Oncology, Washington showed multiple microabscesses within the liver and
University School of Medicine, St. Louis, MO spleen. Sampling of the spleen lesions grew C.
262 J Clin Immunol (2016) 36:235–334

parapsilosis. Her PBMC showed deficient IFNg produc- 4421: BRUTON AGAMMAGLOBULINEMIA:
tion in response to Candida, but not lipopolysaccharide or WELL-KNOWN, BUT STILL DIFFICULT TO
Pam3Cys. STAT-1 phosphorylation was impaired. The pa- DIAGNOSE (CASE REPORT)
tient’s monocytes had defective phagocytosis and killing
of Candida. Conclusion The patient required a prolonged Oksana Boyarchuk, MD, PhD1, Lubov Volyanska, MD,
duration of treatment consisting of a range of anti-fungals PhD1, Lubov Dmytrash, MD2 and Olha Denefil, MD, PhD3
before the addition of steroids which seemingly controlled
1
her condition. This is the first case of non-hematologic Department of Pediatric Diseases, I. Horbachevsky Ternopil
hepatosplenic candidiasis in which a functional immune State Medical University, Ternopil, Ukraine,
2
deficit is described. Ternopil District Hospital, Ternopil, Ukraine,
3
Pathological Physiology Department, I.Horbachevsky
Ternopil State Medical University, Ternopil, Ukraine
4414: REQUESTS FOR MMUNODEFICIENCY
AND IMMUNOLOGY ARTICLES IN UPTODATE X-linked agammaglobulinemia (XLA), or Bruton agamma-
IN 2014 globulinemia is primary immunodeficiency caused by muta-
tions of Bruton’s tyrosine kinase (BTK) and occurs with fre-
Elizabeth C. TePas, MD, MS1, E. Richard Stiehm, MD2 and quency approximately 1 case per 250,000 population.
Anna M Feldweg, MD The patient was a 10-year-old male who was treated in pedi-
atric rheumatology department with 1,5 year history of juve-
1
UpToDate Walters Kluwer Health, Waltham, MA, nile idiopathic arthritis (JIA). Immunosuppressive therapy
2
Pediatrics; Division of Allergy, Immunology, and with methotrexate and metilpred throughout the year was
Rheumatology, UCLA Medical Center, Los Angeles, ineffective.
CA His medical history included first pneumonia at the age of
4.5 months, recurrent pneumonia twice a year since 5 year
Authors: Stiehm ER, Tepas EC, Feldweg AM, UCLA of age, skin lesions by type trophic ulcer and chronic anemia.
Medical Center, Los Angeles CA and UpToDate/ At the age of 7 years bronchiectasis disease was established.
WoltersKluwer Health, Waltham MA The patient has no family history of immunodeficiency.
Title: Annual use of UpToDate topics on Immunology and Concentration of serum immunoglobulins A and G and the
Immunodeficiency (IDD) number of B cells in the peripheral circulation were decreased.
UpToDate is a web-based information resource available Two hemizygous mutations in the BTK gene were identified.
in medical centers, physician offices, and mobile devices Regular intravenous gammaglobulin replacement therapy re-
in over 150 countries. There are currently over 10,000 sulted in improvement in the arthritis.
topics, authored by nearly 6000 authors from around the Conclusion. This case shows difficulties of diagnosis of pri-
world and reviewed by outside editors and peer re- mary immunodeficiency by primary care physicians that re-
viewers, as well as 53 staff physician editors. quire more careful approach. Arthritis may be one of the man-
UpToDate covers 22 specialties, including immunology ifestation of XLA and may be a symptom of autoimmune
and immunodeficiency. Each topic is 10 to 20 pages in diseases (JIA) that associated with XLA and might mislead
length and includes references, graphics, and evidence- the physician and lead to the wrong treatment.
based treatment recommendations. An analysis of use of
these topics provides a profile of the information needs
of physicians in the subjects of immunology and 4423: PSTPIP1 CONTROLS IMMUNE SYNAPSE
immunodeficiency. FORMATION IN HUMAN T-CELLS.
UpToDate IDD articles accessed in 2014 are presented.
The 113 articles were viewed 1 million times including Marianne Boes, PhD
Basic immunology (30 topics,) General aspects of IDD
(29 topics and specific IDDs (54 topics)), The most Pediatrics department, UMC-Utrecht, Utrecht, Netherlands
viewed topics were Immunoglobulinadverse efffects (54,
717 viewings) . Neutropenia in children (54,363), CVID PSTPIP1 controls immune synapse formation in human T-
(50,538) DiGeorge (39,380), Selective IgA deficency cells. Janssen WJM, Grobarova V, Leleux J, Jongeneel CH,
(35,585) van Gijn M, van Montfrans JM, Boes M. PSTPIP1 is an adap-
Less common disorders such as CGD and periodic fevers are tor protein that upon T-cell receptor triggering is recruited to
also accessed since they are in the differential diagnosis of the cytosolic domain of CD2, and mediates remodeling of the
many disorders f-actin-based cytoskeleton. The function of CD2 and PSTPIP1
J Clin Immunol (2016) 36:235–334 263

in activation of human T-cells is not fully understood. From mutations (c.730T>G, c.871A>T and c.939T>G) and two de-
genetic screening of two immunodeficiency patients, we iden- letions (c.995delT and c.1334delC) leading to a premature
tified mutations in the PSTPIP1 coiled coil domain, R228C stop codon. The three different bioinformatics tools gave con-
and T274M. The R228C PSTPIP1 patient exhibits a relative cordant results and predicted these missense mutations to be
increase in naive T-cells, while the T274M patient has a deleterious, affecting functional ability and structural stability
strongly increased memory T-cell compartment. We therefore of the C1-INH protein. Conclusions: New mutations were
investigated the role of PSTPIP1 and CD2 signaling in early identified and characterized in SERPING1 gene causing C1-
T-cell activation. We show that CD2 crosslinking on R228C INH-HAE in Brazilian patients.
cells impairs yet on T274M cells enhances f-actin polymeri-
zation, compared to the common PSTPIP1 variant. Both
R228C and T274M PSTPIP1 mutations debilitated T-cells to 4425: RUBELLA VIRUS IN CUTANEOUS
make stable immune synapses with interacting beads. Co- GRANULOMAS IN IMMUNE DEFICIENT
immunoprecipitation experiments suggest that CD2 PATIENTS
crosslinking triggers stronger binding of T274M PSTPIP1 to
CD2, for enhanced f-actin polymerization. Our data supports a Ludmila Perelygina, PhD1, Stanley Plotkin, MD2, Pierre
critical role for PSTPIP1 in the formation of a productive T- Russo, MD3, Timo Hautala, MD4, Francisco Bonilla, MD
cell immune synapse. Current experiments are aimed at clar- PhD5, Hans Ochs6, Avni Y. Joshi, MD, MSc7, John M
ifying a role for CD2 signaling and PSTPIP1 in naive and Routes, MD8, Kiran Patel, MD9, Claudia Wehr, MD10 and
memory T-cells. Kathleen Sullivan, MD, PhD11

1
CDC, Atlanta, GA,
2
4424: NEW SERPING1 GENE MUTATIONS University of Pennsylvania Perelman School of Medicine,
CAUSING HEREDITARY ANGIOEDEMA WITH Philadelphia, PA,
3
C1 INHIBITOR DEFICIENCY IN BRAZILIAN The Children’s Hospital of Philadelphia, Philadelphia, PA,
4
PATIENTS Oulu University Hospital, Oulu, Finland,
5
Childrens Hospital Boston, Boston, MA,
6
Mariana Paes Leme Ferriani, MD, Luana Sella Motta Maia, Center for Immunity and Immunotherapies, Seattle
BSc, Janaina Michelle Lima Melo, MD, PhD, Thais Children’s Research Institute, Seattle, WA,
7
Mendonca Nociti, MD, Marina Mendonca Dias, Chem, Mayo Clinic, Rochester, MN,
8
Adriana Santos Moreno, PhD and Luisa Karla de Paula Department of Allergy and Clinical Immunology, Medical
Arruda, MD, PhD College of Wisconsin, Milwaukee, WI,
9
UCSF, San Francisco, CA,
10
Department of Internal Medicine, Allergy and Immunology University of Freiburg, Freiburg, Germany,
11
Division, Ribeirao Preto Medical School University of Sao Children’s Hospital of Philadelphia, Philadelphia, PA
Paulo, Ribeirão Preto, Brazil
Cutaneous granulomas represent a serious complication of
Rationale: Hereditary Angioedema with C1 inhibitor deficien- immune deficiencies. Therapy has focused on immune sup-
cy (C1-INH-HAE) is a rare disorder caused by mutations in pression. The purpose of this study was to examine cutaneous
the gene encoding C1-INH (SERPING1). Over 240 different granulomas for the presence of persistent rubella virus, as was
mutations have been described. We aimed to identify and previously reported in a study from France. Fifteen patients
characterize new mutations in SERPING1 gene among were examined using immunohistochemistry for the rubella
Brazilian patients with C1-INH-HAE. Methods: Eight pa- nucleocapsid protein. Seven patients exhibited positive stain-
tients diagnosed with C1-INH-HAE based on clinical symp- ing within the granulomas, largely M2 macrophages.
toms and low serum levels of C1-INH and C4 underwent Sequencing one isolate revealed RA27/3 vaccine strain rubel-
genetic evaluation. PCR was carried out in genomic DNA la with multiple mutattions. The natural history ranged from
using specific primers for the eight exons of the SERPING1 very aggressive to full resolution. The types of immune defi-
gene. PCR products were purified and sequenced by the ciencies associated with rubella nucleocapsid positivity were
Sanger method. Computer-based algorithms SIFT, largely T cell defects: Combined immune deficiency (n = 2),
PolyPhen-2 and HOPE were used to predict the pathogenicity ataxia telangiectasia (n = 3), Madin Walker syndrome (n = 1)
of new missense mutations. This study was approved by the and cartilage hair hypoplasia (n = 1). The immune deficiencies
Ethics Committee of the Clinical Hospital of Ribeir‹o Preto where granulomas were not positive for rubella were CVID
Medical School (14521/2012). Results: Genetic analysis re- (n = 3), XLA (n = 1), ataxia telangiectasia (n = 3), and NEMO
vealed five new mutations, including three missense (n = 1). These data suggest that vaccine strain rubella can set
264 J Clin Immunol (2016) 36:235–334

up a chronic infection and stimulate a non-protective immune 4435: COMPLEMENT BIOMARKER

response associated with chronic granuloma formation. In PROFILING OF ATYPICAL HEMOLYTIC
congenital rubella, virus persists in many tissues but has not UREMIC SYNDROME
been thought to induce chronic infection otherwise. Our study
suggests that immune deficient individuals may be at risk for Dingwu Shao1, Adam Keenan2, Carla M. Nester3, Richard J.
persistent infection. Smith, MD4 and Yuzhou Zhang1

1
Molecular Otolaryngology and Renal Research Laboratories,
4434: EVALUATION OF PENICILLIN University of Iowa, iowa city, IA,
2
HYPERSENSITIVITY IN PATIENTS WITH Molecular Otolaryngology and Renal Research Laboratories,
COMMON VARIABLE IMMUNODEFICIENCY University of Iowa, Iowa City, iowa city, IA,
3
1Molecular Otolaryngology and Renal Research
Heather N Hartman, MD1, Karrie A Schneider, RN, BSN2, Laboratories, 2Department of Internal Medicine, Division of
Mary K Hintermeyer, APNP2, Mary T Bausch-Jurken, PhD3, Nephrology, and 3Department of Pediatrics, Division of
James W Verbsky, MD/PhD4 and John M Routes, MD1 Nephrology, Carver College of Medicine, University of
Iowa, iowa city, IA, (4)University of Iowa, Iowa City, IA
1
Department of Allergy and Clinical Immunology, Medical
College of Wisconsin, Milwaukee, WI, Atypical hemolytic uremic syndrome (aHUS) is a life-
2
Allergy and Clinical Immunology, Children’s Hospital of threatening multi-systemic condition characterized by micro-
Wisconsin, Milwaukee, WI, angiopathic hemolytic anemia, thrombocytopenia and acute
3
Pediatrics, Medical College of Wisconsin, Milwaukee, WI, renal failure. It is caused by increased and uncontrolled activ-
4
Department of Pediatrics, Division of Rheumatology, ity of the alternative pathway of the complement system that
Medical College of Wisconsin, Milwaukee, WI arises secondary to genetic factors such as mutations in com-
plement proteins (factor H, factor I, membrane cofactor pro-
Rationale tein, C3, factor B) or acquired drivers of disease like neutral-
The presence of allergy in the Common Variable izing autoantibodies to factor H. In this study, we sought to
Immunodeficiency (CVID) population is not well described. validate and define the association of complement dysregula-
There has been no report of rate of penicillin (PCN) allergy or tion with aHUS in 36 aHUS patients; 200 controls were ob-
testing for clinical hypersensitivity in the CVID population. tained from regional blood banks. Eighteen complement bio-
We hypothesize that patients with CVID do not make specific markers were assayed on all patients and controls.
IgE and thus would not have clinical immediate hypersensi- Assessment of the alternative complement pathway showed
tivity to PCN. that aHUS patients had normal serum levels of C3, factor B
Methods and the C3 breakdown product, C3c. However, Ba and Bb,
Patients have been selected from the Medical College of which are factor B degradation products, were significant el-
Wisconsin Immunodeficiency Clinic with the diagnosis of evated in aHUS patients (Ba, p < 0.001; Bb p < 0.05 respec-
CVID by standard criteria and reported history of allergy to tively). In aHUS, the complement breakdown product Ba is
PCN. Eligible patients undergo skin testing with PRE-PEN® most significantly elevated, consistent with ongoing comple-
and Penicillin G. Following negative testing a dose challenge ment activation. These data substantiate the link between
of Amoxicillin is administered. complement dysregulation and aHUS.
Results
Overall 32 % (32/100) CVID patients have reported PCN aller-
gy. At the time of submission five patients have tested negative 4437: UTILITY OF DISEASE-TARGETED
with a combination of skin testing and in-office dose challenge; PANELS AND WHOLE EXOME SEQUENCING
two patients had positive intradermal skin tests to PRE-PEN® FOR THE DIAGNOSIS OF PRIMARY
and have not been dose challenged. Testing is ongoing. IMMUNODEFICIENCIES
Conclusions
We report an increased rate of PCN allergy (32 %) in the Susan A. Lagerstedt, BS1 and Roshini Abraham, Ph.D.2
CVID population over the 10 % reported rate in the general
1
population, similar to that of the Cystic Fibrosis population. Department of Laboratory Medicine and Pathology, Mayo
Seventy-one percent (5/7) of reported PCN allergic CVID Clinic, Rochester, MN,
2
patients at time of submission have shown lack of clinical Cellular and Molecular Immunology Laboratory, Dept. of
hypersensitivity to PCN. PCN allergy should be evaluated in Laboratory Medicine and Pathology, Mayo Clinic,
patients with CVID. Rochester, MN
J Clin Immunol (2016) 36:235–334 265

Primary immunodeficiencies (PIDs) are usually monogen- Results: 311 adults who completed the survey were compared
ic disorders of the immune system with severe clinical to the US population. PI patients reported significantly higher
phenotype. Early diagnosis is essential to reducing mor- scores for anxiety (M = 57.5, SD = 8.12), (M = 50.4, SD = 9.0)
bidity and mortality. The collective incidence of PIDs is p < .05, depression (M = 55.4, SD = 8.84), (M = 50.5, SD = 9.1)
~1:2000. Phenotypic and immunological diagnosis often p < .05; fatigue (M = 61.2, SD = 9.56), (M = 50.0, SD = 10.0)
has to be confirmed or supplemented with genetic analy- p < .05 and pain interference (M = 58.3, SD = 9.76),
sis for accurate diagnosis. We have designed disease- (M = 52.8, SD = 8.1) p < .05. Additionally, PI patients reported
targeted gene panels (DTGPs) covering more than 270 significantly lower scores for physical function (M = 42.2,
genes, for specific PIDs: Combined T-/B-cell, Antibody, SD = 8.33), (M = 47.9, SD = 9.5) p < .05 and satisfaction with
Well-defined syndromes, Immune dysregulation, their social roles (M = 43.7, SD = 8.32), (M = 49.4, SD = 10.7)
Phagocytic, Innate, Autoinflammatory and Complement. p < .05
The diagnostic advantage of DTGPs is the ability to as- Conclusions: These results suggest that patients with PI have
sess genetic regions that are highly correlated with the significantly worse HRQoL scores compared to the general
clinical/immunological phenotype more quickly and at a population. Further, the IDF ePHR was found an appropriate
lower cost than whole exome sequencing (WES). vehicle for administering the PROMIS-29.
Supplemental testing is performed in relevant low cover-
age, non-coding, and homologous regions; regions missed
by WES. Selection of the right gene panel is essential, and 4440: CLINICAL CHARACTERISTICS AND
may require laboratory counseling using clinical/immuno- DIAGNOSIS IN PATIENTS WITH
phenotype and pre-genetic analysis. Since monogenic de- PREDOMINANTLY ANTIBODY
fects have manifold clinical presentations and are seen in DEFICIENCIES: BASELINE FEATURES OF
multiple clinical sub-specialties, it is relevant and essen- PATIENTS ENROLLED IN THE UNITED
tial for physicians involved in the care of these patients to STATES IMMUNODEFICIENCY NETWORK
recognize the unique features of WES and DTGP in (USIDNET) REGISTRY
selecting the right diagnostic genetic test for the right
patient. Albert O. Antonio, DO1, Marla Goldsmith, BA2, Guillaume
J. Stoffels, MS, MA3 and Artemio M Jongco III, MPH MD
PhD4,5
4438: PATIENT REPORTED OUTCOMES IN PI:
1
PROMIS-29 QOL SURVEY RESULTS Division of Neonatal-Perinatal Medicine, Cohen Children’s
UTILIZING THE IDF ELECTRONIC Medical Center of New York, Hofstra North Shore- LIJ
PERSONAL HEALTH RECORD (EPHR) School of Medicine, New Hyde Park, NY,
2
PLATFORM Immune Deficiency Foundation, Towson, MD,
3
Biostatistics Unit, Feinstein Institute for Medical Research,
Kathleen Sullivan, MD, PhD1, Christopher Scalchunes, Manhasset, NY,
MPA2, Tiffany Henderson, PhD2, Tara Caulder, MS2, Marla 4
Division of Allergy & Immunology, Cohen Children’s
Goldsmith, BA2, Erin Poff, BS2 and Julieann Magnusson, Medical Center of New York, Great Neck, NY,
BA2 5
Center for Immunology and Inflammation, Feinstein Institute
for Medical Research, Manhasset, NY
1
Children’s Hospital of Philadelphia, Philadephia, PA,
2
Immune Deficiency Foundation, Towson, MD Background: Disease registries improve our understanding
of primary immunodeficiencies.
Objectives:To evaluate the health-related quality of life of Objective: We queried the US Immunodeficiency Network
patients with primary immunodeficiency (PI) disease com- (USIDNET) Registry to better understand the natural history
pared to the general U.S. population. and clinical characteristics of agammaglobulinemic and
Methods: Adult patients in the IDF and IDF ePHR da- hypogammaglobulinemic registry subjects.
tabases were invited to complete an online version of Design/Methods: This retrospective study included 409 hu-
the Patient-Reported Outcomes Measurement moral immunodeficient subjects enrolled from 2008 to 2015
Information System® (PROMIS®), the PROMIS-29. (14.2 % of total registrants). Pairwise association between
The survey measured 7 health-related quality of life variables was assessed via the Mann–Whitney, Fisher’s exact,
(HRQoL) domains. T-tests were conducted to compare or incidence density ratio tests.
HRQoL scores for patients with PI to those of the U.S. Results: Eleven specific diagnoses were represented. X-
population. linked agammaglobulinemia (85.8 %) and
266 J Clin Immunol (2016) 36:235–334

hypogammaglobulinemia of unknown cause (61.8 %) were and Women’s Hospital, both of which are large tertiary care
the most prevalent. The sample was 69.2 % male and centers but not referral centers for CVID). Our cohort of ap-
58.7 % Caucasian. The two disease groups significantly dif- proximately 180 CVID patients was comparable to the
fered by gender, race, history of ≥1 infection, median age of USIDNET with regard to age at diagnosis, native immuno-
symptom onset and diagnosis (p < 0.005 for each). The globulin levels, and overall complication rates, although de-
hypogammaglobulinemia group had longer median diagnos- tailed analysis showed increased frequency of asthma (46.5
tic delay (0.5 years; IQR: 0–2.7 vs. 3.0 years; IQR: 0.3–7.0) vs. 32.7 %), thyroid disease (11.2 vs. 0.9 %), and noninfec-
(p = 0.0002). The two groups did not differ in antibiotic pro- tious rheumatologic complications (14.2 vs. 5.1 %) in the
phylaxis use, number of antibiotic courses, infection count Partners’ cohort. We also observed lack of routine B cell mat-
and serious infection count. uration phenotyping (only 20 %) and a range of replacement
Conclusions: Registries can reveal clinically relevant dif- trough IgG levels (899 +/− 252 mg/dL) in the Partners’ cohort.
ferences between disease groups. This study highlights Future work will address whether autoimmune disease devel-
some of the strengths and limitations of registry-based opment is significantly related to immunoglobulin replace-
research. ment dosing, B cell phenotype, and/or novel screening
markers.

4443: TERTIARY CARE PATIENTS WITH

COMMON VARIABLE IMMUNE DEFICIENCY 4445: IL-10-PRODUCING REGULATORY B
(CVID) ARE AT SIMILAR RISK FOR CELLS ARE DECREASED IN PATIENTS WITH
NONINFECTIOUS COMPLICATIONS: A COMMON VARIABLE IMMUNODEFICIENCY
COMPARATIVE COHORT ANALYSIS
BETWEEN PARTNERS-AFFILIATED Nathalia Silveira Barsotti1, Rafael Ribeiro Almeida2, Myrthes
HOSPITALS IN BOSTON, MA AND THE Toledo Barros3, Jorge Kalil3 and Cristina M. Kokron, MD,
USIDNET NATIONAL REGISTRY. PhD3

Jocelyn Farmer, MD, PhD1, Lael M. Yonker, MD2, Daniel 1

Division of Clinical Immunology and Allergy, University of
Suez, MD 3 , Kathleen Sullivan, MD, PhD 4 , Charlotte São Paulo School of Medicine, São Paulo, Brazil,
Cunningham-Rundles, MD, PhD5 and Jolan Walter, MD, 2
Division of Clinical Immunology and Allergy, University of
PhD6 São Paulo School of Medicine, Brazil,
3
Division of Clinical Immunology and Allergy, University of
1
Department of Allergy & Immunology, Massachusetts São Paulo Medical School, São Paulo, Brazil
General Hospital, Boston, MA,
2
Pediatric Pulmonary, Massachusetts General Hospital, Common variable immunodeficiency (CVID) is the most
Boston, MA, prevalent symptomatic primary immunodeficiency in
3
Division of Allergy and Immunology, University of Texas adults. CVID patients often present changes in the frequen-
Southwestern Medical Center, Dallas, TX, cy and function of B lymphocytes, reduced number of Treg
4
Division of Allergy and Immunology, Children’s Hospital of cells, chronic immune activation, recurrent infections, high
Philadelphia, Philadelphia, PA, incidence of autoimmunity and increased risk for malig-
5
Division of Clinical Immunology, Department of Medicine, nancies. We hypothesized that the frequency of B10 cells
Icahn School of Medicine at Mount Sinai, New York, NY, would be diminished in CVID patients because these cells
6
Department of Pediatrics, Division of Allergy & play an important role in the development of Treg cells and
Immunology, Massachusetts General Hospital, Boston, MA in the control of T cell activation and autoimmunity.
Therefore, we evaluated the frequency of B10 cells in
The epidemiology of CVID has been described almost exclu- CVID patients and correlated it with different clinical and
sively at large referral centers and centralized databases such immunological characteristics of this disease. Forty-two
as the USIDNET. These data demonstrate the morbidity of CVID patients and 17 healthy controls were recruited for
noninfectious sequelae, which occur in the majority of pa- this study. Cryopreserved PBMCs were used for analysis
tients with CVID. Our goal was to establish the frequency of T cell activation, frequency of Treg cells and character-
and severity of noninfectious sequelae at a large tertiary care ization of B10 cells by flow cytometry. We found that
center. We conducted a retrospective cohort analysis of pa- CVID patients presented decreased frequency of B10 cells.
tients with CVID who have been diagnosed or treated at The frequency of B10 cells had no correlation with auto-
Partners HealthCare Network Hospitals in Boston, MA (in- immunity, immune activation and Treg cells in CVID pa-
cluding the Massachusetts General Hospital and the Brigham tients. This work suggests that CVID patients have a
J Clin Immunol (2016) 36:235–334 267

compromised regulatory B cell compartment which is not 4448: PREGNANCY REGISTRY TO COLLECT
correlated with clinical and immunological characteristics LONG-TERM SAFETY DATA FROM WOMEN
presented by these individuals. TREATED WITH RECOMBINANT HUMAN
HYALURONIDASE (rHuPH20)-FACILITATED
SUBCUTANEOUS IMMUNOGLOBULIN G
4447: OUTCOME OF HEMATOPOIETIC STEM (IGHY; HYQVIA)
CELL TRANSPLANTATION IN ADOLESCENTS
AND YOUNG ADULTS WITH NON-SCID Irmgard Baumgartner1, Andras Nagy, Christopher Rabbat,
PRIMARY IMMUNODEFICIENCIES (PID) Barbara McCoy, Heinz Leibl and Leman Yel, MD3

Fabian Hauck, MD, PhD1, Volker Wiebking, MD1, Gundula 1

Baxalta Innovations GmbH, Vienna, Austria,
Notheis, MD2, Volker Aumann, MD3, Sibylle Koletzko, 2
Clinical Science, Immunology, Baxalta US Inc, Cambridge,
MD4, Bernd H. Belohradsky, MD1, Ellen Renner, MD4, MA
Monika Führer, MD1, Johanna Tischer, MD5, Christoph
Klein, MD, PhD 6, Irene Schmid, MD 1 and Michael H Objectives: IGHy is used as an immunoglobulin G replace-
Albert, MD1 ment therapy in adults. This is a non-interventional, 2-arm,
prospective, uncontrolled, open-label, multicenter, post-
1
Pediatric Hematology/Oncology/Immunology, Dr. von authorization pregnancy registry in Europe and North
Hauner University Children’s Hospital, Munich, Germany, America to evaluate the safety of women who become preg-
2
Pediatric Hematology/Oncology/Immunology, Pediatric nant during or after treatment with IGHy, and to assess fetal
Hematology/Oncology/Immunology, Munich, Germany, growth/development. To increase awareness and inform the
3
Pediatric Hematology/Oncolocy, University Hospital scientific community of the design and availability of this
Magdeburg, Germany, registry, the study design is described herein.
4
Pediatric Hematology/Oncology/Immunology, Dr. von Methods: Females becoming pregnant after IGHy exposure
Hauner University Children’s Hospital Munich, Munich, will be encouraged to participate (subjects stopping IGHy will
Germany, be followed and treated with an alternate treatment).
5
Internal Medicine III, Hematology/Oncology, University Assessments will be performed as per standard of care. Overall
Hospital Munich, Germany, study duration is ~6 years from initiation (no pre-specified min-
6
Pediatric Hematology/Oncology/Immunology, Dr. von imum sample size). Data will be obtained from medical records
Hauner University Children’s Hospital, Germany and clinical/office charts. For patients consenting to blood draw-
ing, anti-rHuPH20 antibodies will be assessed every 3 months.
Because of suspected increased morbidity and mortality, Data will be assessed on fetal development in utero, and on the
adolescents and young adults (AYAs) with PID are often growth and development of the infant for 2 years post-delivery.
not considered for HSCT, even though their pediatric Statistical analyses and data displays will be descriptive.
counterparts have excellent HSCT outcomes. Referrals Conclusions: As no clinical studies have been conducted with
of AYAs with PID have recently increased. To assess the IGHy in pregnant women, this study will analyze the long
outcome of AYAs with PID we retrospectively analyzed a term safety data from female subjects who became pregnant
cohort of 18 AYAs (15–22; median 18 years) transplanted during or after treatment with IGHy.
between 2007 and 2014 (2 MSD/MFD,16 MUD) and
compared them to 43 children (median 5 years) with
PID other than SCID transplanted at the same center dur- 4450: DO PIDD PATIENT CHARACTERISTICS
ing that period (15 MSD/MFD, 21 MUD, 7 MMFD). DRIVE TREATMENT CHOICE?
After a median follow-up of 3.8 and 3.9 years overall
survival was 94 and 96 % (p = 0.88) in the AYA and pe- JM Noone, PhD 1,2, CM Blanchette, PhD 1,2, M. Chris
diatric cohorts respectively, while disease free survival Runken, PharmD3, Emily Zacherle, MS1,2 and Deborah
was 94 and 88 % respectively (p = 0.37). Rejection oc- Gelinas, MD3
curred in 4 pediatric patients, one of whom was success-
1
fully re-transplanted. Causes of death were adenovirus (1) University of North Carolina at Charlotte, Charlotte, NC,
2
in the AYA cohort and pneumococcal sepsis and Health Economics, Precision For Medicine, Davidson, NC,
3
metapneumovirus (1 each) in the pediatric cohort. Grade Grifols, Research Triangle Park, NC
II acute and mild chronic GVHD occurred in 11 and 22 %
in the AYAs versus 7 and 2 % in the pediatric cohort Introduction: Primary Immune Deficiency Disorder (PIDD)
(p = 0.16 and is a rare, complex, chronic disease affecting a patient’s
268 J Clin Immunol (2016) 36:235–334

immune response. Treatments include intravenous (IV) and Conclusions: Additional data on IGHy long-term safety will
subcutaneous (SC) immunoglobulin (Ig). We assessed clinical be acquired and prescribed treatment regimens and adminis-
and demographic differences of patients initiating these treat- tration in routine clinical practice assessed.
ments. Methods: Using the 2011–2013 Pharmetrics Plus
dataset, newly-diagnosed PIDD patients initiating Ig treatment
4452: APOPTOSIS RESISTANCE AND
were compared on demographics, physician type, comorbidi-
INTRINSIC DIFFERENTIATION DEFECTS IN
ties and Charleson Comorbidity Index (CCI). Statistical dif-
ACTIVATED BENTA PATIENT B CELLS.
ferences were determined using chi-square and student’s t
tests. Results: Of the 2758 PIDD patients, 22 % started on
Swadhinya Arjunaraja, Ph.D. and Andrew L. Snow, Ph.D.
SCIg while 78 % began on IVIg. SC patients were significant-
ly younger (40.3 vs 48.2), more were female (63.3 vs 54.9 %),
Department of Pharmacology & Molecular Therapeutics,
and healthier having lower average CCI scores (1.1 vs 1.8).
Uniformed Services University of the Health Sciences,
SC patients were less likely to have a history of non-metastatic
Bethesda, MD
cancer (5.3 vs 32.5 %), peripheral vascular disease (2.1 vs
4.5 %) and renal disease (3.8 vs 5.9 %), p < 0.05.
We recently described a novel lymphoproliferative disor-
Conclusions: PIDD patients initiating IV vs SC are character-
der known as BENTA (B cell Expansion with NF-kB and
istically different. Whether this selection bias stems from phy-
T cell Anergy) disease. BENTA disease is caused by
sician clinical or personal preference or patient choice needs to
germline, gain-of-function mutations in the lymphocyte
be further studied.
scaffolding protein CARD11, resulting in constitutive
NF-kB signaling. Beyond dramatic polyclonal B cell ex-
pansion, BENTA patients also present with signs of pri-
4451: NON-INTERVENTIONAL
mary immunodeficiency, including reduced percentages
POST-MARKETING SAFETY STUDY ON THE
of class-switched/memory B cells and poor humoral re-
LONG-TERM SAFETY OF HYQVIA (GLOBAL)
sponses to certain vaccines. Using purified B cells from
our BENTA patient cohort, here we show that BENTA B
Katharina Fielhauer1, Andras Nagy, Christopher Rabbat,
cells exhibit profound, intrinsic defects in B cell differen-
Barbara McCoy, Heinz Leibl and Leman Yel, MD3
tiation. Compared with normal donor B cells, differentia-
1 tion of BENTA patient B cells into short-lived
Baxalta Innovations GmbH, Vienna, Austria,
2 IgDloCD38hi plasmablasts or CD138+ long-lived plasma
Clinical Science, Immunology, Baxalta US Inc, Cambridge,
cells was severely impaired following activation. These
MA
defects corresponded with less IgG antibody secretion
and reduced induction of key proteins required for class
Rationale: Herein, we describe the design of a non-interven-
switch recombination and plasma cell commitment.
tional, prospective, uncontrolled, multicenter, open-label, post-
Despite these differentiation defects, stimulated BENTA
marketing surveillance study to be conducted in the US and other
B cells demonstrated an overwhelming survival advantage
countries where recombinant human hyaluronidase (rHuPH20)-
in vitro, which may result from a CARD11-dependent,
facilitated subcutaneous infusion of immunoglobulin G (IGHy;
NF-kB-independent signaling process. Collectively, these
HYQVIA) is licensed to obtain additional safety and tolerability
findings provide important mechanistic clues to help ex-
data in pts with primary immunodeficiency diseases.
plain both B cell lymphocytosis and humoral immunode-
Methods: A target of 250 adults who were prescribed/
ficiency in BENTA disease.
initiated IGHy will be recruited over 3 years. Treatment
regimens/schedules will be at physician discretion. All pts will
enroll in Epoch 1 (~1-year duration). Pts who test positive for 4453: EFFICACY OF RECOMBINANT HUMAN
rHuPH20 antibodies (titer ≥1:160) during Epoch 1, or were HYALURONIDASE-FACILITATED
positive pre-enrollment, will continue to Epoch 2 (2-years SUBCUTANEOUS INFUSION OF
duration). Overall study duration will be ~6 years. There will IMMUNOGLOBULIN G (IGHy) IN PATIENTS
be no required predefined visits, medical/laboratory tests, and WITH PRIMARY IMMUNODEFICIENCY
procedures beyond the treatment centers’ standard clinical DISEASES: INFECTIONS OVER TIME
practice, except rHuPH20 antibody assessment. All assess-
ments will be performed during routine clinical visits. Richard L. Wasserman1, Mark Stein2, Lisa Kobrynski,
Documented data will include safety (including binding/ Sudhir Gupta, MD, PhD, MACP4, J. Andrew Grant, Arye
neutralizing rHuPH20 antibody titers), health-related quality Rubenstein, Christopher Rabbat, Werner Engl, Barbara
of life, and health resource use. McCoy, Heinz Leibl and Leman Yel, MD5
J Clin Immunol (2016) 36:235–334 269

1
Dallas Allergy, Dallas, TX, Dedicator of cytokinesis 8 (DOCK8) immunodeficiency is
2
Allergy Associates of the Palm Beaches, North Palm Beach, FL, characterized by eczema, allergy, sinopulmonary infections,
3
University of California, Irvine, Irvine, CA, cutaneous viral infections, and malignancy. Reports also show
4
Clinical Science, Immunology, Baxalta US Inc, Cambridge, MA significant vascular abnormalities. We describe one patient
with cerebral vasculopathy and retrospectively reviewed CT
Rationale: IGHy provides protection against infections at and MRI/MRA imaging on 44 patients in our DOCK8 patient
similar doses and dosing intervals as intravenous immuno- cohort at the NIH (2005–2015).
globulin G (IGIV). We report IGHy efficacy over time in We diagnosed a 6-year-old male with DOCK8 deficiency with
patients with primary immunodeficiency diseases (PIDD) eczema, sinopulmonary infections and chronic EBV viremia.
aged ≥16 years treated for up to ~3.5 years in the IGHy pivotal Brain MRA revealed stenoses of the basilar and right posterior
phase 3 study and its extension. cerebral arteries, with evidence of prior left posterior cerebral
Methods: Following a 3-month IGIV treatment period, pa- artery infarct. Brief episodes of vision loss and headache were
tients received IGHy every 3 to 4 weeks for ~18 months, noted. He received a haplo-identical BMT without complica-
followed by up to an additional 21 months. tion. Brain MRA done on 17 patients revealed two others with
Results: Of the 63 enrolled patients aged ≥16 (range 16–78) vascular abnormalities, including one with Moyamoya and
years, 61 were administered IGHy for up to ~3.5 years at the one with stenosis of the right MCA, its branches and basilar
established dose. Rates of validated acute serious bacterial in- artery. Thoracic and abdominal CT imaging for 29 patients
fections (VASBIs) and all infections were 0.01/patient-year (up- identified four patients with vasculopathies including aortic
per limit of 99 % confidence interval [CI]: 0.01) and 3.05/pa- aneurysm, mid aortic stenosis with bilateral renal artery steno-
tient-year (95 % CI: 2.63–3.52), respectively. For the subset of sis, and diffuse aortic dilatation and calcification.
patients completing IGHy through the extension study (n = 37), Vasculopathy as a manifestation of DOCK8 deficiency is
the infection rate/patient-year (3.18 overall) remained relatively demonstrated by this case and retrospective review of patients.
constant (3.14 for months 1–12; 3.60 for months 12–24; and Screening for brain, thoracic and abdominal vasculopathies is
2.70 for months 25–33.6). Over the course of IGHy treatment, integral for DOCK8 clinical care.
serum trough levels of antibodies to Haemophilus influenza,
Clostridium tetani toxoid, and hepatitis B virus were protective.
Conclusions: In patients aged ≥16 years with PIDD who were 4455: LOCAL ADVERSE REACTION RATES
treated with IGHy for up to ~3.5 years, efficacy remained DECREASED OVER TIME DURING
constant over time. RECOMBINANT HUMAN
HYALURONIDASE-FACILITATED
SUBCUTANEOUS INFUSION OF
4454: DOCK8 IMMUNODEFICIENCY IMMUNOGLOBULIN G (IgG) (IGHy)
ASSOCIATED WITH VASCULOPATHY TREATMENT IN PATIENTS WITH PRIMARY
IMMUNODEFICIENCY DISORDERS (PIDD) IN
Ashleigh A Hussey, MSN, RN 1, Anahita Agharahimi, THE IGHy PHASE 3 STUDIES
CRNP1, Nirali Shah, MD2, Dennis D. Hickstein, M.D.3,
Helen C. Su4, Lauren Sanchez, MD5, Adam DeZure, MD6, Mark Stein1, Richard L. Wasserman2, Isaac Melamed, Sudhir
Gulbu Uzel, MD7 and Alexandra F Freeman, MD7 Gupta, MD, PhD, MACP4, Lisa Kobrynski, Arye Rubenstein,
Christopher Rabbat, Werner Engl, Barbara McCoy, Heinz
1
Laboratory of Clinical Infectious Diseases, National Institute Leibl and Leman Yel, MD5
of Allergy and Infectious Diseases/NIH, Bethesda, MD,
2 1
Pediatric Oncology Branch, National Cancer Institute/NIH, Allergy Associates of the Palm Beaches, North Palm Beach,
Bethesda, MD, FL,
3 2
Experimental Transplantation and Immunology Branch, Dallas Allergy, Dallas, TX,
3
Division of Basic Sciences, National Cancer Institute, University of California, Irvine, Irvine, CA,
4
National Institutes of Health, Clinical Science, Immunology, Baxalta US Inc, Cambridge,
4
Laboratory of Host Defenses, National Institute of Allergy and MA
Infectious Diseases, National Institutes of Health, Bethesda,
MD, Rationale: IGHy can be administered at similar doses/
5
LCID, NIAID, NIH, Bethesda, MD, volumes and dosing intervals as intravenous immunglobulin
6
Vaccine Research Center, NIAID, NIH, Bethesda, MD, G (IGIV) but, similar to conventional subcutaneous IgG, is
7
Laboratory of Clinical Infectious Diseases, NIAID/NIH, associated with a lower risk of systemic and higher risk of
Bethesda, MD local adverse reactions (ARs). We report local AR rates over
270 J Clin Immunol (2016) 36:235–334

time in patients (pts) with PIDD aged ≥16 years (yrs) treated a nonsense mutation at position Q138 in IL-12Rβ2 in a con-
with IGHy for up to ~3.5 years in the IGHy pivotal phase 3 sanguineous Turkish family: one suffered from localized BCG
study and its extension. disease, another from bona fide tuberculosis, and the third
Methods: After a 3-month IGIV treatment period, pts initiated remains asymptomatic. In in vitro assays we demonstrated
IGHy on a dose ramp-up schedule and then received IGHy that the mutation leads to a loss of IL-12Rβ2 expression and
every 3 (Q3W) or 4 weeks (Q4W) for ~18 months, followed function. These findings were corroborated in immortalized T-
up to an additional 21 months. Local AR (temporally associ- cells from the patients. We demonstrated that, like in IL-
ated and/or causally related adverse events) rates were evalu- 12Rβ1 deficient patients, IL-12Rβ2 patient PBMCs did not
ated over time. respond to BCG and IL-12 by inducing IFN-γ. Contrary to
Results: Of the 63 enrolled pts aged ≥16 (16–78) years, 61 IL-12Rβ1 deficient patients, their response to IL-23 was in-
were administered IGHy for up to ~3.5 years at the established tact. Additionally we observed an impaired production of Th1
dose. The local AR rate per infusion was 0.191; discomfort/ cytokines in CD4 memory T-cells from both IL-12Rβ1-
pain was the most commonly reported local AR. Rates of ARs deficient and IL-12Rβ2-deficient patient. Th17 cytokine pro-
per infusion decreased over time: 0.28 (months 1–12), 0.15 duction was also decreased in IL-12Rβ1 CD4 memory T-
(months 13–24), and 0.08 (months 25–33.6). The percentage cells, but was normal in IL-12Rβ2-deficient CD4 T cells.
of pts experiencing ≥1 local AR per infusion was highest These data suggest that autosomal recessive IL-12Rβ2 defi-
during the dose ramp-up period (33.3–41.7 % [Q3W] and ciency is a novel genetic etiology of MSMD and tuberculosis,
29.2–37.5 % [QW4]), and rapidly declined over time. due to impaired IL-12-dependent induction of IFN-γ.
Conclusions: In adults treated with IGHy for up to ~3.5 years,
rates of local ARs per infusion and the percentage of pts
experiencing ≥1 local AR markedly declined over time. 4457: CHARACTERIZATION
OF ANTICYTOKINE AUTOANTIBODIES
IN INTRAVENOUS IMMUNOGLOBULIN (IVIG)
4456: INHERITED IL-12Rβ2 DEFICIENCY PREPARATIONS
CAUSES MYCOBACTERIAL SUSCEPTIBILITY
Lindsey B. Rosen, BS1, Rebecca M. Glowinski1, Melvin
1 2
Ruben Martinez-Barricarte , Caner Aytekin , Janet Berger, MD, PhD2, Sarah K. Browne, MD3 and Steven M.
Markle1, Xiao-Fei Kong1, Bernhard Fleckenstein3, Stuart G. Holland, MD1
Tangye4, Esther van de Vosse5, Stephanie Boisson-Dupuis1,
Jacinta Bustamante6,7 and Jean-Laurent Casanova1,6,7,8 1
Laboratory of Clinical Infectious Diseases, NIAID/NIH,
Bethesda, MD,
1 2
St. Giles Laboratory of Human Genetics of Infectious Immunology R&D, CSL Behring LLC, King of Prussia, PA,
Diseases, The Rockefeller University, New York City, NY, USA, King of Prussia, PA,
2 3
Department of Pediatric Immunology, Dr. Sami Ulus Food and Drug Administration, Silver Spring, MD
Maternity and Children’s Health and Diseases Training and
Research Hospital, Ankara, Turkey, Background: Intravenous Immunoglobulin (IVIg) has been
3
Institute for Clinical and Molecular Virology, University used extensively for its immunomodulatory effects, although
Erlangen-Nuremberg, Germany, the mechanisms by which it confers benefit are still largely
4
Immunology Division, Garvan Institute of Medical unknown. It has been suggested that the presence of antibod-
Research, Sydney, Australia, ies against cytokines may contribute to IVIg’s effectiveness in
5
Leiden University Medical Center, Leiden, Netherlands, the management of certain inflammatory and autoimmune
6
Laboratory of Human Genetics of Infectious Diseases, diseases by selected cytokine neutralization.
Necker Branch, INSERM U1163, Necker Hospital for Sick Methods: Three lots of a commercially available pooled IVIg
Children, INSERM, Paris, France, product (Privigen®, CSL Behring) were screened for antibod-
7
Paris Descartes University, Imagine Institute, Paris, France, ies against cytokines using a particle-based approach.
8
Howard Hughes Medical Institute Autoantibody function was assessed by direct neutralization
of cytokines using Luminex-based cytokine determination as-
Mendelian susceptibility to mycobacterial disease (MSMD) is says or by assessing downstream signaling molecules in nor-
a rare syndrome causing severe infection by non-pathogenic mal peripheral blood mononuclear cells (PBMC) in the pres-
mycobacteria in otherwise healthy individuals. Autosomal re- ence of IVIg by flow cytometry.
cessive complete IL-12Rβ1 deficiency is the most frequent Results: Binding activity of IVIg against various cytokines
cause of MSMD and abolishes cellular responses to IL-12 was low in diluted IVIg stocks. Physiologic levels of IVIg
and IL-23. We have identified three homozygous carriers of (1000 mg/dL) did not block cytokine activity in vitro.
J Clin Immunol (2016) 36:235–334 271

Conclusions: Anticytokine autoantibodies are present at low 4459: ALTERED INVARIANT NKT:B CELL
levels in IVIg preparations, but lack neutralizing activity. HELP AND DECREASED SAP EXPRESSION IN
Anticytokine autoantibodies are unlikely to contribute to BLOOD LYMPHOCYTES FROM PATIENTS
IVIg’s immunomodulatory effects. WITH COMMON VARIABLE
IMMUNODEFICIENCY

4458: EFFICACY, SAFETY, TOLERABILITY, Lucia Erazo Borras, MSc1, Jesus Alvarez Alvarez, MSc1,
AND PHARMACOKINETICS OF HUMAN Camilo Perez Romero1, Julio C Orrego, MD. MSc2, Jose Luis
IMMUNE GLOBULIN SUBCUTANEOUS, 20 % Franco Restrepo, MD. MSc PhD1 and Claudia Trujillo
(IGSC 20 %): FINAL ANALYSIS OF A PHASE 2/3 Vargas, MSc, PhD1
STUDY IN PATIENTS WITH PRIMARY
1
IMMUNODEFICIENCY DISEASE (PIDD) IN Group of Primary Immunodeficiencies, University of
NORTH AMERICA Antioquia, Medellin, Colombia,
2
Group of Primary Immunodeficiencies, University of
Daniel Suez1, Isaac Melamed, Iftikhar Hussain, Mark Stein, Antioquia, Medellín, Colombia
Sudhir Gupta, MD, PhD, MACP3, Kenneth Paris, Sandor
Fritsch, Christelle Bourgeois, Heinz Leibl, Barbara McCoy Common Variable Immunodeficiency (CVID) is a syndrome
and Leman Yel, MD4 with predominantly defective B cell function. However, abnor-
malities in number and function of other lymphocyte subpopu-
1
Allergy, Asthma & Immunology Clinic, Irving, TX, lations in peripheral blood (PB) have been described in most
2
University of California, Irvine, Irvine, CA, patients. We have analyzed the distribution of iNKT cell subpop-
3
Clinical Science, Immunology, Baxalta US Inc, Cambridge, ulations in PB from CVID patients and their ability to provide in
MA vitro cognate B cell help. Reduced total, CD4+ and remarkably,
double negative together with those CCR5+/CXCR3+ iNKT
Rationale: We report final results from a study of IGSC 20 % cells were observed in PB from CVID. These findings were
in patients (pts) aged ≥2 years with PIDD. associated with an enrichment of memory-like and the reduction
Methods: Epoch 1 (13 weeks): intravenous IG 10 % of IFN-g- and TNF-a-expressing effector iNKT cells in PBMC
(IGIV) at prestudy doses/3–4 weeks (Q3W/Q4W). from CVID patients. Moreover, aGalCer-pulsed iNKT cells
Epochs 2–4: IGSC 20 %/weekly (Epoch 2 [~12–16 weeks], from CVID patients are not able to induce autologous B cell
145 % of the weekly equivalent Epoch 1 dose; Epoch 3 proliferation although this function is normal in presence of
[12 weeks] dose adjusted per AUC in Epochs 1–2; Epoch 4 healthy donor B cells. Also, autologous and heterologous co-
[40 week], dose adapted individually per Epoch 3 IG cultures did not differ in the amount of immunoglobulin secreted
trough levels). Primary endpoint = validated acute serious by B cells in vitro. Interestingly, reduced intracellular SAP ex-
bacterial infection (VASBI) rate. pression in iNKT cells and other lymphocytes, together with an
Results: In total, 74 pts aged 3–83 years received IGSC accumulation of follicular helper iNKT cells in PB from CVID
20 %; 67 completed. No pt discontinued IGSC 20 % due patients was observed. These results provide further insights into
to a serious adverse event (SAE) or adverse reaction (AR). the immunological mechanisms underlying the iNKT cell defect
One VASBI was reported (rate = 0.012/year; P < 0.0001); and the potential targets to improve B cell help in CVID.
the all-infection rate was 2.41/pt-yr. All local ARs
(rate = 0.022/infusion [INF]) were mild (92.5 %) or moder-
ate (7.5 %). In 4327 IGSC 20 % INFs, the median INF rate 4460: REAL-WORLD USE OF RECOMBINANT
was 60 mL/h/site (median INF time <1 h). A 30–59-mL HUMAN HYALURONIDASE-FACILITATED
volume per site was used in 67.4 % of INFs; 7.4 % INFs SUBCUTANEOUS (SC) INFUSION OF
employed a ≥60 mL volume per site without tolerability IMMUNOGLOBULIN G (IG) (IGHY; HYQVIA)
issues. Overall, 84.9 % of INFs were administered into ≤2 IN PATIENTS (PTS) WITH PRIMARY
INF sites; 99.8 % of INFs were completed without admin- IMMUNODEFICIENCY DISORDERS (PIDD)
istration changes. Ratio of geometric means of AUC/week
for IGSC 20 % treatment over IGIV 10 % was 109 % Kevin P. Rosenbach, Stephanie M. Hughes and Leon Rozen
(90 % CI = 103.94–113.36).
Conclusion: With IGSC 20 % treatment, VASBI and CareOne HealthCare, Naples, FL
infection rates were low, and INFs—most administered
into ≤2 sites—were well-tolerated at relatively high INF Rationale: Data from a single-practice cohort was analyzed to
rates. understand IGHy treatment adoption in pts with PIDD.
272 J Clin Immunol (2016) 36:235–334

Methods: A chart review of pts who initiated IGHy, or trough levels in all pts (age ≥2y). Simulations generated IgG
switched from intravenous IG (IGIV) or conventional IGSC levels vs time profiles (median; 90 % prediction intervals)
to IGHy. representing 100 pts—each weighed 60 kg and received 1:1
Results: Between October 2014 and July 2015, 19 pts monthly equivalent doses (MED) of 500 mg/kg (mean dose in
(aged 32–74 years; 86 % female) began IGHy. IG replace- phase 3 studies). For IG-naive pts, an endogenous baseline
ment before switching included IGIV (n = 2), IGSC level of 4 g/L was assumed. Simulations were conducted for
(n = 15), or none (n = 2). Reasons for switching from IGIV (every 28 days) and IGHy dose ramp-up (1/4 MED [wk
IGIV were poor venous access (n = 1) and desire to self- 1], 1/2 MED [wk 2], 3/4 MED [wk 4], full MED [wk 7], and
infuse (n = 1), and from IGSC were desire for less fre- then every 28 days.
quent infusions (n = 11), less needle sticks (n = 2), system- Results: A 1-compartment model with allometrically scaled
ic adverse reactions (ARs) (n = 1), and non-adherence weight as a covariate on clearance and volume was developed
(n = 1). Five pts (among the first 9 treated with IGHy), with 1975 IGHy and 680 IGIV samples from 81 pts. Time to
switched back to IGIV (poor training experience [n = 1]) reach 90 % of predicted SS IgG trough levels was 16 weeks
or IGSC (local AR [n = 1]; infusion site discomfort [n = 1]; for IGIV and 18 weeks for IGHy. Simulated median IgG
preferred lower volume with weekly IG [n = 2];). 3 of 4 trough levels were >7 g/L by end of ramp-up with IGHy
pts who experienced IGHy as their first IGSC remain on (10 week post-initiation).
treatment. As the multidisciplinary care team (MCT) Conclusion: In IG-naïve pts, therapeutic IgG trough levels
gained expertise with IGHy, pt experience improved and were reached at end of ramp-up with IGHy. Time to reach
pts opted to continue IGHy. Key learnings included pro- SS IgG trough levels with IGHy was similar to IGIV.
viding details on post-infusion site appearance, choosing
proper needle length, and the option of adding a second
infusion site. 4462: INFLUENCE OF BAFF/BAFF-R AXIS
Conclusions: In this real-world cohort, as the MCT gained UPON COMMON VARIABLE
experience with IGHy, pt retention improved. These data IMMUNODEFICIENCY INTERSTITIAL LUNG
highlight the importance of an individualized pt infusion ex- DISEASE
perience with IGHy.
Paul J. Maglione, MD, PhD1, Emily Gotschlich, MD2, Lin
Radigan, BMed1, Montserrat Cols, PhD2, Huaibin M Ko,
4461: POPULATION PHARMACOKINETIC MD3, Andrea Cerutti, MD, PhD2 and Charlotte
(POPPK) SIMULATIONS TO ADDRESS TIME Cunningham-Rundles, MD, PhD1
TO REACH STEADY STATE OF
1
RECOMBINANT HUMAN Division of Clinical Immunology, Department of Medicine,
HYALURONIDASE-FACILITATED Icahn School of Medicine at Mount Sinai, New York, NY,
2
SUBCUTANEOUS INFUSION OF Division of Clinical Immunology, Icahn School of Medicine
IMMUNOGLOBULIN (IG) (IGHY) IN IG-NAÏVE at Mount Sinai, New York, NY,
3
PATIENTS WITH PRIMARY Department of Pathology, Icahn School of Medicine at
IMMUNODEFICIENCY DISEASES (PIDD) Mount Sinai, New York, NY

Todd Dumas 1, Robert Numerof, Vadryn Pierre, David Common variable immunodeficiency (CVID) is often
Gelmont and Leman Yel, MD3 complicated by interstitial lung disease (ILD) which can
worsen morbidity and mortality. While the mechanisms
1
Overland Park, KS, driving CVID ILD are not known, lung pathology is char-
2
Clinical Science, Immunology, Baxalta US Inc, Cambridge, acterized by profound lymphoid hyperplasia. As CVID pa-
MA tients have elevated B cell activating factor (BAFF) and
transgenic overexpression of BAFF causes lymphoid hy-
Rationale: A popPK model for IGHy (fSCIG) was developed perplasia in mice, we looked for evidence of BAFF expres-
based on data from 2 phase 3 PIDD studies. Model-based sion and signaling in CVID ILD. Our institutional review
simulations determined when therapeutic and steady state board approved study combined laboratory and pulmonary
(SS) IgG trough levels would be reached with IGHy in IG- function tests with measurements of cytokines in cell cul-
naïve patients (pts) with PIDD. ture and serum as well as immunofluorescence of lung
Methods: Simultaneous modeling of IgG levels after intrave- biopsies. Worsening lung function coincided with greater
nous IG (IGIV) and IGHy administration was based on serial pulmonary lymphoid hyperplasia and higher levels of IgM
sampling data for PK profiling in pts aged ≥12y and IgG production in the lung. Rituximab monotherapy transiently
J Clin Immunol (2016) 36:235–334 273

improved pulmonary function and CT evidence of ILD in 4464: RITUXIMAB AND

conjunction with reduction of IgM. While both APRIL and HYPOGAMMAGLOBULINEMIA—
BAFF are elevated in CVID, only BAFF-R was highly COMPARATIVE OUTCOMES AT
expressed in CVID ILD and localized within ectopic pul- MASSACHUSETTS GENERAL HOSPITAL
monary follicles where there was high Bcl-2 expression—
an anti-apoptotic mediator downstream of BAFF-R. BAFF Sara Barmettler, MD1, Jocelyn Farmer, MD, PhD1, Hyon
was predominantly produced by innate immune cells in Choi, MD, Dr. P.H.2 and Jolan Walter, MD, PhD3
CVID, including monocytes and neutrophils in the lungs.
1
These results suggest a role of BAFF in driving pulmonary Department of Allergy & Immunology, Massachusetts
lymphoid hyperplasia in CVID through the anti-apoptotic General Hospital, Boston, MA,
2
functions of BAFF-R. Department of Rheumatology, Massachusetts General
Hospital, Boston, MA,
3
Department of Pediatrics, Division of Allergy &
4463: PROTECTIVE LEVELS Immunology, Massachusetts General Hospital, Boston, MA
OF NEUTRALIZING ANTIBODIES
TO INFLUENZA ARE PRESENT IN AN IVIG Rituximab is a monoclonal antibody used in the treatment of B-
(RI-002) PREPARED WITH STANDARDIZED cell malignancies and autoimmune diseases. There are several
AND ELEVATED LEVELS OF NEUTRALIZING small case series describing hypogammaglobulinemia in patients
ANTIBODIES TO RSV receiving rituximab, with a subgroup of patients with recurrent
infectious complications prompting Ig replacement therapy
James Mond1, Terrence Tumpey, PhD2 and Lucy DeMario, (IgR). We conducted a retrospective review of patients who re-
PhD3 ceived rituximab at Massachusetts General Hospital. We identi-
fied a total of 6108 patients (median age = 65; 51 % male) who
1
ADMA Biologics, Ramsey, NJ, (2)CDC, Atlanta, GA, received rituximab between 1997 and 2015. Of these patients,
3
ADMA Biologics, Inc., Ramsey, NJ 893 (14.6 %) carried a co-diagnosis of hypogammaglobulinemia.
We compared outcomes of patients who received rituximab with
Introduction: Patients with primary immune deficiency dis- or without a co-diagnosis of hypogammaglobulinemia. We iden-
ease (PIDD) are poorly responsive to influenza vaccines. RI- tified an increase in all adverse outcomes queried in the
002 contains elevated and standardized levels of neutralizing hypogammoglobulinemia subgroup as compared to the total ri-
anti RSV antibodies and elevated levels of binding antibodies tuximab treated population, including incidence of sinusitis (10.6
to other respiratory viruses. vs. 7.0 %), bronchitis (11.4 vs. 7.6 %), pneumonia (63.5 vs.
Purpose: To measure the neutralizing activity present in 6 43.6 %), and sepsis (26.5 vs. 16.6 %). Among the
different manufactured lots of RI-002 to different strains of hypogammaglobulinemia subgroup, we identified 27.9 % who
influenza virus. had been prescribed IgR. To our knowledge, this is the largest
Methods: Hemagglutination Inhibition (HAI) assays were review evaluating hypogammaglobulinemia and rituximab treat-
performed in V-bottom 96-well plates using four ment to date. Future directions will explore B cell screening in
hemagglutinating units (HAU) of virus using currently circu- the rituximab treated population, effects of early initiation of IgR
lating influenza A and B viruses. on adverse outcomes, and cause of mortality in these patients.
Results: HAI titers to the different strains of influenza
ranged from 1:160 to 1:1280 with consistency observed
between 6 different manufactured lots of RI-002. Data de- 4466: PERSISTENT, DISSEMINATED
rived from studying the dilutional effect observed in the BORDETELLA HINZII INFECTION IN A
concentration of neutralizing anti RSV antibody when RI- PATIENT WITH INTERLEUKIN-12 RECEPTOR
002 was infused into patients with PIDD suggests that ad- BETA 1 DEFICIENCY
ministration of this product could achieve protective levels
of anti -influenza antibodies when given to patients with
PIDD. Katherine E Clarridge, MD, MSc1, Julie E Niemela, MS,
Conclusions: RI-002 contains standardized, elevated levels of MLS2, Amy P. Hsu, BA3, Christa S. Zerbe, MD3, Sergio
neutralizing antibodies to RSV and elevated levels of neutral- Rosenzweig, MD, PhD3, Dawn Shaw, RN, MBA, MN4 and
izing antibodies to influenza virus with quantities of influenza Steven Holland, MD3
antibodies which may confer protection. RI-002 may provide
1
a useful adjunct to currently available therapies for the PIDD National Institute of Allergy and Infectious Diseases,
population. National Institutes of Health, MD
274 J Clin Immunol (2016) 36:235–334

2 4
Department of Laboratory Medicine, CC/NIH, Bethesda, Pathology Unit, Department of Molecular and Translational
MD Medicine, University of Brescia, Brescia, Italy
3
National Institute of Allergy and Infectious Diseases,
National Institutes of Health Leucine-rich repeat (LRR) containing 8A (LRRC8A) is a
4
Clinical Monitoring Research Program/Frederick National ubiquitously expressed transmembrane protein that con-
Laboratory, Leidos Biomedical Research, INC support to tains 17 LRRs at its C-terminal end. LRRC8A is an
NIAID/LCID, Bethesda, MD essential component of the volume regulated anion chan-
nel (VRAC), and its LRR-containing region is essential
Patients with defects in the IFN-g/IL-12/IL-23 axis, often re- for VRAC activity. A female with agammaglobulinemia
ferred to as Mendelian susceptibility to mycobacterial disease and absent B cells was found to have a heterozygous
(MSMD) are susceptible to nontuberculous mycobacterial and translocation t(9;20)(q33.2;q12) that led to truncation of
salmonella infections, as well as some viruses and fungi. We the two terminal LRRs of LRRC8A. We previously re-
report a unique case of persistent, disseminated Bordetella ported that Lrrc8a−/− mice have a SCID phenotype with
hinzii bacteremia, colitis, and osteomyelitis associated with severely defective T cell development and function, as
complete IL-12Rβ1 deficiency. well as increased prenatal and postnatal mortality, curly
A 20 year-old man was seen for 2 years of chronic diarrhea. hair, multiple tissue abnormalities, infertility, and growth
Colonoscopy and histology showed ulceration with abun- retardation. We now demonstrate that the spontaneous
dant intracellular Gram negative rods; blood cultures con- mouse mutant ébouriffé (ebo/ebo), which displays curly
firmed B. hinzii. Nexgen and sequencing of IL12RB1 hair and infertility, harbors a homozygous 2 bp frame-
showed homozygous IL12RB1 c.94C>T, p.Q32X, Sanger shift mutation in exon 3 of Lrrc8a. This mutation leads
confirmed. Flow cytometry for signal transducer and acti- to truncation of the 15 terminal LRRs of LRRC8A and
vator of transcription 4 (STAT4) activation showed no markedly reduced VRAC activity in T cells. In addition
phosphorylation after IL-12 stimulation. Interferon gamma to curly hair and infertility, ebo/ebo mice have reduced
(IFNγ) therapy led to mild fevers and modest clinical im- longevity and abnormal liver and salivary gland duct
provement, but bacteremia persists. This is the first case of histology, but intact T cell development and function.
persistent B. hinzii bacteremia and colitis in IL-12Rβ1 de- These results suggest that the 15 terminal LRRs of
ficiency. It joins other cases of intracellular Burkholderia LRRC8A are important for VRAC activity, normal hair
associated with defects in the IL-12 pathway, suggesting a development and fertility, but dispensable for T cell de-
previously unappreciated role for IL-12 signaling in intra- velopment and function.
cellular Gram negative rod clearance.

4472: PATTERNS OF CYTOKINE

4467: A PATHOGENEIC HYPOMORPHIC ABNORMALITIES IN IMMUNE-RELATED
MUTATION IN LRRC8A IMPAIRS VOLUME DISEASES: A RETROSPECTIVE CHART
REGULATED ANION CHANNEL ACTIVITY REVIEW
BUT SPARES T CELL DEVELOPMENT AND
FUNCTION
Amanda V Grippen Goddard, DO1 and Zuhair K Ballas,
MD2
Craig D. Platt, MD, PhD1, Janet Chou, MD1, Lalit Kumar,
PhD1, Wayne Bainter, BS1, Patrick Houlihan, PhD2, Carlos J. 1
Internal Medicine, University of Iowa Hospitals and Clinics,
Perez, DVM, PhD3, P. Luigi Poliani, MD, PhD4, David E. Iowa City, IA,
Clapham, MD, PhD2, Fernando Benavides, DVM, PhD3 and 2
Allergy and Immunology, University of Iowa Hospitals and
Raif S. Geha, MD1 Clinics, Iowa City, IA

1
Immunology Division, Department of Pediatrics, Boston Purpose: Identifying cytokine abnormalities associated with
Children’s Hospital, Harvard Medical School, Boston, MA, particular diseases might allow specific targeting by biological
2
Howard Hughes Medical Institute, Department of response modifiers.
Cardiology, Department of Neurobiology, Boston Children’s Methods: A single center, retrospective chart review of pa-
Hospital, Harvard Medical School, Boston, MA, tients who had a serum cytokine panel tested.
3
Department of Epigenetics and Molecular Carcinogenesis, Results: 87 patients were identified. Certain diseases were
University of Texas MD Anderson Cancer Center, associated with elevations in specific cytokines (Table 1).
Smithville, TX, However, a different pattern emerged when clusters of,
J Clin Immunol (2016) 36:235–334 275

rather than single cytokines, were evaluated. Elevations in sequencing of other alleles revealed a splicing mutation in a
cytokines of innate immunity (IL-1β and TNFα) were as- gene encoding strawberry notch homologue 2 (SBNO2),
sociated with autoimmune disorders (p = 0.04). TH2 cyto- which belongs to a novel member of the Notch family of
kines (IL-4, IL-5 and IL-13) were associated with primary transcriptional repressors. The loss-of-function mutation in
immunodeficiency (p = 0.05) and ocular disease (p = 0.03). the patient was confirmed by western blotting. Overexpression
TH1 cytokines (IL-12 and IFNγ) were associated with vi- of this gene showed nuclear translocation, suggesting a function
ral infection (p < 0.01). IL-2, IL-6, IL-8, IL-10, IL-13 and in transcription regulation. An anti-inflammatory effect was pre-
TNFα each had a significant association with mortality. viously reported through repression of inflammatory gene tran-
Conclusion: An unexpected pattern of disease association scription. However, we did not observe any difference in tran-
with cytokines and cytokine clusters has emerged suggesting scriptional profiles between monocytes from the patient as com-
that this approach might be useful in therapeutic targeting and pared to normal controls. qRT-PCR showed that SBNO2 was
in understanding pathogenesis of disease. highly expressed in myeloid lineages. Ongoing work will ad-
dress if SBNO2 affects gene expression in neutrophils.
Identification of potential gene targets will help us understand
Table 1.
the function of this gene and potentially explain the disease
Autoimmunity Bacterial HLH Malignancy MODS SIRS Viral
Infection Infection pathogenesis in the patient.
IL-1 beta X
IL-2 X X
IL-2 receptor X X X X X
4477: LONG-TERM IMMUNE
IL-4 X
IL-5 X
RECONSTITUTION POST-HEMATOPOIETIC
IL-6 X X X X X
STEM CELL TRANSPLANTATION IN
IL-8 X X X X X IL2RG/JAK3 SCID, NEWCASTLE EXPERIENCE
IL-10 X X X X X
IL-12 X X
IL-13 X X X
Intan Juliana Abd Hamid1,2, Mary Slatter3, Mark S. Pearce4
IFN gamma X X X X
and Andrew R. Gennery5
TNF alpha X X X X
BX^ indicates statistically significant association (p-value <0.05).
1
Institute of Cellular Medicine, Newcastle University,
Newcastle upon Tyne, United Kingdom of Great Britain and
Northern Ireland,
2
4473: NOVEL IMMUNODYSREGULATION Regenerative Medicine Cluster, Institut Perubatan &
DISORDER CAUSED BY LOSS-OF-FUNCTION Pergigian Termaju, USM, Kepala Batas, Malaysia,
3
MUTATIONS IN SBNO2 Department of Paediatric Immunology, Newcastle upon
Tyne Hospital NHS Foundation Trust, UK,
4
Institute of Health & Society, Newcastle University,
Huie Jing1, Christopher Dove, BS1, Yu Zhang, PhD1, Susan Newcastle, United Kingdom of Great Britain and Northern
Price2, Rao Koneti, MD2 and Helen C. Su1 Ireland,
5
Department of Paediatric Immunology, Newcastle upon
1
Laboratory of Host Defenses, National Institute of Tyne Hospitals, Newcastle upon Tyne, UK, United Kingdom
Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD, Introduction: HSCT cures SCID. We examined effect of donor
2
Laboratory of Clinical Infectious Diseases, National chimerism on immunity for IL2RG/JAK3 SCID post-HSCT.
Institute of Allergy and Infectious Diseases, NIH, Methods: A study of 31/43 surviving patients, transplanted
Bethesda, MD 1987–2012. Conditioning regimens were reduced intensity
(RIC - Flu/Mel), low toxicity myeloablative (LTMAC -
We studied an 8-year-old girl who had a history of transfusion- Treo/Flu or Treo/Cyclophos) and myeloablative (MAC - Bu/
dependent anemia, thrombocytopenia, leukocytosis, spleno- Cyclophos). CD3+CD4+45RA+ was used as post-HSCT thy-
megaly, severe pneumonias, and multiple episodes of respira- mic output indicator. Results: 71.9 % 10-year survival.
tory failure. Vaccine titers waned over time and hypogamma- Median age at last follow up-10 years, range 2–25. >95 %
globulinemia developed. To identify a genetic cause respon- donor T cell chimerism observed for all patients. B cell and
sible for immune dysregulation, we performed comparative myeloid donor chimerism was best following LTMAC or
genomic hybridization array, which revealed a 120 kB hetero- MAC with matched related (MRD) or matched unrelated do-
zygous deletion on chromosome 19. Targeted gene nor (MURD) compared to unconditioned or matched sibling
276 J Clin Immunol (2016) 36:235–334

donor (MSD) recipients. Most haploidentical recipients have Koneti, MD4, David Parenti, MD7, Virginia Sheikh, MD1 and
50 % donor, 6 B/myeloid chimerism Irini Sereti, MD1

1
Laboratory of Immunoregulation, National Institute of
4478: B CELL HOMEOSTASIS IS ALTERED IN Allergy and Infectious Diseases, NIH, Bethesda, MD,
2
ALPS PATIENTS WITH PERIPHERAL Department of Laboratory Medicine, NIH, Bethesda, MD,
3
EOSINOPHILIA Immunology Service, Department of Laboratory Medicine,
National Institutes of Health, Bethesda, MD,
Natalia S Chaimowitz, MD, PhD1, Jack J. Bleesing, MD, 4
Laboratory of Clinical Infectious Diseases, National Institute
PhD2 and Patricia C Fulkerson, MD, PhD3 of Allergy and Infectious Diseases, NIH, Bethesda, MD,
5
Program in Physical Biology, Eunice Kennedy-Shriver
1
Department of Pediatrics, Cincinnati Children’s Hospital National Institute of Child Health and Human Development,
Medical Center, Cincinnati, OH, Bethesda, MD,
2 6
Division of Bone Marrow Transplantation and Immune Laboratory of Immunology, National Institute of Allergy and
Deficiency, Cincinnati Children’s Hospital Medical Center, Infectious Diseases, NIH, Bethesda, MD,
7
Cincinnati, OH, Division of Infectious Diseases, George Washington
3
Allergy & Immunology, Cincinnati Children’s Hospital University Medical Center,, Washington, DC
Medical Center, Cincinnati, OH
Background: Idiopathic CD4 T lymphopenia (ICL) is a het-
Autoimmune lymphoproliferative syndrome (ALPS) is a dis- erogeneous clinical syndrome defined by persistent CD4 lym-
order characterized by immune dysregulation secondary to phopenia in the absence of any other cause of immunodefi-
impaired lymphocyte apoptosis leading to lymphadenopathy, ciency. A comprehensive clinical and immunogenetic evalua-
hepatosplenomegaly, increased risk of lymphoma and autoim- tion of patients with presumed ICL can lead to the identifica-
mune diseases. Previous studies have demonstrated a correla- tion of new inborn errors of T cell development/homeostasis
tion between peripheral eosinophilia and increased mortality or atypical presentation of other primary immunodeficiencies.
rate in ALPS patients. While eosinophilia has traditionally Herein, we present a patient with CD4 lymphopenia, who was
been associated with parasitic infections and allergic disease, found to have autoimmune lymphoproliferative syndrome
recent studies suggest a broader role for eosinophils in health (ALPS) caused by a new mutation in the FAS gene.
and disease, including B cell homeostasis. In this study, we Case Presentation: A 33-year-old female developed a vesic-
sought to evaluate whether there was a relationship between ular rash after receiving a post-partum varicella vaccine.
peripheral eosinophilia and alterations in B cell development Persistent leucopenia led to an initial work-up, which revealed
in patients with ALPS by reviewing charts of ALPS patients selective IgA deficiency and CD4 lymphopenia (111–118
seen at Cincinnati Children’s Hospital. Most notably, the pro- cells/μL). Evidence of splenomegaly, adenopathy and an in-
portion of CD5-B220- and CD38-CD138- B cells were in- creased proportion of double negative αβ T cells (4.3 %)
creased, while the proportion of CD5+B220+ and CD27- prompted an immunogenetic evaluation. A novel missense
B220+ B cells were decreased in ALPS patients with eosino- mutation in the FAS death domain was found. Deficient
philia. There was also a trend for decreased incidence of cy- FAS-induced apoptosis and increased IL-10, IL-18 and solu-
topenias and increased incidence of atopic disease in ALPS ble FAS ligand were also documented.
patients with peripheral eosinophilia, despite comparable im- Conclusions: ALPS is characterized by impaired T cells apo-
munoglobulin levels. Our work suggests a role for eosinophils ptosis and autoimmune phenomena and is not commonly as-
in influencing B cell homeostasis in ALPS patients. sociated with CD4 lymphopenia. Further studies are warrant-
ed to investigate impaired homeostasis and/or autoimmune
depletion of CD4 T cells in patients with ALPS.
4480: PERSISTENT CD4 LYMPHOPENIA
LEADING TO A DIAGNOSIS OF AUTOIMMUNE
LYMPHOPROLIFERATIVE SYNDROME (ALPS) 4481: A CASE OF ATAXIA TELANGIECTASIA
CAUSED BY A NOVEL MUTATION IN THE FAS WITH IMMUNODEFICIENCY DUE TO A RARE
DEATH DOMAIN VRIANT

Andrea Lisco, MD, PhD1, Julie Niemela, PhD2, Jennifer L Lahari Rampur, MD and Jenny Shliozberg, MD
Stoddard, BS3, Sergio D. Rosenzweig, MD, PhD3, Amy P
Hsu, BA4, Susan Price4, JoAnn MIcan, MD1, Christophe Allergy and Immunology, Montefiore Medical Center, Bronx,
Vanpouille, PhD5, Bernice Lo, PhD6, Irina Maric, MD2, Rao NY
J Clin Immunol (2016) 36:235–334 277

Introduction: Ataxia Telangiectasia (AT), a rare genetic disor- autoimmunity. Laboratory: 66 % Hipergammaglobulinemia
der due to mutations in ATM gene with progressive neurolog- ( C D 2 5 , S TAT 1 , S TAT 5 b a n d S TAT 3 L O F ) a n d
ical defects, immunodeficiency and telangiectasia. Severity of hipogammaglobulinemia in STAT3 GOF. 33 % Hiper IgE (3
Immunodeficiency correlates with deleterious mutations such STAT3 LOF and 1 STAT5b), 50 % showed CD4+
as frameshift, nonsense and splicing or large gene deletions. Lymphopenia and, 10/10 impairment of B cells compartment
Cases of pathogenic single nucleotide defects causing AT and (low IgM memory, Low Post switched) CONCLUSION:
leading to immunodeficiency are rarely described. We de- High morbidity of this patients shows the complexity of these
scribe a case of AT due to a rare variant in the ATM gene. syndromes in which immune system and specific organs are
Case description: This patient initially presented as a 2 year severely compromised. These diseases show the importance
girl with failure to thrive, recurrent respiratory infections and of these molecules in the transcription of essential genes in
pneumococcal bacteremia. She was noted to have ocular tel- endocrine and immune system.
angiectasia and progressive gait and speech abnormalities.
Upon investigation she was found to have low B cell and
CD4 counts and profound humoral immune deficiency with 4490: A NOVEL PRIMARY
very low IgA and IgG and no response to pediatric vaccines. IMMUNODEFICIENCY ASSOCIATED WITH
She was started on IVIG with reductions in subsequent infec- EPSTEIN-BARR VIRUS SUCEPTIBILITY AND
tions. Genetic screening for common SCID defects was neg- ASSOCIATED B-CELL MALIGNANCIES
ative on exon array CGH/next generation sequencing. Alpha
fetoprotein was noted to be elevated. Sequencing of the ATM Benjamin E Gewurz 1, Boris Juelg2, Honghuang Lin3,
g e n e s h o w e d 2 v a r i a n t s i n AT M g e n e , c . 4 3 6 2 Cormack Cosgrove2, Michael Walsh 4, Lindsey Baden4,
A>C(p.Lys1454Asn) and c.7788G>C (p.Glu2596Asp) with Francisco Marty4 and Patrick Ellinor5
unknown significance but the latter is more likely a pathogen-
1
ic variant per evidence. Medicine, Infectious Disease, Brigham & Women’s Hospital,
Conclusion: We present a case of AT with early onset immu- Boston, MA,
2
nodeficiency with variants in ATM gene. Ragon Institute, Cambridge, MA,
3
Boston University, Boston, MA, (4)Brigham & Women’s

4489: JAK-STATS PATHWAYS DEFECTS: Hospital, Boston, MA, (5)Broad Institute, Cambridge, MA
CLINICAL FEATURES AND Epstein-Barr virus (EBV) is an oncogenic B cell-tropic
IMMUNOLOGICAL FINDINGS. herpesvirus that infects 95 % of adults worldwide. Innate
and adaptive immune responses control EBV infection, but
Maria Soledad Caldirola1, Analía Gisela Seminario, M.D.1, EBV colonizes and periodically reactivates from the mem-
María Esnaola Azcoiti1, Lorena Regairaz2, María Isabel ory B-cell compartment. Specific primary immunodefi-
Gaillard1 and Liliana Bezrodnik1 ciencies (PIDs), nearly all with autosomal or X-linked re-
cessive inheritance, cause the failure to control EBV infec-
1
Immunology Group, Ricardo Gutiérrez Children’s Hospital, tion and result in life-threatening disorders. The molecular
Buenos Aires, Argentina, basis of EBV susceptibility remains incompletely under-
2
Immunology, Sor Ludovica, La Plata, Argentina stood, and consequently, many patients with PID charac-
terized by EBV susceptibility do not have a molecular di-
INTRODUCTION: Genetic mutations in the Janus kinase agnosis. We identified a family with a PID manifest by
(JAK)-signal transducer of activators of transcription (STAT) EBV susceptibility. The proband has persistent active
pathway signaling are functionally relevant to a variety of EBV with markedly elevated blood viral loads. Her father
human diseases. Aim: Describe clinical features and immu- died at age 36 of an EBV+ B-cell lymphoma, despite ab-
nological findings of a cohort of 12 patients (pts) sence of known immunodeficiency. A brother of the pro-
MATERIAL AND METHODS: Retrospective study of band died at age 7 of an EBV+ Burkitt lymphoma. Whole
medical histories from: 1 CD25 deficiency, 4 STAT1 (GOF), exome sequencing did not reveal mutations in known EBV
3 STAT5b, 3 STAT3 (LOF) and 1 STAT3 (GOF) RESULTS: susceptibility genes, but has identified promising candidate
Clinical features: 83 % Skin manifestations (eczema, atopy, genes. In parallel, we identified T and NK-cell deficits that
urticaria), 40 % enteropathy, 58 % characteristic features may underlie the PID. Candidate genes are being tested by
(dismorphic features, short stature), 100 % infections of CRISPR/Cas9 mutagenesis. Our results will highlight key
which: 7/12 viral (especially severe varicella in STAT5b and immune processes that control EBV infection, and will
CD25), 9/12 fungal and 5/12 bacterial. 66 % of pts suffer from inform rational therapeutic and EBV vaccine development
chronic lung disease (CD25, STAT5b and STAT3) and 33 % efforts.
278 J Clin Immunol (2016) 36:235–334

4493: WHICH RESPIRATORY Deist, MD PhD2, Aspasia Karalis, MD1 and Elie Haddad,
MANIFESTATIONS MAKE US THINK OF MD PhD1
COMMON VARIABLE IMMUNODEFICIENCY?
1
Department of Pediatrics, CHU Sainte-Justine, University of
1 2
Nadezhda Camacho-Ordóñez , R Sotelo-Robledo , ML Montreal, Montreal, QC, Canada,
García-Cruz1, MD Mogica-Martinez3, M Nuñez-Velazquez3, 2
Department of Pediatrics, CHU Sainte-Justine, Montreal,
M Becerril-Angeles3 and LM Teran1 QC, Canada

1
Immunogenetics and Allergy, National Institute of Veno-occlusive disease with immunodeficiency (VODI) is an
Respiratory Diseases, Mexico City, Mexico, autosomal recessive disorder characterized by combined im-
2
Radiology, National Institute of Respiratory Diseases, munodeficiency (CID) and hepatic injury.
Mexico City, Mexico, We report a 14-year-old boy with a homozygous mutation of
3
Allergy and Immunology, Centro Medico Nacional BLa Sp110 which manifested as a CID phenotype. He was born
Raza^, IMSS, Mexico City, Mexico from consanguineous Lebanese parents with a familial history
of cystic fibrosis and is known to be a heterozygous carrier. He
Background. Recurrent pulmonary infections are often presented with recurrent and persistent lung infections since
the first warning sign of common variable immunodefi- his first years of life, which were complicated by multiple
ciency (CVID). The purpose of this study was to assess bronchiectasis despite being treated with IVIG. He first
the initial respiratory manifestations of Mexican patients underwent two right pulmonary lobectomies at age 6, follow-
with CVID. ed by removal of the third right lobe at 10 years of age because
Methods. Respiratory manifestations, chest-HRCT and of pulmonary hemorrhage. At age 11, he developed an atyp-
corresponding spirometry were evaluated in patients with ical seronegative autoimmune hepatitis with brutal hepato-
CVID between March 2012 and June 2015 at two refer- megaly, T lymphocytic infiltration, absence of plasma cells
ence centers in Mexico City. Chest-HRCT was evaluated and an extensive fibrosis.
by a radiologist and clinical information was obtained Immunologic workup showed a hypogammaglobulinemia
from the case records. with severe defect in memory B cell. The T cell compartment
Results. Diagnosis was confirmed in 22 patients (17 female, 5 was normal in terms of number and function. Genetic testing
male). Age at diagnosis ranged from 5 to 53 years. Delay in by WES showed a homozygous mutation in the Sp110 gene
diagnosis was 8.5 years. We found recurrent pneumonia in six (c.642delC, p.Ser215Alafs*15).
patients (27.2 %), infected bronchiectasis (18.2 %) and atypi- The diagnosis of VODI should be considered in all patients
cal pneumonia (18.2 %) in four, suggestive of intersticial lung with a severe clinical phenotype of combined immunodefi-
disease (13.7 %) and organizing pneumonia (13.7 %) in three ciency without evidence of T cell dysfunction, especially
and empyema (9 %) in two patients. On HRCT the when signs of hepatic lesions are present.
commonest finding was bronchiectasis that was observed in
16 patients (72.7 %). Spirometry was abnormal in 13 patients
(7 obstructive, 6 restricted). 4496: RECURRENT ATYPICAL MAS IN A
Conclusion. To reduce the morbidity associated with PATIENT WITH STILL’S DISEASE AND
CVID, it needs to be greater awareness of respiratory HETEROZYGOUS MUTATIONS IN BOTH
manifestations. It is essential to monitor lung function. STXBP2 AND UNC13D
Besides, HRCT play an important role in detecting, char-
acterizing and quantifying the kind and extent of lung Roxane Labrosse, MD 1, Guilhem Cros, MD1, Charles
damage. Morin, MD2, Isabel Fernandez, PhD1, Caroline Laverdière,
MD1, Françoise Le Deist, MD PhD3, Claire Saint-Cyr, MD1
and Elie Haddad, MD PhD1
4494: SEVERE RECURRENT LUNGS
1
INFECTIONS, HYPOGAMMAGLOBULINEMIA Department of Pediatrics, CHU Sainte-Justine, University of
AND ATYPICAL HEPATITIS IN A 14-YEAR-OLD Montreal, Montreal, QC, Canada,
2
BOY WITH A HOMOZYGOUS MUTATION OF Department of Pediatrics, CSSSC, Chicoutimi, QC, Canada,
3
Sp110 Department of Pediatrics, CHU Sainte-Justine, Montreal,
QC, Canada
Guilhem Cros, MD 1 , Roxane Labrosse, MD 1, Sophie
Laberge, MD1, Fernando Alvarez, MD1, Dorothée Bouron- Macrophage activation syndrome (MAS) is a severe compli-
DalSoglio, MD1, Isabel Fernandez, PhD1, Françoise Le cation of systemic juvenile idiopathic arthritis (sJIA).
J Clin Immunol (2016) 36:235–334 279

Heterozygous mutations in genes involved in cytolytic path- 2014 Feb;34(2)]. He had abdominal pain and S. aureus
way are increasingly reported with sJIA. sepsis. Both patients were given broad-spectrum antibi-
We report a 7-year-old boy with no familial history who was otics with vancomycin along with antifungal coverage. IR
diagnosed with sJIA at 4 years of age, with persisting fever guided aspiration of abscesses was done for microbiology.
and one episode of polyarthritis after a year of evolution. Surgery was precluded by location, size and risk of the
Despite successive treatments with methotrexate, etanercept, liver abscesses. Both patients were started on steroids
tocilizumab and anakinra, he continued to have flare ups of his (1 mg/kg/day initially for 1 month then slow taper) with
disease with MAS whenever the prednisone was decreased monthly CT scans to follow progress. Under this treatment
under 0,5 mg/kg. The episodes consisted of fever with for 1 month, both patients have clinically and biologically
hepatosplenomegaly, neutropenia, high ferritin and increased significantly improved; their liver abscesses have remained
activated T cells. His last two episodes occurred while under stable on CT scan. High dose steroids associated with an-
cyclosporine. He never presented any neurological tibiotics coverage may offer an alternative therapy when
involvement. surgery is precluded.
He has normal levels of immunoglobulins and number of T
cells, naive T cells, B cells, memory B cells and NK cells.
EBV serology and PCR were negative. The hair study and 4502: ICF SYNDROME REVEALED BY
the perforine expression was normal. NK degranulation was PNEUMOCYSTIS JIROVECII INFECTION
performed and was mildly decreased. A genetic panel was
performed and found a heterozygous mutation of STXBP2 Roxane Labrosse, MD1, Guilhem Cros, MD1, Pierre Teira,
and a heterozygous mutation of UNC13D. MD1, Isabel Fernandez, PhD1, Françoise Le Deist, MD PhD2,
This complex case could be considered as an atypical primary Anne-Marie Laberge, MD1 and Elie Haddad, MD PhD1
HLH, or as a sJIA-related MAS. These patients are challeng-
1
ing and treatment strategies could differ depending on which Department of Pediatrics, CHU Sainte-Justine, University of
diagnosis is considered. Montreal, Montreal, QC, Canada,
2
Department of Pediatrics, CHU Sainte-Justine, Montreal,
QC, Canada
4497: HIGH DOSE STEROID THERAPY
FOR LIVER ABSCESS IN PATIENTS WITH Immunodeficiency, centromeric instability and facial
CHRONIC GRANULOMATOUS DISEASE dysmorphism (ICF syndrome) is a rare autosomal recessive
(CGD). disease characterized by immunoglobulin deficiency.
We report a 12-month-old girl born from non-consanguineous
Yael Gernez, MD, PhD1, Tukisa D. Smith, MD, MS1, Angela parents with no familial history. She was born prema-
Tsuang, MD, MSc1, Paul J. Maglione, MD, PhD1, Steve M. turely with severe intrauterine growth retardation, partly
Holland, MD2 and Charlotte Cunningham-Rundles, MD, attributed to vascular insufficiency. She was hospitalized
PhD1 at 3 months of age for acute respiratory distress due to
pneumocystis jirovecii infection. She fully recovered un-
1
Division of Clinical Immunology, Department of Medicine, der Bactrim and Prednisone. Her neurocognitive devel-
Icahn School of Medicine at Mount Sinai, New York, NY, opment was moderately delayed. She also developed a
2
Laboratory of Clinical Infectious Diseases, NIAID/NIH, digestive intolerance with failure to thrive, which led to
Bethesda, MD the diagnosis of FPIES, with improving weight gain
under a strict diet. Patient is presently undergoing cord
Liver abscesses in CGD are difficult to treat. IR guided blood transplantation.
cultures are important, but liver abscesses in CGD are thick Immunologic workup showed agammaglobulinemia and dis-
and drainage is impractical. Surgery has been most often crete naive T cell lymphopenia. PHA proliferation was normal
done, but abscesses may be large, locations difficult and but OKT3 proliferation was slightly decreased.
these sites may not heal well. High dose steroids and in- Karyotype showed multibranched chromosomes and centro-
tensive antibiotic coverage may result in better outcomes. meric abnormalities of chromosomes 1,2,10 and 16. Gene
We report two cases of liver abscess in patients with X- sequencing was also done and found no mutations in
CGD. One is a 17-year-old male, with a history of peri- DNMT3B and ZBTB24 genes.
odontitis and neck abscesses, who had fever for 2 weeks. Although ICF syndrome is rarely complicated by
The second is a 27-year-old male, with previous liver ab- pneumocystis jirovecii infection,it should be considered espe-
scess at age 5, and more recently neck and leg abscesses cially in the context of normal T and B cell phenotyping,
with Phellinus tropicalis [Ramesh et al. J Clin Immunol. normal PHA proliferation and agammaglobulinemia.
280 J Clin Immunol (2016) 36:235–334

1
4503: REFRACTORY AUTO-IMMUNE UVEITIS Institute of Cellular Medicine, Newcastle University,
SUCCESSFULLY TREATED WITH SIROLIMUS Newcastle upon Tyne, United Kingdom of Great Britain and
AS AN AUTOIMMUNE MANIFESTATION OF A Northern Ireland,
2
HEMIZYGOUS FOXP3 MUTATION Regenerative Medicine Cluster, Institut Perubatan &
Pergigian Termaju, USM, Kepala Batas, Malaysia,
Guilhem Cros, MD 1 , Roxane Labrosse, MD 1 , Isabel 3
Department of Paediatric Immunology, Newcastle upon
Fernandez, PhD 1 , Françoise Le Deist, MD PhD 2 , Eric Tyne Hospital NHS Foundation Trust, UK,
Fortin, MD3 and Elie Haddad, MD PhD1 4
Institute of Health & Society, Newcastle University,
Newcastle, United Kingdom of Great Britain and Northern
1
Department of Pediatrics, CHU Sainte-Justine, University of Ireland,
5
Montreal, Montreal, QC, Canada, Department of Paediatric Immunology, Newcastle upon
2
Department of Pediatrics, CHU Sainte-Justine, Montreal, Tyne Hospitals, Newcastle upon Tyne, UK, United Kingdom
QC, Canada,
3
Department of Ophthalmology, Hôpital Maisonneuve- We explored long-term clinical outcome of SCID survivors in
Rosemont, Montreal, QC, Canada a single center cohort with a cross-sectional review of post-
HSCT SCID patients in the HSCT follow-up clinic. 88/120
IPEX (Immune dysregulation, Polyendocrinopathy, patients survived to latest follow up in 2015. Median follow
Enteropathy, X-linked) syndrome is characterized by systemic up 11.5 years, range 2–27. 65/88 (74 %) have on-going med-
autoimmunity, and is caused by hemizygous mutations in the ical issues, 41/88 (47 %) require on-going medication. 5 de-
FOXP3 gene. The clinical spectrum has been progressively veloped bronchiectasis [IL-7Ra (3) & IL2RG SCID (2)] and 1
extended to a less severe phenotype with atypical autoimmu- has chronic pulmonary disease (IL2RG SCID). All have nor-
nity and no clear genotype correlation. mal lung function except 1 IL-7Ra SCID with major restric-
We report a 16-year-old boy, with no family history, who tive deficit. 4 patients had autoimmune hypothyroidism, 5
presented with type 1 diabetes (T1D) at 5 months of autoimmune hemolytic anemia (2 resolved, 3 on-going). 23/
age. He was diagnosed with bilateral uveitis at age 6, 81 (28 %) have short stature (7 ADA, 4 IL2RG, 4 IL7Ra, 3
which was initially treated with topic corticosteroids, Artemis, 4 others & 1 RAG1 SCID- 12 received
methotrexate and azathioprine. Despite maximal treatment myeloablative & 8 low toxicity myeloablative conditioning).
including adalimumab, his uveitis was poorly controlled 11 patients have hearing loss (6 ADA SCID). 4 patients have
and was complicated by steroid-induced cataracts and lymphoedema [IL2RG SCID (3), JAK3 SCID (1)]. 12 patients
glaucoma. His clinical picture was free of other autoim- have cutaneous papillomavirus infection (5 IL2RG SCID, 2
mune manifestations. JAK3 SCID). 12/16 patients aged >12 years have started men-
Given the atypical severity of the uveitis, immunological test- ses and 38 (86 %) >13 years have achieved puberty. 9 patients
ing was performed and despite the normal expression of experienced neurocognitive problems. 64/88 (73 %)
FOXP3, genetic analysis was performed and found a hemizy- discontinued immunoglobulin replacement therapy (50 were
gous mutation of the FOXP3 gene (1040G>A, R347H) which conditioned pre-HSCT). Survival outcome is good, but a sig-
has previously been described with different phenotypes such nificant number experience on-going medical issues which
as severe enteropathy, eczema and AIHA. requires treatment and monitoring.
A treatment with sirolimus was initiated and a complete re-
mission was quickly obtained and steroid therapy could be
stopped. 4505: HUMAN PAPILLOMA VIRUS (HPV)
Patients with early-onset T1D combined with other autoim- PAPILLOMATOSIS IN A PATIENT WITH
mune manifestations should be tested for FOXP3 mutations as GRANULOMATOUS-LYMPHOCYTIC
it modifies the therapeutic strategies. INTERSTITIAL LUNG DISEASE (GL-ILD)
ASSOCIATED COMMON VARIABLE
IMMUNODEFICIENCY (CVID)
4504: A SINGLE CENTRE COHORT REPORT OF
LONG TERM CLINICAL OUTCOME OF Megan S Motosue, MD1, Stella Hartono2, Anja Roden2,
SEVERE COMBINED IMMUNODEFICIENCY William Holland2, Dale Ekbom2, Bibek Pannu2 and Avni Y.
FOLLOWING HAEMATOPOIETIC STEM CELL Joshi, MD, MSc3
TRANSPLANTATION.
1
Allergic Disease, Mayo Clinic, Rochester, MN,
1,2 3 4 2
Intan Juliana Abd Hamid , Mary Slatter , Mark S. Pearce Rochester, MN,
and Andrew R. Gennery5 3
Mayo Clinic, Rochester, MN
J Clin Immunol (2016) 36:235–334 281

Background: The underlying etiology of GL-ILD has the first trimester of pregnancy. Patient was followed
remained elusive. Human herpes virus 8 (HHV-8) has closely throughout her pregnancy and serum levels for
been reported to be associated with granulomatous- anti rHuPH20 antibody titers were collected periodically.
lymphocytic interstitial lung disease (GLILD) in the From her first infusion there on, patient experienced a
past,so, it is plausible that other viruses such as significant gradual and complete reduction in systemic
human papilloma virus (HPV) may be similarly side effects other than expected limited local swelling.
involved. Her infusion time was shortened to 2 h as compared to
Case Description: 59 years old female with recurrent 8 h infusion with other intravenous products. Patient gave
tracheal and vocal cord HPV 6 papillomatosis since age birth to a healthy full term boy whom we intend to follow
7 presented to our center. Immune work up was notable and evaluate for presence of anti rHuPH20 antibodies. In
for reduced IgG (171 mg/dL) and IgA (<1, mg/dL) with the event of a positive antibody titer we intend to follow
normal IgM. Total T, B and NK cell counts along with the child for the next few years.
NK cell cytotoxicity were normal with decreased class
switched memory B cells and poor vaccine responses.
Chest CT scan demonstrated micronodularity and 4508: COMPARISON OF MISSED SCHOOL
adenopathy with ground-glass changes. Lung biopsy DAYS AND HOSPITALIZATION RATE
demonstrated non-necrotizing granulomas and organiz- BETWEEN PRIMARY IMMUNODEFICIENCY
ing pneumonia with immunostaining showing scattered CHILDREN RECEIVING INTRAVENOUS VS.
CD3-positive T cells and CD20-positive B cells sugges- SUBCUTANEOUS IMMUNOGLOBULIN
tive of GLILD. HPV in situ hybridization (ISH) studies REPLACEMENT
were performed on the lung tissue to rule out HPV-
inducing GLILD and were negative for HPV- 6,11,16, Bob Geng, MD1, Peg Gruenemeier, RN2 and Carol Ernst,
18,31,33 and 51. RN2
Conclusion: Despite negative testing, this case highlights the
1
importance of appropriate infection screening in patients with Allergy & Immunology, University of California, San Diego,
GLILD associated CVID. It remains uncertain if infectious La Jolla, CA,
2
triggers truly contribute to the development of GL-ILD in BioRX
patients with CVID.
Steady state of serum IgG throughout dosing cycle in SCIG is
often suggested as potentially beneficial. Phenomenon of
4506: CASE REPORT OF SUBCUTANEOUS Bwear-off^ effect in IVIG may be related to declining level
HYQVIA TRATEMNT IN A CVID PREGNANT of serum IgG at end of cycle.
PATIENT Sixty-nine children receiving IG from one specialty pharmacy
were surveyed regarding hospitalizations and school days
Daniel Suez, MD, FAAAAI, Daniel Suez MD missed over 12 months period. 13 were receiving IVIG and
56 were receiving SCIG. The 1:4 ratio of IVIG to SCIG in this
Allergy, Asthma & Immunology Clinic PA, Associate Clinical study is representative of overall ratio of IG patients serviced
Professor, UT Southwestern Medical School at Dallas, Irving, by this pharmacy.
TX Among IVIG subjects, 54 % were female and mean age was
8 years. Among SCIG subjects, 38 % were female and mean
Human Recombinant Hyaluronidase (rHuPH20) is de- age was 7.3 years. 9 of 13 IVIG subjects were school aged,
rived from a sperm head protein. Clinical studies indicate and 40 of 56 SCIG subjects were school aged. There was 1
18 % of HyQvia treated subjects developed transient, non- child among 13 IVIG subjects vs. 3 among 56 SCIG subjects
neutralizing antibodies to rHuPH20. Due to the hypothet- who had hospitalization over 12 months period (p = 0.78).
ical related fertility issues and concerns raised by regula- Among school-aged children, average school missed was
tory authorities, pregnancies occurring during HyQvia 7.3 days in IVIG vs. 4.4 days in SCIG group (p = 0.45).
treatment are of interest. Benefits of HyQvia include Pharmacokinetic differences are recognized between IVIG
milder systemic side effects compared to intravenous and SCIG, but differences in clinical outcome have yet to be
forms of therapy (IVIG). We present here a 30 year old well elucidated. While this study showed that average number
female with Common Variable Immune Deficiency of missed school days trended higher in IVIG vs. SCIG group
(CVID) with sever prolonged systemic side effects fol- (7.3 vs. 4.4 days), it did not reach significance. Further con-
lowing IVIG treatments. Patient consented to the alterna- trolled prospective studies are warranted to explore potential
tive HyQvia therapy solution which was initiated during differences in outcome measures.
282 J Clin Immunol (2016) 36:235–334

1
4509: DEVELOPMENT AND VALIDATION OF A D i v i s i o n o f B o n e M a r r o w Tr a n s p l a n t a t i o n a n d
QUESTIONNAIRE TO MEASURE Immunodeficiency, Cincinnati Children’s Hospital Medical
HEALTH-RELATED QUALITY OF LIFE OF Center, Cincinnati, OH,
2
ADULTS WITH PRIMARY ANTIBODY Department of Pediatric Hematology and Oncology,
DEFICIENCIES: THE PADQOL Ospedale Pediatrico Bambino Gesu’, Roma, Italy,
3
QUESTIONNAIRE Texas Children’s Cancer and Hematology Centers, Texas
Children’s Hospital, Houston, TX,
Federica Pulvirenti 1 , Stefano Tabolli, MD 2 , Patrizia 4
Rheumatology Department, Ospedale Pediatrico Bambino
Giannantoni2, Joud Hajjar, MD3, Debra L Canter4, Cinzia Gesu’, Roma, Italy,
Milito1, Jordan S. Orange, MD, PhD3 and Isabella Quinti1 5
Division of Pediatric Rheumatology, Cincinnati Children’s
Hospital, Cincinnati, OH,
1 6
Dpt of Molecular medicine, Sapieza, University of Rome, Clinical Science, Novimmune sa, Plan-les-Ouates,
Rome, Italy, Switzerland,
2 7
Health Services Research Unit IDI, IRCCS, Rome, ESTM, Novimmune sa, Plan-les-Ouates, Switzerland,
3 8
Texas Children’s Hospital, Houston, TX, Clinical Development, Novimmune sa, Plan-les-Ouates,
4
Texas Children’s Hospital Switzerland

Background: Generic health status quality of life instruments Primary HLH (pHLH) is a rare disorder lethal if untreated.
have been used in Primary Antibody Deficiencies (PAD). High IFNγ production is considered pivotal in driving HLH.
However, by their nature, they may over-or under-estimate NI-0501 is a fully human anti-IFNγ mAb.
the true impact of diseases on individual’s quality of life (QoL). An open-label Phase 2 concentration controlled study was
Objective: To assess reliability and construct validity of a conducted in the US and Europe to evaluate NI-0501 treat-
specific-health-related QoL questionnaire for PAD adults. ment in pHLH children. NI-0501 was administered initially at
Methods: We developed the 32-items of PADQoL using fo- 1 mg/kg on a dexamethasone background. Treatment duration
cus groups and individual patients interviews. PADQoL was was 4 to 8 weeks.
validated in 131 PAD completing SF-36, SGRQ, GHQ-12 and Of the 16 patients enrolled (8F/8M, median age 1.2y), 14
EQ5D questionnaires. We evaluated construct validity by con- patients received NI-0501 in 2nd line, having failed conven-
firmatory factor analysis; test-retest reliability by Cronbach’s tional therapy or being intolerant to it, and 2 in 1st line. Twelve
alpha and Pearson’s correlation; convergent validity by patients had a known HLH mutation. Most patients had severe
Pearson’s correlations between similar dimensions of HLH and significant toxicities from previous HLH treatments.
PADQoL and existing QoL instruments; discriminant validity Of the 15 evaluable patients, 13 completed treatment. NI-0501
by comparing scores across groups of patients. significantly improved HLH parameters: 9 of 13 patients
Results: Factor analysis identified 3 dimensions: Emotional achieved a satisfactory response, 7 proceeded to HSCT, and
Functioning, Relational Functioning and Gastrointestinal 2 are awaiting transplant with good HLH control. Eleven pa-
Symptoms with good internal consistency (Cronbach’s al- tients were alive prior to HSCT. Four patients showed insuf-
pha > 0.78) and high test-retest reliability (r = 0.89). ficient response: 2 died of HLH/MOF, and 2 moved to HSCT.
PADQoL had good convergent validity correlating with con- Significant dexamethasone tapering occurred in 10/13 pa-
ceptually similar dimensions of SF-36 (PCS:0.59; MCS 0.45) tients. IFNγ neutralization was demonstrated by a sharp de-
and SGRQ (activity:0.65; impact:0.63), with GHQ-12 (0.64) crease in CXCL9, a chemokine exquisitely IFNγ-induced.
and EQ-5D VAS (0.66). NI-0501 was well tolerated and no safety concern was identi-
Conclusions: PADQoL is a reliable and valid instrument to fied, nor infection favored by IFNγ neutralization reported.
assess QoL in adult PAD. This study suggests NI-0501 to be a safe, effective option in
HLH.

4511: A NOVEL TARGETED APPROACH TO

THE TREATMENT OF HEMOPHAGOCYTIC 4512: CLINICAL PHENOTYPE OF BIALLELIC
LYMPHOHISTIOCYTOSIS (HLH) WITH AND MONOALLELIC TNFRSF13B VARIANTS
NI-0501, AN ANTI-INTERFERON GAMMA IN ITALIAN PRIMARY ANTIBODY
MONOCLONAL ANTIBODY DEFICIENCY SYNDROMES.

Michael B Jordan, MD1, Franco Locatelli2, Carl Allen3, Federica Pulvirenti1, Roberta Zuntini2, Cinzia Milito1,
Fabrizio De Benedetti4, Alexei Grom5, Maria Ballabio6, Fernando Specchia3, Giuseppe Spadaro4, Maria G Danieli5,
Walter Ferlin7, Cristina De Min8 and NI-0501-04 Study Group Andrea Pession3, Isabella Quinti1 and Simona Ferrari6
J Clin Immunol (2016) 36:235–334 283

1
Dpt of Molecular medicine, Sapieza, University of Rome, PhD17, Daniele Moratto18, Alessandro Plebani16, Jolan E.
Rome, Italy, Walter, MD PhD 1 9 , Silvia Parolini 2 0 and Luigi D
2
Dpt of Medical Genetics, Policlinico S. Orsola-Malpighi, Notarangelo, MD21
University of Bologna,
3 1
Dpt of Pediatrics, Policlinico S. Orsola-Malpighi, University Division of Immunology, Boston Children’s Hospital,
of Bologna, Boston, MA,
4 2
Dpt of Clinical Medicine and Surgery, University of Naples Brescia, Italy,
3
Federico II, Pediatric Department, Faculty of Medicine, Kuwait
5
Dpt of Medical and Molecular Sciences, Torrette Hospital of University, Kuwait, Kuwait,
4
Ancona, Division of Bone Marrow Transplantation and Immune
6
dpt of Medical Genetics, Policlinico S. Orsola-Malpighi, Deficiency, Cincinnati Children’s Hospital Medical Center,
University of Bologna Cincinnati, OH,
5
Department of Paediatric Immunology, Great Ormond Street
Mutations in TNFRSF13B gene are associated with autoim- Hospital, London, United Kingdom of Great Britain and
mune manifestations in PADs, especially in CVID and in Northern Ireland,
6
IgAD. We analyzed 189 CVID, 67 IgAD and 330 healthy- Department of Pediatrics, Children’s Hospital Bambino Gesù
control to assess the prevalence of TACI mutations, their clin- and University of Rome Tor Vergata School of Medicine,
ical correlates and to verify the role of TACI genetic testing in Rome, Italy,
7
PADs diagnostic work-up. Frequeny of TACI mutations was Immunology Division, Department of Pediatrics, Boston
11.1 % for CVID and 13.4 % for IgAD; 73 % of TACI muta- Children’s Hospital, Harvard Medical School, Boston, MA,
8
tions were monoallelic. Biallelic-mutations were found only in University of California San Francisco, San Francisco, CA,
9
CVID. Frequency of monoallelic C104R-mutation was similar Department of Pediatrics, UT Southwestern Medical Center/
in PADs and healthy-control. In CVID, heterozygous- Children’s Medical Center Dallas, Dallas, TX,
10
mutations were associated with limphadenopathy (P < .001), Department of Pediatric Immunology and Institute of
granulomatous disease and autoimmune cytopenias. Cellular Medicine, Newcastle upon Tyne Hospitals,
Heterozygosity for mutation-other-than-C104R was associated Newcastle upon Tyne, United Kingdom of Great Britain and
with high incidence of lymphoprolipherative and autoimmune Northern Ireland,
11
features, low levels of Treg and low IgA serum levels. In com- Department of Molecular and Traslational Medicine,
parison to CVID wild-typ, patients carrying biallelic-mutations A.Nocivelli Institute of Molecular Medicine, Dept. of
had similar clinical features, higher IgA levels and strong post- Pathology, University of Brescia,
12
vaccination response. TACI-impaired IgAD subjects didn’t Laboratory of Clinical Infectious Diseases, NIAID/NIH,
display clinical difference from wild-type. In conclusion, iden- Bethesda, MD,
13
tification of novel TACI-variants by screening of hypogamma- Department of Immunology-Histocompatibility,
globulinemic patients could help to understand the mechanism Specialized Center and Referral Center for Primary
underlying the pathogenesis of PADs. However the potential Immunodeficiencies-Pediatric Immunology, Aghia Sophia
impact of TACI variants on PADs clinical management is still Children’s Hospital, Athens, Greece, Athens, Greece,
14
limited. Division of Pediatric Immunology, Hospital Luis Calvo
Mackenna, Santiago, Chile,
15
Emma Children’s Hospital, Academic Medical Center,
4514: NK CELLS FROM PATIENTS WITH RAG Amsterdam, Netherlands,
16
AND ARTEMIS DEFICIENCY HAVE AN Pediatrics Clinic and Institute for Molecular Medicine A.
IMMATURE PHENOTYPE AND DISPLAY Nocivelli, Department of Clinical and Experimental
INCREASED DEGRANULATION Sciences, University of Brescia, Spedali Civili, Brescia,
CAPACITY—IMPLICATIONS FOR Italy, Brescia, Italy,
17
HEMATOPOIETIC CELL TRANSPLANTATION Childhood Immunology, University Hospitals Leuven,
Leuven, Belgium,
Kerry Dobbs1, G Tabellini2, Maria Paula Martinez1, Waleed 18
A.Nocivelli Institute of Molecular Medicine, Dept. of
Al-Herz, MD3, Jack J. Bleesing, MD, PhD4, Claire Booth, Pathology, University of Brescia, Brescia, Italy,
PhD 5 , Caterina Cancrini 6 , Janet Chou, MD 7 , Morton 19
Center for Immunology and Inflammatory Diseases,
Cowan, MD8, M Teresa de la Morena, MD9, Raif S. Geha, Massachusetts General Hospital, Harvard Medical School,
MD7, Andrew Gennery10, Silvia Giliani11, Steve M. Holland, Boston, MA,
MD 12, Maria Kanariou, MD13, Alejandra King14, Taco 20
Dipartimento di Medicina Molecolare e Traslazionale,
Kuijpers 15 , Vassilios Lougaris 16 , Isabelle Meyts, MD, University of Brescia, Brescia, Italy,
284 J Clin Immunol (2016) 36:235–334

21
Division of Immunology, Boston Children’s Hospital, (DINOGMI), University of Genoa and Istituto Giannina
Harvard Medical School, Boston, MA Gaslini, Genoa, Italy,
3
Division of Immunology, Boston Children’s Hospital and
Unconditioned haploidentical hematopoietic cell trans- Harvard Stem Cell Institute, Harvard Medical School,
4
plantation (HCT) for RAG and ARTEMIS deficiency is Department of Immunology, Sunnybrook Research Institute,
associated with a high rate (75 %) of graft rejection. It University of Toronto, Canada,
5
has been recently shown that NK lymphocytes from Division of Clinical Immunology and Transfusion Medicine,
Rag−/− mice display an activated phenotype and have in- Department of Laboratory Medicine, Karolinska Institutet at
creased cytotoxicity. To test the hypothesis that RAG and Karolinska University Hospital Huddinge, Stockholm,
ARTEMIS deficiencies in humans cause NK cell abnor- Sweden,
6
malities that may contribute to the inferior outcome of Division of Respiratory Diseases, Boston Children’s
HCT, we have used multicolor flow cytometry to study Hospital, Harvard Medical School, Boston, MA, United
NK cell maturation, activation, and degranulation in 32 States,
7
patients with RAG deficiency, 11 with ARTEMIS deficien- Stem Cell Program and Division of Hematology/Oncology,
cy, 10 with other forms of severe T cell lymphopenia Stem Cell Program and Division of Hematology/Oncology,
(TCL), and in 29 healthy controls. As compared to healthy Boston Children’s Hospital, Harvard Stem Cell Institute,
controls and infants with other forms of TCL, patients with Harvard Medical School and Howard Hughes Medical
severe RAG or ARTEMIS deficiency had a markedly in- Institute, Boston, MA, USA,
creased proportion of immature (CD56 bright CD16 -/int 8
Division of Immunology, Boston Children’s Hospital and
NKG2A+++ CD57− CXCR1-/lo) NK cells. Moreover, NK Harvard Stem Cell Institute, Harvard Medical School,
lymphocytes from these patients displayed higher degranula- Boston, MA, USA,
9
tion capacity (as shown by CD107a expression) upon co- Division of Immunology, Boston Children’s Hospital,
culture with K562 cells in the absence of IL-2 stimulation. Harvard Medical School, Boston, MA,
10
This is the first demonstration that RAG and ARTEMIS defi- Stem Cell Program and Division of Hematology/Oncology,
ciencies in humans affect development and function of NK, in Boston Children’s Hospital, Harvard Stem Cell Institute,
addition to T and B cells. Because of the increased NK cell Harvard Medical School and Howard Hughes Medical
degranulation capacity, NK-depleting strategies should be Institute, Boston, MA, USA,
11
considered to reduce the risk of graft rejection after HCT for Pediatria 2, Istituto Giannina Gaslini, Genoa, Italy,
12
RAG and ARTEMIS deficiency. Unit of Rare Diseases, Department of Pediatrics, Gaslini
Institute, Genoa, Italy,
13
Department of Medical Genetics, University of Lausanne,
4515: EXOSTOSIN-LIKE GLYCOSYL Lausanne, Switzerland,
14
TRANSFERASE 3 (EXTL3) GENE MUTATION Department of Molecular and Traslational Medicine,
CAUSES A NOVEL FORM OF A.Nocivelli Institute of Molecular Medicine, Dept. of
IMMUNO-OSSEOUS DYSPLASIA AND Pathology, University of Brescia,
15
UNVEILS A CRITICAL ROLE OF HEPARAN Pathology Unit, Department of Molecular and Translational
SULFATE IN THYMOPOIESIS Medicine, University of Brescia, Brescia, Italy,
16
Centro di ricerca emato-oncologica AIL (CREA), Spedali
Stefano Volpi, PhD1,2, Yamazaki Yasuhiro3, Patrick Brauer4, Civili, Brescia, Italy,
Likun Du5, Atsuko Hayashida6, Ellen van Rooijen7, Lisa Ott 17
Division of Immunology, Boston Children’s Hospital,
De Bruin8, Kerstin Felgentreff, MD9, Elliott Hagedorn10, Boston, MA,
Kelly Capuder8, Akiko Ohno6, Antonella Boncompagni11, 18
Neurobiology and Anatomy Department, University of
Maja Di Rocco12, Carlo Rivolta13, Silvia Giliani14, Luigi Utah, Salt Lake City, UT, USA,
Poliani, MD, PhD 15 , Luisa Imberti 16 , Kerry Dobbs 17 , 19
Pediatria 2 and Department of Pediatrics, Istituto Giannina
Fabienne Poulain18, Alberto Martini19, Juan Carlos Zuniga- Gaslini and University of Genoa, Genoa, Italy,
Pflucker4, Leonard Zon10, Pyong Woo Park6, Andrea Superti- 20
Department of Pediatrics, Lausanne University Hospital,
Furga20 and Luigi D Notarangelo, MD9 Lausanne, Switzerland

1
Division of Immunology, Boston Children’s Hospital and Immuno-osseous dysplasias (IOD) are a group of disorders
Harvard Stem Cell Institute, Harvard Medical School, characterized by immune deficiency and skeletal dysplasia.
Boston, MA, To identify novel genetic defects responsible for this con-
2
Department of Neuroscience, Rehabilitation, dition we studied two siblings with rapidly progressive and
Ophthalmology, Genetics, Maternal and Child Health fatal IOD characterized by severe skeletal dysplasia,
J Clin Immunol (2016) 36:235–334 285

9
laryngotracheomalacia, developmental delay and severe Division of Immunology, Boston Children’s Hospital,
immunodeficiency that presented with Omenn Syndrome Harvard Medical School, Boston, MA
in the first born and as T− B+ SCID in the second born
infant. Human and mouse studies have shown that regulatory T lym-
Using whole exome sequencing we identified in both sib- phocytes (Tregs) lacking the expression of the Wiskott-
lings an homozygous missense mutation (p.R339W) af- Aldrich syndrome protein (WASp) have defective suppressor
fecting a highly conserved residue of Exostosin-like 3 activity and altered homing potential. However, the following
(EXTL3), a member of the exostosin (EXT) family of two limitations have hindered the study of the cell-intrinsic
glycosyltransferases involved in heparan sulfate (HS) bio- role of WASp in Tregs: 1) the effect of WASP deficiency on
synthesis. Patient derived lymphoblastoid cell line other hematopoietic cells that are involved in regulatory func-
showed abnormal HS size compared to control. FGF2 tion; and, 2) the difficulties in identifying Tregs using only
signaling was altered in patient primary cells and this membrane markers.
defect was rescued by lentiviral complementation with a To overcome these problems, we crossed Was floxed mice to
WT copy of the gene. Extl3 mutant zebrafish (box) shows Foxp3-Cre-eGFP transgenic mice that also harbor a lox-stop-
impairment of pharyngeal cartilage morphogenesis and of lox-YFP cassette in the ROSA26 locus. In this model, Foxp3-
the pectoral fin, indicative of defective limb bud development. positive Treg cells are WASp-negative, GFP-positive and
Crossing box zebrafish with a rag2:gfp transgenic zebrafish, YFP-positive. In addition to marking Foxp3-expressing
we demonstrated that extl3 mutation in zebrafish causes a Tregs, this model allowed us to follow the exTreg population
severe defect of thymic lymphopoiesis which was rescued (T cells no longer expressing Foxp3), identified as GFP-
by injection of wild-type EXTL3 RNA. negative and YFP-positive T cells.
These data identify EXTL3 mutations as a novel cause of IOD We found that conditional deletion of Was in Tregs causes mi-
in humans. nor alterations of lymphocyte subsets, but induces autoimmu-
nity, with production of a broad range of IgG autoantibodies,
and inflammatory cell infiltration of colon, lung and liver.
4516: SELECTIVE DEFICIENCY OF WASP IN These results confirm an intrinsic role of WASP in Treg
TREG CELLS IS SUFFICIENT TO CAUSE function. Studies of the stability of FoxP3 expression and the
AUTOIMMUNITY IN MICE contribution of exTreg to autoimmunity in the absence of
WASP expression are ongoing.
Stefano Volpi, PhD1,2, Elettra Santori3, Francisco Beca4,
Masayuki Mizui5, Kelly Capuder6, Eva Csizmadia7, Adrian
Thrasher, MD, MBBS8, Luigi D Notarangelo, MD9 and Fabio 4519: APECED AUTOIMMUNE
Candotti3 POLYENDOCRINOPATHY WITH CANDIDIASIS
AND ECTODERMAL DYSTROPHY AND
1
Division of Immunology and Allergy, University Hospital of ESOPHAGEAL RUPTURE BY CANDIDIASIS
Lausanne, Laboratory Center of Epalinges (CLE), Epalinges, IMMUNODEFICIENCY
Switzerland, Epalinges, Lausanne, Switzerland,
2
Division of Immunology, Boston Children’s Hospital and Dalton Luis Bertolini1, Dewton Moraes-Vasconcelos2,
Harvard Stem Cell Institute, Harvard Medical School, Maurício Domingues-Ferreira 3 and Thiago de Almeida
Boston, MA, Bezerra3
3
Division of Immunology and Allergy, University Hospital of
1
Lausanne, Laboratory Center of Epalinges (CLE), Epalinges, Department of Dermatology, Dermatological Manifestations
Switzerland, of Primary Immunodeficiencies, University of Sao Paulo,
4
Department of Pathology, Beth Israel Deaconess Medical School of Medicine, SAO PAULO, Brazil,
Center, Boston, MA, USA, 2
Laboratory of Dermatology and Immunodeficiencies –
5
Division of Rheumatology, Department of Medicine, Beth LIM56, Faculdade de Medicina da Universidade de São
Israel Deaconess Medical Center, Boston, USA, Paulo, São Paulo, Brazil,
6 3
Division of Immunology, Boston Children’s Hospital and Dermatological Manifestations of Primary Immunodeficiencies
Harvard Stem Cell Institute, Harvard Medical School, - ADEE3003, University of São Paulo School of Medicine, São
Boston, MA, USA, Paulo, Brazil
7
Department of Medicine, Transplantation Institute, Beth
Israel Deaconess Medical Center, Harvard Medical School, Case report
Boston, USA, The 42-years-old-patient presented chronic and persistent oral
8
University College London, and cutaneous lesions due to Candida infection since
286 J Clin Immunol (2016) 36:235–334

childhood, including persistent onychomycosis, oral and genetic etiology reports, 1 review, and the ESID guidelines.
esophageal candidiasis and balanitis with poor control for de- Papers from Cell, Nature, Science, NEJM, and Medicine are
cades even taking antifungals and autoimmune manifestations among the most cited, but also Clin Immunol. JL Casanova
(hypoparathyroidism, hypoadrenalism and insulin-dependent led by number of papers (109), followed closely by A Fischer,
diabetes mellitus). with 99.
He had stenosis of the esophagus and was subjected to dilation DISCUSSION: The steeping of the curve can be traced to
of the esophagus five times before rupture the esophagus. around 1995, when several genes were being cloned, the
Discussion Human genome was on its way, and the first descriptions of
The molecular analysis revealed the 13-bp deletion in exon 8 a new group of defects were published. A high-impact paper
(1085–1097(del)) mutation on gene encoding AIRE in an ho- in the field describes a novel genetic etiology, a new success-
mozygous fashion and APECED was diagnosed. ful tx, or includes hundreds of patients, with a long list of
Candida species are recognized by a variety of innate immune international coauthors.
receptors, as the transmembrane c-type lectin β-glucan recep-
tor Dectin-1 whose genetic alteration was correlated with
Chronic Mucocutaneous Candidiasis (CMC). 4521: A CASE OF A BRAIN ABSCESS
AIRE participates in the well-defined signaling complex re- SECONDARY TO SPECIFIC GRANULE
quired for anticandidal defense, incluiding Dectin-1, phos- DEFICIENCY
phorylated Syk and CARD9.
As far we know, this is the first reported case of esophageal Bhumika Patel, MD1, Matthew Morrow, MS2, Wilfredo
perforation associated with chronic esophageal candidiasis in Chamizo, MD2 and Jennifer W. Leiding, MD1
a patient with APECED. Despite the rarity and the uncommon
1
finding of esophageal perforation in patients with CMC, it Pediatrics, Division of Allergy, Immunology, and
demonstrates an example of complication by candidiasis in Rheumatology, University of South Florida, St. Petersburg,
immunosuppressed patients. FL,
2
All Children’s Hospital, University of South Florida, St
Petersburg, FL
4520: RESEARCH ON PRIMARY
IMMUNODEFICIENCY: A GLOBAL Introduction: Specific granule deficiency (SGD) is a rare
BIBLIOMETRIC ANALYSIS innate immunodeficiency placing affected individuals at
risk of severe pyogenic infections and is due to muta-
Saul Oswaldo Lugo Reyes, MD, MS.1 and Layla Michan tions in CBEPE, which is responsible for terminal differ-
Aguirre, PhD2 entiation of granulocyte progenitor cells. SGD patients
lack several primary and secondary granule proteins
1
Immunodeficiencies Research Unit, National Institute of and have impaired bactericidal activity. Case: A 13
Pediatrics, Mexico City, Mexico, month-old male developed recurrent high fever that
2
Ensenada Center for Scientific Research and Higher persisted despite antibiotics for acute otitis media. He
Education (CICESE), Ensenada, Mexico then developed emesis, worsening irritability and right
hemiparesis. A large left-sided brain mass was visualized
BACKGROUND: The growth of PID research has been ver- associated with significant midline shift and cerebral ede-
tiginous. We aimed to draw a global picture of the field during ma. He underwent left parietal craniotomy, evacuation of
the past 45 years. brain abscess and placement of external ventricular drain.
METHODS: We conducted a bibliometric review on PID in Bacterial cultures yielded MSSA. As part of this patient’s
Pubmed and processed the records with 3 bioinformatic immune evaluation, a dihydrorhodamine assay (DHR)
applications. was performed, which repeatedly showed loss of discern-
RESULTS: We found 3414 documents from 1971 to 2015. able resolution between lymphocyte and granulocyte
The mean number of authors per article is 6.1, and that of populations indicating loss of granularity among
citations is 2.96 after self-citations. The top 10 journals pub- granulocytes. Microscopic examination of peripheral neu-
lished 21.3 % of papers. J of Clin Immunol leads with 167 trophils was also consistent with a loss of granularity.
articles on PID, starting in 1981. JACI, CEI, Clin Immunol Further genetic studies confirmed a mutation in
and Blood complete the top 5, and get more citations. The CBEPE. Conclusion: SGD requires a high index of sus-
most cited paper (256 cits) appeared in Nat Med 2006, on picion to diagnose. Examination of neutrophil morpholo-
gene therapy for X-CGD; number 2, Cell 1993 on the cloning gy should be included for any patient with severe pyo-
of CIITA, has 151. The top ten is complete with 2 case series, 4 genic infections.
J Clin Immunol (2016) 36:235–334 287

4523: SUBCUTANEOUS GAMMAGLOBULIN: developed clinical signs consistent with systemic granulo-
EFFECTIVE INMUNOMODULATORY matous disease.
TREATMENT IN SEVERE Case 1: A 25-year-old male diagnosed with 22q11 deletion
THROMBOCYTOPENIA syndrome at birth treated with thymic transplantation. He was
found to have hypogammaglobulinemia and started on immu-
Analía Gisela Seminario, M.D.1, Lorena Regairaz2 and noglobulin replacement. His course has been complicated by
Liliana Bezrodnik1 systemic granulomatous disease involving the liver, spleen,
lungs and lymph nodes. He underwent therapeutic splenecto-
1
Immunology Group, Ricardo Gutiérrez Children’s Hospital, my following autoimmune hemolytic anemia.
Buenos Aires, Argentina, Case 2: An 11-year-old female with 22q deletion syndrome
2
Immunology, Sor Ludovica, La Plata, Argentina diagnosed by FISH at 3 years of age treated with bone marrow
transplant. She was found to have low IgG and IgM during
Introduction: Immunoglobulin(Ig)is widely used in autoim- immunology screening and has since been started on immuno-
mune disease. Some effects of Immunoglobulin are readily globulin therapy. Calcified pulmonary nodules were noted on
reversible and highly dependent on the serum IgG levels. routine scoliosis radiographs and subsequent CT chest and ab-
The most common route of administration of Ig has been domen showed evidence of systemic granulomatous disease.
intravenous(iv), although the subcutaneous(sc)route is an al- These cases bring up important questions with regard to the
ternative. The therapeutic benefits of Ig may also be due to an management and surveillance of patients with 22q deletion
active role in various anti- inflammatory and immunomodu- syndrome.
latory activities,The initial dose used for most autoimmune
disease is 2 g/kg/monthly dose Aim:Demonstrate sc Ig, as
an alternative and effective treatment in patientswith autoim- 4525: NEONATAL AUTOINFLAMMATORY
mune disease. Results: Healthy young boy up to 19 years, DISEASE AND HYPOGAMMAGLOBULINEMIA
when he presented first episode of thrombocytopenia, He used
to have good response only to high dose of ivIg but he pre- Analía Gisela Seminario, M.D.1, Lorena Regairaz2, Paula
sented adverse effects.he received treatment with steroids, ri- Luna3, Maria Soledad Caldirola1, Marco Gattorno4 and
tuximab, and sirolimus but he didn’t has good response and Liliana Bezrodnik1
persists with chronic cytopenia. As scIg is using in others
1
autoimmune diseases and considering his response to Ig we Immunology Group, Ricardo Gutiérrez Children’s Hospital,
begin scIg treatment 300 mg/kg/weekly dose. Since he began Buenos Aires, Argentina,
2
this treatment he recovered from thrombocytopenia and only Immunology, Sor Ludovica, La Plata, Argentina,
3
receives scIg with good tolerance. Conclusion: We could re- Dermatology Service in Aleman Hospital and Ramos Mejia
duce Ig to 1,2gr/ monthly dose, maintaining high steady state Hospital, CABA, Argentina, (4)Rheumatology, IRCCS
serum IgG levels with weekly IgG infusions may lead to more Istituto G. Gaslini - Ospedale Pediatrico, GENOVA, Italy
stable symptom control and better long term outcomes.
Introduction: Autoinflammatory diseases are inborn errors of
the innate immune system that generally associate inflamma-
4524: GRANULOMATOUS DISEASE IN TWO tion of the skin since the neonatal period and other organs with
PATIENTS WITH 22q11 DELETION SYNDROME raised inflammatory markers in the blood. Aim: Present fe-
male patient with severe autoinflammatory disorder without
Travis M Sifers, MD1, Nikita Raje, MBBS, MD2 and Maya fever Results: 7 months (mo) baby with chronic and general-
Nanda, MD, MSc3 ized pustulosis since birth. At 2 months persists with severe
skin ulcers, splenomegaly, chronic anemia and thrombocyto-
1
University of Missouri - Kansas City, Kansas City, MO, penia with hypogammaglobulinemia and low B cell counts.
2
Allergy- Immunology, Children’s Mercy Hospital, Kansas She received anti-TNF treatment with good response but at
City, MO, 4 months suffered from respiratory distress needing mechan-
3
Allergy, Asthma and Immunology, Children’s Mercy Clinics ical ventilation. Persistent several skin exacerbation. Biopsy:
on Broadway, Kansas City, MO neutrophil infiltrate. Partial response with steroids and cyclo-
sporine with marrow aplasia. No mutation in ADA2,
Granulomatous and lymphocytic proliferation—a known TNFRSF1A and NLRP3 Waiting stem cell transplantation
complication of CVID—is all but absent in the literature and whole exome sequencing. Conclusion:We must consider
regarding 22q11.2 deletion syndrome. Here we present 2 that autoinflammatory disorders may be early manifestations
cases of patients with known 22q11 mutations that of PID.
288 J Clin Immunol (2016) 36:235–334

4526: COMMON VARIABLE Health, Bethesda, MD,

2
IMMUNODEFICIENCY WITH C4 DEFICIENCY Clinical Research Core, National Institute of Dental and
Craniofacial Research, National Institutes of Health,
Chelsea Michaud, D.O.1,2, Robert W. Hostoffer Jr., DO2,3 3
Laboratory of Clinical Infectious Diseases, National Institute
and Haig Tcheurekdjian, MD2,3 of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD,
1 4
University Regional Hospitals, Richmond Heights, OH, Microbiology Service, Department of Laboratory Medicine,
2
Allergy/Immunology Associates, Inc, Mayfield Heights, National Institutes of Health, Bethesda, MD,
5
OH, Leidos Biomedical Research, Inc., NCI-Frederick, Frederick,
3
Case Western Reserve University, Cleveland, OH MD,
6
Translational and Functional Genomics Branch, National
Common variable immunodeficiency (CVID) exhibits a high Human Genome Research Institute, National Institutes of
incidence of complement component 4A (C4A) gene dele- Health, Bethesda, MD,
7
tions. Due to presence of both C4A and C4B in the human Bioinformatics and Computational Biosciences Branch,
genome, C4 deficiency has not been seen in conjunction with National Institute of Allergy and Infectious Diseases,
CVID. The patient described herein was found to have both National Institutes of Health,
8
CVID and C4 deficiency. Department of Veterinary Medicine, University of Cambridge
This is a 67 year old male who suffered from diffuse lymph-
adenopathy, chronic sputum production, arthritis, myalgia, fa- Long-term follow up of patients with p47phox-deficient chron-
tigue, anorexia and a maculopapular rash over a 2 year period. ic granulomatous disease (CGD) shows that almost 40 % de-
He required multiple rounds of high dose steroids but eventu- velop inflammatory bowel disease. The role of the intestinal
ally maintained symptom control on prednisone 10 mg daily. microbiome in this immunodeficiency has not been explored.
Bone marrow, lymph node and skin biopsies were non-diag- Although CGD mice do not spontaneously develop colitis, we
nostic. Initial workup showed transiently high CRP and mild- demonstrate that p47phox−/− mice have increased susceptibility
ly low IgG but was otherwise unremarkable. to dextran sodium sulfate (DSS) colitis in association with
Immunology consult was sought 2 years later at which point distinct colonic transcript and microbiome signatures.
he had panhypogammaglobulinemia (IgG 349, IgA 47, IgM Neither restoring phagocyte-derived reactive oxygen species
30 mg/dL), absence of humoral response to pneumococcal (ROS) production nor normalizing the microbiome using
immunization, near absence of memory B cells (0.6 % cohoused adult p47phox−/− with WT mice reversed this phe-
CD19+) with absent C4 (<2 mg/dL, normal 10–40 mg/dL). notype. However, interbreeding p47phox+/− mice, thereby ho-
He developed persistent herpes zoster with difficult to treat mogenizing the microbiota between littermate p47phox−/− and
sinsusitis and was subsequently started on IVIG therapy. WT mice from birth, significantly reduced severe DSS colitis
This is the first report of C4 deficiency in CVID. The patient in p47phox−/− mice. We found similarly decreased colitis sus-
clinically manifested with a late-onset, severe autoimmune ceptibility in littermate p47phox−/− and WT mice treated with
phenotype followed by infections. C4 deficiency should be Citrobacter rodentium. Our findings suggest that the
considered in patients with CVID presenting with severe au- microbiome signature established at birth plays an important
toimmune phenotypes. role in mediating colitis susceptibility in CGD mice. These data
support a role for the intestinal microbiome in CGD colitis.

4528: COLITIS SUSCEPTIBILITY IN p47phox−/−

MICE IS MEDIATED BY THE INTESTINAL 4530: SUCCESSFUL OUTCOME FOLLOWING
MICROBIOME. REDUCED INTENSITY CONDITIONING
ALLOGENEIC HSCT FOR REFRACTORY
Emilia Liana Falcone, MD1, Loreto Abusleme, DDS2, SYSTEMIC ONSET JUVENILE IDIOPATHIC
Muthulekha Swamydas, PhD1, Michail S. Lionakis, MD, ARTHRITIS. IL-18: A BIOMARKER FOR
ScD1, Li Ding, MD1, Amy P Hsu, BA1, Adrian Zelazny, MONITORING AND RESPONSE TO HSCT?
PhD3,4, Niki Moutsopoulos, DDS, PhD2, Douglas B. Kuhns,
PhD5, Clay Deming, PhD6, Mariam Quiñones, PhD7, Julia A. Sharat Chandra, MD1, Michael Henrickson2, Stella M
Segre, PhD6, Clare E. Bryant, DVM, PhD8 and Steven M. Davies, MD3 and Rebecca Marsh, MD1
Holland, MD1
1
Division of Bone Marrow Transplantation and Immune
1
Laboratory of Clinical Infectious Diseases, National Institute Deficiency, Cincinnati Children’s Hospital Medical Center,
of Allergy and Infectious Diseases, National Institutes of Cincinnati, OH,
J Clin Immunol (2016) 36:235–334 289

2 3
Division of Rheumatology, Cincinnati Children’s Hospital Haematology, Hospital das Clínicas da Universidade Federal
Medical Center, Cincinnati, OH, de Minas Gerais, Belo Horizonte, Brazil,
3 4
D i v i s i o n o f B o n e M a r r o w Tr a n s p l a n t a t i o n a n d Pediatrics, Santa Casa de Misericórdia de Barbacena,
Immunodeficiency, Cincinnati Children’s Hospital Medical Barbacena, Brazil,
5
Center, Cincinnati, OH Hospital das Clínicas da Universidade Federal de Minas
Gerais, Belo Horizonte, Brazil,
6
Introduction FEDERAL UNIVERSITY OF MINAS GERAIS,
7
Despite significant advances in biologic therapy, some chil- Instituto de Medicina Integral Prof. Fernando Figueira,
dren with systemic onset juvenile idiopathic arthritis (sJIA) Recife, Brazil,
8
remain refractory to any form of conventional or novel treat- Universidade Federal de Minas Geria, Belo Horizonte, Brazil
ment. Allogeneic HSCT is a potential treatment option for
affected children; however, limited data exist regarding effi- Case report: An 8-month-old boy born to parents who are first
cacy and outcome. cousins was admitted to the hospital with a coombs positive
Method haemolytic anaemia and viral bronchiolitis. The mother re-
We report our experience for two patients who underwent ported the death of two previous children, the first daughter
allogeneic HSCT for sJIA at our center. died of pneumonia and sepsis at age of 4 months and the
Results second one died of sepsis and haemolytic anaemia at age of
Patient 1 (4 years old girl) and patient 2 (16 years old girl) had 5 months. He presented persisted wheezing, mild tachypnea,
sJIA with recurrent episodes of macrophage activation syn- good nutritional status. The haemolytic anaemia was treated
drome and chronic corticosteroid dependence refractory to successfully with corticosteroids.
both conventional and novel treatments. Both patients had The investigation of Primary Immunodeficiency showed: CD3
markedly elevated serum IL-18 (range 10,361–28,891 pg/ cells = 1290/mm3, CD4CD45RA = 5/ mm3,
ml, ULN: 540 pg/ml). Both received a RIC regimen that in- CD4CD45RO = 116 mm 3 , CD8CD45RA = 652/mm 3 ,
cluded alemtuzumab, fludarabine and melphalan. GVHD pro- CD8CD45R0 = 15/mm3, CD16 = 296/mm3, CD19 = 334/mm3,
phylaxis included cyclosporine and steroids (n = 2) and NKT = 104/mm3, O.5 % of CD4 cells are CCR7+CD62L+, and
maraviroc (n = 1). Patient 1 received a 10/10 MSD marrow 1 % are CD45RA+CD62L+. None of CD8 cells are CCR7+
graft and patient 2 received a 9/10 MUD PBSC graft. Both CD62L+, and 1,21 % are CD45RA+CD62L+. The genetic
patients engrafted, have maintained full donor chimerism and analysis showed a RAG1 variance c.251C>T:p.R841W.
are alive and well at 1 year and 6 months post HSCT. Neither The patient had receveid BCG and, despite he did not present
has experienced recurrence of sJIA. Serum IL-18 normalized clinical signs of BCG infection, he was treated with ethambu-
post HSCT. tol, rifamycin, isoniazid. Prophylactic azithromycin,
Conclusion sulfamethxazole+trimethoprim, acyclovir and immunoglobu-
Allogeneic RIC HSCT can be curative with favorable out- lin replacement are initiated. Haploidentical transplant was
comes for refractory sJIA. Serum IL-18 can potentially be a performed and the patient is currently doing well.
useful biomarker for monitoring disease activity and response
to HSCT.
4532: HAPLOIDENTICAL RELATED DONOR
HEMATOPOIETIC STEM CELL
4531: HAEMOLYTIC ANAEMIA AS FIRST TRANSPLANTATION FOR DOCK8
MANIFESTATION OF RAG1 SEVERE DEFICIENCY
COMBINED IMMUNODEFICIENCY (SCID)
Alexandra F Freeman, MD1, Nirali Shah, MD2, Helen C.
1,2
Luciana Araújo Oliveira Cunha, MD, PhD , Ana Karine Su3, Gulbu Uzel, MD1, Juan Gea-Banacloche, MD, Stephanie
Vieira, MD3, Arles Mescolin de Paula, MD4, Rhaianny Cotton, Steven M. Holland, MD5 and Dennis D. Hickstein,
Gomes Souza, MD 2 , Thalita Rodrigues Dias, MD 5 , M.D.6
Fernanda Gontijo Minafra Silveira Santos, MD, MS2, Maria
Luiza Silva, PHD6, João Bosco Oliveira, MD, PhD7 and Jorge 1
Laboratory of Clinical Infectious Diseases, NIAID/NIH,
Andrade Pinto, MD, PhD8 Bethesda, MD,
2
Pediatric Oncology Branch, National Cancer Institute/NIH,
1
Pediatrics, Hospital da Polícia Militar de Minas Gerais, Belo Bethesda, MD,
3
Horizonte, Brazil, Laboratory of Host Defenses, National Institute of Allergy
2
Immunology, Hospital das Clínicas da Universidade Federal and Infectious Diseases, National Institutes of Health,
de Minas Gerais, Belo Horizonte, Brazil, Bethesda, MD,
290 J Clin Immunol (2016) 36:235–334

4
Laboratory of Clinical Infectious Diseases, National Institute be part of the phenotypic spectrum of Dyskeratosis
of Allergy and Infectious Diseases, National Institutes of Congenita (DC). Significant development delay can be pres-
Health, Bethesda, MD, ent in theses two variants of DC.We report two distinct cases
5
Experimental Transplantation and Immunology Branch, of children. CASE 1: The first patient was referred after nu-
Division of Basic Sciences, National Cancer Institute, merous episodes of bacterial infections, failure to thrive, de-
National Institutes of Health layed psychomotor development and thrombocytopenia. The
child showed an important psychomotor delayed, petechias in
Hematopoietic stem cell transplant (HSCT) is effective for the shoulders, microcephaly, tongue leukoplakia.
DOCK8 deficiency. We transplanted six patients without Investigations demonstrated anaemia, thrombocytopenia and
matched donors using T-cell replete haploidentical bone marrow shortened telomere lengths. The magnetic resonance imaging
and post-transplant, high-dose cyclophosphamide (CY) followed of the brain showed microcalcifications. CASE 2: The second
by tacrolimus and mycophenolate mofetil. Conditioning patient was referred at the age 8 yo. He also suffered from
consisted of low dose CY, busulfan, fludarabine, and TBI. Co- microcephaly, psychomotor delayed and recurrent bacterial
morbidities in this cohort included: lymphoma (2), vulvar squa- respiratory infections. Petechiae in the region of legs revealed
mous cell carcinoma (1), aortic vasculopathy (2) including one mild thrombocytopenia. The child showed some degree of
with significant renal artery stenosis and cardiomyopathy, cere- malnutrition, psychomotor delayed, microcephaly, nail
bral vasculopathy (2) with history of stroke, cholestatic liver distrophy. Investigations demonstrated anaemia, thrombocy-
disease (2) (including one with end-stage disease requiring a liver topenia. The test that measure telomere length is in progress.
transplant prior to HSCT), bronchiectasis (3), bleomycin- The clinical diagnosis of DC is based on the presence of the
associated pulmonary fibrosis (1), and chronic EBV viremia four major features of the disease, which include the mucocu-
(4). At mean follow-up of 7.5 months, four patients were alive taneous triad and BMF. It’s very important for clinical experts
and fully engrafted. One died from graft rejection and veno- to make a correct diagnosis of the disease.
occlusive disease in the transplanted liver, and one from pulmo-
nary fibrosis. Two patients had grade 2 GVHD; there was no
grade 3 or 4 GVHD. Warts and molluscum resolved by 3– 4540: ANTI-CITRULLINATED PROTEIN
6 months. Three had antiviral responsive CMV reactivation, ANTIBODY AND RHEUMATOID FACTOR
and 3 had limited EBV reactivation. No patients had complica- PROFILES PREDICT THE DEVELOPMENT OF
tions related to the underlying vasculopathy. Thus, haploidentical RHEUMATOID ARTHRITIS
related donor HSCT corrects DOCK8 deficiency in the setting of
considerable co-morbidities with minimal GVHD. Nithya Lingampalli, B.S.1,2, Jeremy Sokolove, M.D.3,4 and
William H Robison, M.D.2,3

1
4533: REVESZ SYNDROME AND Department of Immunology and Rheumatology, Stanford
HOYERAAL-HREIDARSSON SYNDROME: University School of Medicine, Stanford, CA,
2
POSSIBLE DIAGNOSIS FOR TWO CHILDREN Rheumatology, VA Palo Alto, Palo Alto, CA,
3
WITH TYPICAL SYMPTOMS Rheumatology, Stanford University School of Medicine,
Stanford, CA,
Tiago Nunes Guimarães, Guimarães, TN1, Livia Pierone B 4
Internal Medicine and Rheumatology, VA Palo Alto, Palo
Cruz, MD2, Rhaianny Gomes Souza, MD3, Thalita Rodrigues Alto, CA
Dias, MD3, Fernanda Gontijo Minafra Silveira Santos, MD,
MS3, Luciana Araújo Oliveira Cunha, MD, PhD3 and Jorge A biochemical hallmark of rheumatoid arthritis (RA) is
Andrade Pinto, MD, PhD4 the presence of rheumatoid factor (RF) and autoanti-
bodies targeting citrullinated proteins, known as anti-
1
Immunology Division of Clinical Hospital, Universidade citrullinated protein antibodies (ACPA). Early diagnosis
Federal de Minas Gerais, Belo Horizonte, Brazil, of RA provides a window of opportunity for aggressive
2
Immunology, Federal University of Minas Gerais, Belo management to slow disease progression. Given that
Horizonte, Brazil, ACPA and RF are present in serum several years before
3
Immunology, Hospital das Clínicas da Universidade Federal clinical diagnosis, we hypothesized that characterization
de Minas Gerais, Belo Horizonte, Brazil, of preclinical autoantibody profiles would be a viable
4
Universidade Federal de Minas Geria, Belo Horizonte, Brazil predictive biomarker for RA onset. To this end, we
performed multiplex autoantibody and cytokine analysis
Previously thought to be distinct disorders, Revesz syndrome of pre-clinical sera from patients that eventually deve-
and Hoyeraal-Hreidarsson syndrome are now recognized to loped RA. We found that the combined occurrence of
J Clin Immunol (2016) 36:235–334 291

RF and ACPA is directly associated with elevated levels 4543: SUCCESFUL TREATMENT OF
of cytokines (e.g., TNF-a, and IL-17) and ACPA (e.g., AUTOIMMUNE NEUTROPENIA WITH
fibrinogen). Furthermore, patients that are seropositive RITUXIMAB IN A PATIENT WITH HYPER IgM
for both RF and ACPA can be identified up to 2 years SYNDROME
before clinical manifestation, and at least 2 years earlier
than single seropositive or seronegative patients. Our Mónica Rodríguez-González, Miriam Martinez-Perez, Edna
findings suggest that the presence of both RF and Venegas-Montoya, Giovanni Sorcia-Ramierz
ACPA is associated with increased inflammation, and
more importantly, with a more imminent onset of RA. Selma Scheffler-Mendoza and Marco Antonio Yamazaki-
Taken together, our data show that RF and ACPA status Nakashimada, CLINICAL IMMUNOLOGY AND
can be utilized as a predictive biomarker to identify PEDIATRIC ALLERGY, NATIONAL INSTITUTE OF
patients at high risk for imminent development of RA PEDIATRICS, MEXICO CITY, Mexico
such that clinical intervention is more efficacious.
Four-year-old boy, the second child of the family and was
born after a full-term uncomplicated pregnancy. Endogamy
4541: CONNECTING THE DOTS: A CASE OF and consanguinity denied. At age two, he presented perianal
RARE B CELL IMMUNODEFICIENCY abscess with severe neutropenia. Bone marrow biopsy ruled
out lymphoprolipherative disease so he was started on GM-
Amer M Khojah, MD1 and Ramsay L Fuleihan, MD2 SCF with poor response until high doses were reached. Non-
reactive result for HIV. A primary immunodeficiency with
1
Allergy Immunology department, Ann & Robert H. Lurie neutropenia was suspected, so prophylactic antimicrobials
Children’s Hospital of Chicago, Chicago, IL, and IFN-gamma were started. No mutations identified on
2
Division of Allergy & Immunology and Jeffrey Modell ELANE gene. Autoimmunity was detected Ab antineutrophil
(positive). He was admitted to cord blood transplantation.
Diagnostic Center for Primary Immunodeficiencies, Ann After 60 days, graft failure was documented and neutropenia
& Robert H. Lurie Children’s Hospital of Chicago, persisted. Hyper IgM Syndrome was suspected and diagnosed
Chicago, IL with identification of X-linked hemizygous mutation in
A 2 year old boy with mild developmental delay, CD40LG (ENST00000370629) c.208C>T,p.Q70* (HGMD:
GERD and microcytic hypochromic anemia presented CM050343). The mother is heterozygous carrier, the father
to the hospital for evaluation of recurrent febrile ill- is homozygous normal. Human Immunoglobulin was started.
nesses. At 10 month of age, he was diagnosed with Neutropenia persisted so he was started on immunosuppres-
developmental delay. A few months later, he started to sive therapy with prednisone and rituximab was considered
have recurrent febrile illnesses associated with vomiting due to refractory autoimmune neutropenia. Rituximab was
and diarrhea every 4–5 weeks. He was also found to administered at a dose of 375 mg/m2 as an intravenous infu-
have anemia and was referred to hematology due to sion weekly for 4 weeks. He did not present adverse effects;
the lack of response to iron replacement therapy. severe neutropenia was resolved as well as admissions due to
Further work up revealed normal hemoglobin electro- infections. He was allocated to substitution with IVIG.
phoresis and basophilic stippling on peripheral smear
suggestive of sideroblastic anemia which was confirmed
on bone marrow biopsy. Flow cytometry showed de- 4544: p85alpha IS AN INTRINSIC REGULATOR
creased absolute B cell count with relatively low naive OF HUMAN NATURAL KILLER CELL
B cell percentage. Immunoglobulins level and antibody EFFECTOR FUNCTIONS
response to tetanus and Prevnar were normal. Whole
genome sequencing revealed 2 different heterozygous Vassilios Lougaris1, Ornella Patrizi, Manuela Baronio3, G
mutations of the TRNT1(tRNA-nucleotidyltransferase Tabellini 4 , Giacomo Tampella, Gaetana Lanzi, Filippo
1) gene suggestive of SIFD syndrome (congenital Salvini, Antonino Trizzino, Silvia Parolini5 and Alessandro
sideroblastic anemia, B-cell immunodeficiency, periodic Plebani6
fevers and developmental delay). Few months after dis-
1
charge, the patient developed dilated cardiomyopathy Department of Clinical and Experimental Sciences,
which is another feature of this syndrome. This case University of Brescia, Brescia, Italy,
2
illustrate the importance of the whole genome sequenc- Department of Pediatrics and Institute of Molecular Medicine
ing in finding a unified diagnosis for a complex clinical A. Novicelli, University of Brescia, Spedali Civili di Brescia.
presentation. Brescia, Italy,
292 J Clin Immunol (2016) 36:235–334

3 6
Brescia, Italy, 7- Department of Hematology., Aziza Othmana Hospital,
4
Dipartimento di Medicina Molecolare e Traslazionale, Tunis, Tunisia,
7
University of Brescia, Brescia, Italy, The University of Hong Kong,
5 8
Pediatrics Clinic and Institute for Molecular Medicine A. Department of Immunology., Institut Pasteur de Tunis, Tunis,
Nocivelli, Department of Clinical and Experimental Tunisia
Sciences, University of Brescia, Spedali Civili, Brescia,
Italy, Brescia, Italy TCF3 (E2A) gene encodes E12 and E47 transcription factors
which are essential in differentiation process of common lym-
PIK3R1 encodes for p85α, one of the catalytic subunits in- phoid progenitors into B-lineage cells and are key regulators
volved in the PI3K cascade. Available data from animal of B-cell development. Herein, we report the first patient with
models regarding the role of p85α in NK cell maturation and a homozygous mutation in TCF3 gene, who presented with
function are contrasting. Recently, a dominant activating mu- agammaglobulinemia, absent peripheral B cells and devel-
tation in p85α was identified in 12 patients affected with a rare oped B-cell acute lymphoblastic leukemia (B-ALL).
form of primary immunodeficiency. We decided to evaluate The patient was born to Tunisian first cousins parents. He had
the role of the dominant p85α activating mutation in human recurrent pneumonia and meningitis since early childhood and
NK cell maturation and function. We how that p85α plays an mild facial dysmorphia. At age 7 years he presented pancyto-
essential role in human NK cell effector functions: while indi- penia and splenomegaly, the diagnosis of B-ALL was con-
viduals with dominant activating p85α mutations show normal firmed. Complete remission was obtained under chemothera-
NK maturation, their functional capacities are impaired. py but at age 10 years he relapsed and died despite treatment.
Mutant human NK cells fail to degranulate upon IL-2 stimula- Whole exome sequencing revealed a novel homozygous mu-
tion against the K562 target line and fail to produce IFN-γ tation within exon 9 of TCF3 (c.C807T) and resulted in a
upon IL-12 and IL-18 stimulation. Interestingly, although mu- premature stop codon (p.Q270X). The resulting proteins are
tant human IL-2 activated NK cells maintain their cytotoxic predicted to be deleterious since they lack two functional do-
capacity in redirected killing experiments, they fail to do so mains, the activation domain 2 and the bHLH domain. The
against autologous and heterologous EBV infected B cells. parents were heterozygous for the variant.
These data suggest that p85α plays an essential intrinsic Considering the crucial role of TCF3 in the regulation of normal
role for human NK cell effector functions such as cytotoxicity, B cell development, it is not surprising that disruption of this
IFN-γ production and autologous and heterologous EBV- transcription factor causes a profound B cell defect. Since TCF3
infected B cell recognition. These findings may be of impor- is also known to be affected (translocations and deletions) in B-
tant significance for better understanding and managing dif- ALL, this could explain the clinical phenotype herein observed.
ferent clinical conditions, such as primary immunodefi-
ciencies and lymphoid malignancies.
4548: RAPAMYCIN EMPOWERS THE
SUPPRESSIVE ACTIVITY OF
4547: AN AUTOSOMAL RECESSIVE TCF3 FOXP3-MUTATED T REGULATORY CELLS
MUTATION UNDERLIES ASSOCIATION OF AND REVERTS AUTOIMMUNE TISSUE
AGAMMAGLOBULINEMIA AND B-CELL DAMAGE IN ATYPICAL IMMUNE
ACUTE LYMPHOBLASTIC LEUKEMIA. DYSREGULATION POLYENDOCRINOPATHY
ENTEROPATHY X-LINKED (IPEX) SYNDROME
Meriem BEN-ALI1, Koon-Wing Chan2, Najla Mekki3, Imen
Ben-Mustapha3, Fethi Mellouli4, Mohamed Bejaoui, MD5, Laura Passerini 1 , Federica Barzaghi 2 , Rosalia Curto 3 ,
Lamia Aissaoui6, Yu-Lung Lau7 and Mohamed-Ridha Graziano Barera4, Maria Pia Cicalese5, Luca Albarello6,
Barbouche8 Alberto Mariani7, Alessandro Aiuti2 and Rosa Bacchetta8

1 1
Department of Immunology., Institut Pasteur de Tunis, Division of Regenerative Medicine, Stem Cells and Gene
Tunis-Belvédère, Tunisia, Therapy, San Raffaele Telethon Institute for Gene Therapy,
2
Department of Paediatrics and Adolescent Medicine, The IRCCS San Raffaele Scientific Institute, Milan, Italy,
2
University of Hong Kong, Hong-Kong, China, Department of Paediatric Immunohematology and Division
3
Department of Immunology, Institut Pasteur de Tunis, of Regenerative Medicine Stem Cells and Gene Therapy, San
4
Department of Pediatrics, Bone Marrow Transplantation Raffaele Telethon Institute for Gene Therapy, IRCCS San
Center,, Tunis, Tunisia, Raffaele Scientific Institute, Milan, Italy,
5 3
Department of Pediatrics, Bone Marrow Transplantation Division of Regenerative Medicine Stem Cells and Gene
Cener, Tunis, Tunisia, Therapy, San Raffaele Telethon Institute for Gene Therapy,
J Clin Immunol (2016) 36:235–334 293

3
IRCSS San Raffaele Scientific Institute, Milan, Italy, Pediatrics, Centre Hospitalier Universitaire Mont-Godinne,
4
Department of Pediatrics, IRCCS San Raffaele Scientific Yvoir, Belgium,
4
Institute, Milan, Italy, Pediatrics, AZ Delta, Roeselare, Belgium,
5 5
Department of Pediatric Immunohematology, IRCCS San Pediatrics, University Hospitals Leuven, Leuven, Belgium,
6
Raffaele Scientific Institute, Milan, Italy, Laboratory Medicine, Ghent University Hospital, Ghent,
6
Department of Pathology, IRCCS San Raffaele Scientific Belgium,
7
Institute, Milan, Italy, Pediatrics, UZ Brussels, Brussels, Belgium
7
Department of Gastroenterology, IRCCS San Raffaele
Scientific Institute, Milan, Italy, Over the past 6 years, we evaluated 770 unique patients for
8
Department of Pediatrics, Division of Stem Cell Toll-like receptor (TLR) signaling dysfunction. PBMCs were
Transplantation and Regenerative Medicine, Stanford isolated and stimulated with Toll/IL-1R (TIR) superfamily li-
University School of Medicine, Stanford, CA gands. After 24 h, IL-6 was quantified in the cell supernatant.
The IL-6 response to LPS, IL-1β, Poly I:C and imiquimod
Immune-dysregulation, Polyendocrinopathy, Enteropathy, X- weakly correlated with age. The response to IL-1β was higher
linked (IPEX) syndrome is a wasting polyautoimmune disease in female patients than in male patients. Principal component
caused by mutations in FOXP3, resulting in the dysfunction analysis demonstrated clustering of the responses triggered by
FOXP3+ regulatory T cells (Tregs). Along with increasing the classical MyD88-dependent pathway away from responses
awareness of the disease, late/atypical presentations have been triggered by Poly I:C, a TLR3 ligand activating the TRIF-
reported. A 10-year-old boy was examined for decreased growth dependent pathway. Heat-killed S. pneumoniae segregated with
rate with recurrent vomiting. Due to severe gastritis with muco- MyD88-dependent ligands, confirming literature findings.
sal inflammatory infiltrates and high serum levels of anti- Due to the unavailability of reference values, we applied the
harmonin autoantibodies IPEX syndrome was suspected and Bhattacharya algorithm to establish cut-off values for abnor-
confirmed by detection of the c.210+1G>C FOXP3 mutation. mal IL-6 levels after ligand stimulation [Bhattacharya, 1967].
The percentage of CD4+FOXP3+ T cells and FOXP3 expres- Using these values, we identified 17 patients with a confirmed
sion within the CD4+CD25+CD127- Tregs were defective and abnormal response to at least one of the TIR ligands, including
Treg suppressive ability was almost absent. After 2 years of a patient with IRAK-4 deficiency and a patient with NEMO
Rapamycin treatment the expression of FOXP3 doubled, al- immunodeficiency (without ectodermal dysplasia). Careful
though it never reached normal levels. In contrast, Treg function analysis of the clinical and microbiological findings revealed
was restored. Histological evaluation of the gut mucosa showed that a low functional response to TLR ligands was significant-
a marked improvement. Aberrant FOXP3 mRNA isoforms in ly associated with a clinical phenotype characterized by in-
PBMC, confirmed during therapy, remain of unclear patholog- creased susceptibility to bacterial skin infections.
ical meaning. The patient is now clinically stable, although the
presence of elevated anti-harmonin antibodies persists. In con-
clusion, we report a case of IPEX in which clinical response to 4553: LIPOPOLYSACCHARIDE-RESPONSIVE
rapamycin is associated with improved Treg function, not pre- AND BEIGE-LIKE ANCHOR (LRBA) PROTEIN
viously reported in the presence of FOXP3 mutations. DEFICIENCY MANIFESTING WITH
LYPODISTROPHY AND ALPS-LIKE
PHENOTYPE TREATED WITH LEPTIN AND
4551: LOW FUNCTIONAL CYTOKINE RAPAMYCIN.
RESPONSE TO TOLL-LIKE RECEPTOR
LIGANDS IS ASSOCIATED WITH INCREASED Federica Barzaghi1, Laura Passerini2, Claudia Sartirana2, Gill
SUSCEPTIBILITY TO BACTERIAL SKIN Bejerano 3 , Matteo Floris 4,5 , Simone Cesaro 6, Rolando
INFECTIONS Cimaz 7 , Maria Grazia Roncarolo 8 , Ferruccio Santini 9 ,
Raphaela Goldbach-Mansky, MD10, Alessandro Aiuti1 and
Glynis Frans, MPharm1, Leen Moens, PhD1, Greet Wuyts1, Rosa Bacchetta8
Heidi Schaballie, MD2, David Tuerlinckx, MD, PhD3, Mia De
Bie, MD4, François Vermeulen, MD5, Joris Delanghe, MD, 1
Department of Paediatric Immunohematology and Division
PhD6, Jutte van der Werff ten Bosch, MD, PhD7, Isabelle of Regenerative Medicine Stem Cells and Gene Therapy, San
Meyts, MD, PhD2 and Xavier Bossuyt, MD, PhD1 Raffaele Telethon Institute for Gene Therapy, IRCCS San
Raffaele Scientific Institute, Milan, Italy,
1 2
Microbiology and Immunology, KU Leuven, Leuven, Belgium, Division of Regenerative Medicine, Stem Cells and Gene
2
Childhood Immunology, University Hospitals Leuven, Therapy, San Raffaele Telethon Institute for Gene Therapy,
Leuven, Belgium, IRCCS San Raffaele Scientific Institute, Milan, Italy,
294 J Clin Immunol (2016) 36:235–334

3
Department of Developmental Biology, Department of Mohamed Bejaoui, MD 6 , Lamia Boughamoura 7 , Leila
Computer Science, and Division of Medical Genetics, Essaddam8, Saayda BEN-Becher8, Saida Hassayoun9 and
Department of Pediatrics, Stanford University, Stanford, CA, Mohamed-Ridha Barbouche10
4
IRGB CNR, Cittadella Universitaria Monserrato, Cagliari,
1
Italy, Department of Immunology., Institut Pasteur de Tunis,
5
Department of Biomedical Sciences, University of Sassari, Tunis-Belvédère, Tunisia,
2
Sassari, Italy, Department of Immunology, Institut Pasteur de Tunis, Tunis,
6
Pediatric Hematology Oncology, Department of Pediatrics, Tunisia,
3
Azienda Ospedaliera Universitaria Integrata, Verona, Italy, Department of Immunology, Institut Pasteur de Tunis,
7 4
Pediatric Rheumatology, Anna Meyer Children Hospital, Department of Pediatrics, Bone Marrow Transplantation
Florence, Italy, Center,, Tunis, Tunisia,
8 5
Department of Pediatrics, Division of Stem Cell Department of Pediatrics, Children’s Hospital, Tunis,
Transplantation and Regenerative Medicine, Stanford Tunisia,
6
University School of Medicine, Stanford, CA, Department of Pediatrics, Bone Marrow Transplantation
9
Obesity Center, Endocrinology Unit, University Hospital of Cener, Tunis, Tunisia,
7
Pisa, Pisa, Italy, (10)National Institute of Health, National Department of Pediatrics, Farhat Hached Hospital, Sousse,
Institute of Arthritis and Musculoskeletal and Skin Diseases, Tunisia,
8
Bethesda, MD Service de pédiatrie PUC, Hôpital Bechir Hamza de Tunis,
Tunis, Tunisia,
9
LRBA mutations cause autoimmunity, lymphoproliferation Service de pédiatrie de Sousse, Hôpital Sahloul, Sousse,
and humoral immuneÊdeficiency. We describe a patient Tunisia,
10
affected, since the age of 6 months, by autoimmunity/ Department of Immunology., Institut Pasteur de Tunis,
autoinflammation including: panniculitis, evolved in gene- Tunis, Tunisia
ralized lipodystrophy, hypertriglyceridemia, hyperglycemia,
diffuse lymphadenopathy, hepatomegaly with hepatic Phosphoglucomutase 3 (PGM3) enzyme converts N-acetyl-
steatosis, splenomegaly, autoimmune neutropenia, hypo- glucosamine-6-phosphate into N-acetylglucosamine-1-phos-
gammaglobulinemia and periodic fever. Exome sequencing phate, an important precursor for protein glycosylation.
revealed two novel heterozygous mutations in LRBA gene. Recently, mutations in PGM3 gene have been shown to
She showed increased CD4:CD8 ratio with elevated memory underly a new congenital disorder of glycosylation often as-
T cells. Ki67 was increased in CD3, memory CD4 and double sociated to hyper IgE like syndrome. So far, 21 patients with
negative T cells. FOXP3+ T regulatory cells (Tregs) were or without high IgE levels and with a variable clinical pheno-
present but decreased. LRBA expression was reduced, espe- type and outcome have been reported to carry mutations in
cially on CD4+ T cells. Levels of CTLA4 in Tregs and the PGM3.
kinetic of its expression in activated T cells were altered with Herein, we report nine Tunisian patients born to three
slower upregulation as compared to normal donors and faster consanguineous families with autosomal recessive
downregulation, likely contributing to lymphoproliferation. PGM3 deficiency due to the same homozygous muta-
Autoreactive CD21lowCD38low and activated tion p.Glu340del (c.1018_1020del). All of them origi-
CD24brightCD38low B cells were high, while memory B nate from the same rural area in Central Tunisia.
cells were reduced, supporting autoimmune manifestations Segregation analysis using a set of relevant microsatel-
and hypogammaglobuliemia. Rapamycin dramatically re- lite markers overlapping PGM3 gene showed that all
duced lymphoproliferation although a more targeted therapy patients share a 7-MB common homozygous haplotype.
would be desirable. Leptin treatment solved the atypical met- This mutation is associated with severe clinical pheno-
abolic manifestations whose cause remains unclear. type including eczema, cutaneous abcesses, develop-
mental delay and severe mental retardation. T-cell pro-
liferation defect, reversed CD4/CD8 ratio and hyper
4554: A FOUNDER MUTATION IN PGM3 IS IgE were observed. In addition, these patients have se-
RESPONSIBLE FOR A SEVERE FORM OF verely impaired tri and tetra-antennary N-glycan
HYPER-IGE LIKE SYNDROME IN TUNISIAN structures.
PATIENTS A genotype/phenotype correlation is herein observed. The
founder mutation is helping set out a preventive approach
Meriem BEN-ALI 1 , Leila BEN-Khemiss 2, Imen Ben- by genetic counseling in these highly consanguineous
Mustapha3, Najla Mekki3, Fethi Mellouli4, Monia Khemiri5, families.
J Clin Immunol (2016) 36:235–334 295

4559: CHARACTERIZING IMMUNITY IN Rodrigues Fereira, MSc1 and Magda Carneiro-Sampaio,

NORMAL PREGNANCY MD, PhD4

1
Pediatrics, University of Sao Paulo Medical School
1 2
Ehren K. Dancy, BS , Betty Marciano, MD , Lynne Yockey, (FMUSP), Sao Paulo, SP, Brazil,
RN, BSN1, Sharon M. Osgood, MS, RN3, Lisa Barnhart, RN, 2
Pediatrics, University of Sao Paulo Medical School
MSN, CCRP, CAPT, USPHS1, Steve M. Holland, MD2 and (FMUSP), Sao Paulo, Brazil,
Christa S. Zerbe, M.D.2 3
Instituto de Fisica de Sao Carlos USP, Sao Carlos, Brazil,
4
Department of Pediatrics, Universidade de São Paulo, São
1
Laboratory of Clinical Infectious Disease, NIAID - Paulo, Brazil
National Institute of Allergy and Infectious Disease,
Bethesda, MD, Trisomy 21-driven genomic dysregulation on human thy-
2
Laboratory of Clinical Infectious Diseases, NIAID/NIH, mus was assessed by topological analyses of gene
Bethesda, MD, coexpression networks (GCNs)—obtained for differential
3
Dermatology Branch, National Cancer Institute, expressed genes (DE networks), and for the global gene
Bethesda, MD expression (CO networks)—in thymic tissue of Down syn-
drome (DS) and karyotipically normal subjects (CS). These
Risk of severe disease with influenza, Listeria, and data were integrated with miRNA target analysis in order to
Coccidioides, among many other infections, increases dramat- investigate the mechanism by which trisomy 21 alters the
ically in pregnancy for unknown reasons. Hypotheses have canonical thymic transcriptional program. The integration
revolved around T and NK cell function. Studying basic of community structure (modular transcriptional repertoire)
changes might improve our understanding of pregnancy- and miRNA target analyses allowed the identification of the
associated infections. leading GCNs that correspond to thymus functioning in CS
We analyzed CBC and flow cytometry before and after and DS subjects. DE networks are subnetworks of CO net-
26 weeks gestation and at 12–20 weeks post partum in healthy works and the comparative analysis of DS-DE and CS-DE
pregnant women. networks portrays the Bground zero^: the subnetwork tran-
Thirty-seven pregnancies were analyzed, ages 25–42, BMI sition considering only the genes whose transcription was
25, 70 % Caucasian. significantly altered by trisomy 21. Conversely, the com-
parative analysis of DS-CO and CS-CO networks reveals
Advanced Postpartum P value the derived Bshock-waves^ of trisomy 21 genomic dysreg-
Neutrophil 72.5 r 53–83 57.8 r 39–77 <0.0001 ulation, reflecting its effects on the organ’s global transcrip-
NK Cell 135 r 65–276 198 r 77–535 0.0067 tional program. Finally, most of the highly connected genes
Monocyte .58 r 0.26–1.2 0.39 r 0.24–0.88 0.0007
in DS and CS networks were under tight miRNA control—
Advanced Nulliparous Multiparous
including abundantly expressed miRNAs—thus indicating
Neutrophil 7.4 r 6–12 6 r 2–9 0.0063
that epigenetic mechanisms are involved in the thymic ad-
aptation to trisomy 21 dysregulation.
Miscarriage history No history
NK Cell 94 r 65–178 144 r 80–276 0.007

Pregnancy and immunologically distinct subgroups suggest 4565: CHRONIC MUCOCUTANEOUS

innate mechanisms; an area of future study with cytokine CANDIDIASIS ASSOCIATED WITH AN SH2
stimulation and RNAseq. DOMAIN GAIN OF FUNCTION MUTATION
THAT ENHANCES STAT1 PHOSPHORYLATION

Ali Sobh, MD1,2, Janet Chou, MD1, Lynda Schneider, MD1,

4561: TRISOMY 21-DRIVEN GENE Raif S. Geha, MD1 and Michel J. Massaad, PhD1,
EXPRESSION DYSREGULATION IN HUMAN
1
THYMUS: CONVERGING GENOMIC AND Immunology Division, Department of Pediatrics,
EPIGENOMIC MECHANISMS Boston Children’s Hospital, Harvard Medical School,
Boston, MA,
Carlos Alberto Moreira-Filho, PhD1, Silvia Yumi Bando, 2
Infectious Diseases Unit, Department of Pediatrics,
PhD2, Fernanda Bernardi Bertonha, PhD1, Filipi Nascimento Mansoura University Children’s Hospital, Faculty of
Silva, MSc3, Luciano da Fontoura Costa, PhD3, Leandro Medicine, Mansoura University, Mansoura, Egypt
296 J Clin Immunol (2016) 36:235–334

Signal Transducer and Activator of Transcription 1 RESULTS: OF 110 cases identified, common serious
(STAT1) transmits signals from interferon receptors co-morbidity was cancer (15 (13.6 %) hematologic,
(IFNR) and IL-27R. Following receptor signaling and 21 (19.1 %) solid organ)). Mean age was 63.3
STAT1 is phosphorylated (pSTAT1), dimerizes, and ± 15.6 years, 55 (50 %) male. Median follow-up was
translocates to the nucleus where it drives gene tran- 250 (IQR 47–547) days. All-cause mortality was 23
scription. Loss-of-function (LOF) mutations in STAT1 (20.9 %), 14 (12.7 %) within 30 days. Eighty-one
are associated with intracellular bacterial and viral infec- (76.4 %) of 106 isolates serotyped were vaccine-pre-
tions, while gain-of-function (GOF) mutations result ventable. Seven (6.4 % of 110 of whom 17 were test-
mainly in chronic mucocutaneous candidiasis (CMC) ed) had prior documentation of HGG (IgG level < 7 g/
with autoimmunity, viral infections, and delayed shed- L), and we identified an additional six (40 % of 15
ding of deciduous teeth. GOF mutations have been previously untested survivors subsequently tested in
identified in the coiled-coil and DNA-binding domains our follow-up). An arithmetical of prevalence estimate
and have been found to impair the dephosphorylation of of HGG in IPI is from 13/110 (12 %) as detected over-
the mutant protein. all, to of 7/17 tested prior plus 6/15 later, 41 % of 32
We describe for the first time a gain-of-function mutation actually tested. Eleven of 15 hematologic cancer cases
(p.H629Y) in the src-homology 2 (SH2) domain of STAT1. with IPI had underlying HGG. CONCLUSIONS: IPI
In contrast, to the previously described STAT1 GOF muta- has high mortality, and most are vaccine-preventable.
tions, the mutation we describe is associated with increased We estimated prevalence of HGG at 12–41 %.
phosphorylation of the mutant STAT1, with a normal rate of Patients with IPI should be screened for HGG and con-
pSTAT1 dephosphorylation. ventional preventative treatments should be offered to
The crystal structure of STAT1 in complex with its avoid IPI.
IFNγRα chain docking peptide 440pYDHH444 reveals
that H629 in STAT1 interacts via a hydrogen bond with
D441 in 440pYDHH444. The H629Y mutation might 4567: HYPOGAMMAGLOBULINEMIA IN A
disrupt this interaction within the STAT1-INFR-JAK PATIENT WITH MULTIPLE NON-MELANOMA
complex, to result in a faster rate of STAT1 phosphor- SKIN CANCERS
ylation, the generation of more pSTAT1, and an exag-
gerated response to IFNs. Chelsea Michaud, D.O.1,2, Derrick Heydinger 3 , Brian
Peppers, D.O. 1 , 4 , Devi Jhaveri, D.O. 1 , 2, 4 , 5 , 6 , Haig
Tcheurekdjian, MD1,2,4,5,6 and Robert W. Hostoffer Jr.,
4566: ESIMATED PREVALENCE OF DO1,2,4,5,6
HYPOGAMMAGLOBULINEMIA IN PATIENTS
1
WITH INVASIVE PNEUMOCOCCAL Allergy/Immunology Associates, Inc, Mayfield Heights, OH,
2
INFECTION University Regional Hospitals, Richmond Heights, OH,
3
Ohio University, Athens, OH,
Juthaporn Cowan, MD, PhD, FRCPC 1 , 2 , Sacha 4
Case Western Reserve University, Cleveland, OH,
Desjardins 2 , Karamchand Ramotar, PhD 3 and Donald 5
University Hospitals Case Medical Center, Cleveland, OH,
William Cameron, MD, FRCPC, FACP1,2 6
Lake Erie College of Osteopathic Medicine, Erie, PA

1
Division of Infectious Diseases, Department of Medicine, Hypogammaglobulinemia is characterized by reduced anti-
University of Ottawa, Ottawa, ON, Canada, body production secondary to impaired B-cell differentiation,
2
Clinical Epidemiology Program, The Ottawa Hospital classically resulting in recurrent upper respiratory tract infec-
Research Institute, Ottawa, ON, Canada, tions. To our knowledge, multiple invasive squamous cell
3
Pathology and Laboratory Medicine, University of Ottawa, carcinomas (SCC) are rarely reported in CVID or
Ottawa, ON, Canada hypogammaglobulinemia.
We present a 55 year old female with a 2.5 year history
BACKGROUND: Humoral immunity is essential for of intermittent fevers, lymphadenopathy, arthralgia, my-
controlling encapsulated bacterial infection. algia, weight loss, hair loss, poor wound healing, mul-
METHODS: Chart and database review of Invasive tiple episodes of sinusitis requiring antibiotics and most
pneumococcal infection (IPI) cases (Streptococcus significantly, multiple separate excisions for non-
pneumoniae in blood or cerebrospinal fluid) from melanoma skin cancers including 14 SCC and 4 basal
January 2013 to June 2015 was performed to estimate cell carcinomas. Additionally she had an SCC on Pap
prevalence of hypogammaglobulinemia (HGG). smear as well as vulvar SCC in situ. Initial evaluation
J Clin Immunol (2016) 36:235–334 297

revealed an elevated sedimentation rate (54 mm/h) and all family members as carriers. Premature stop codons often
low IgG (529 mg/dL) with otherwise normal work-up result in nonsense mediated decay of mRNA, leading to ab-
including a lymph node biopsy which was benign. sence of protein product. Pre-transplant plasma ADA2 en-
This patient is currently being evaluated with post vac- zyme activity was absent in the patient and intermediate in
cination titers and flow cytometry to further diagnose the family members; post-transplant ADA2 levels were within
the immune dysfunction. normal limits. Missense mutations in CECR1/ADA2 have
Prolonged immunosuppression can predispose to malignancy, recently been associated with early onset stroke and vasculop-
notably leukemia and lymphoma. The increased incidence of athy (Zhou, 2014) and polyarteritis nodosa (Elkan, 2014).
skin cancer in immunodeficiency is not often reported. This Unlike previously reported cases, our patient did not show
rare case of multiple cutaneous carcinomas in a patient with signs of vasculopathy or stroke. ADA2 deficiency may have
hypogammaglobulinemia may add further to the literature on a broader clinical phenotype than previously known.
immunodeficiency and carcinomas.

4573: DISCRIMINATION AMONG MONOGENIC

4569: NOVEL CECR1 MUTATION MIMICKING AND ACQUIRED DISEASE WITH
GATA2 DEFICIENCY INFLAMMATORY AND AUTOIMMUNE
COMPONENT THROUGH THE IN VITRO
Amy P Hsu, BA1, Robert R. West, PhD2, Katherine Calvo, STUDY OF SIGNAL TRANSDUCERS OF TYPE I
M.D.3, Susan J. Kelly, PhD4, Nancy J. Ganson, PhD4, Mark INTERFERON
Parta, MD5, Jennifer Cuellar-Rodriguez, M.D.1, Michael
Hershfield, MD6, Dennis D. Hickstein, M.D.7 and Steven Donatella Vairo1, Rosalba Monica Ferraro1, Jessica Galli2,
M. Holland, MD1 Micaela De Simone2, Giulia Zani3, Marco Cattalini3, Elisa
Fazzi2 and Silvia Giliani4
1
Laboratory of Clinical Infectious Diseases, National Institute
1
of Allergy and Infectious Diseases, National Institutes of Department of Molecular and Traslational Medicine,
Health, Bethesda, MD, University of Brescia, Brescia, Italy,
2 2
Experimental Transplantation and Immunology Branch, Spedali Civili, Brescia, Italy,
3
National Cancer Institute, Bethesda, MD, University of Brescia, Brescia, Italy,
3 4
Hematology Section, Department of Laboratory Medicine, Department of Molecular and Traslational Medicine,
Clinical Center, National Institutes of Health, Bethesda, MD, A.Nocivelli Institute of Molecular Medicine, Dept. of
4
Department of Medicine, Duke University School of Pathology, University of Brescia
Medicine, Durham, NC,
5
Clinical Research Directorate/Clinical Monitoring Research Type I Interferon (IFNa/b) modulate many aspects of immune
Program, Leidos Biomedical Research, Inc, Frederick and inflammatory reactions. Type I Interferonopathies are a
National Laboratory for Cancer Research, Frederick, MD, heterogeneous group of monogenic and acquired disorders, in
6
Department of Biochemistry, Duke University School of which increased expression of Type I IFN plays a central
Medicine, Durham, NC, pathogenetic role. Here we describe a method to discriminate
7
Experimental Transplantation and Immunology Branch, different diseases belonging to this group by mean of
Division of Basic Sciences, National Cancer Institute, inflammation/autoimmunity signal transduction pathways
National Institutes of Health analysis. We analyzed the various transducers in Aicardi-
Goutières Sindrome (AGS), Systemic Lupus Erythematosus
A 20 year old female was referred to the NIH with a diagnosis (SLE) and SLE-like patients. We assessed on T-cells and
of CVID and history of cytopenias, hypogammaglobulinemia, monocytes by flow cytometry the activation of STAT1 follow-
pulmonary nontuberculous mycobacterial infection and recur- ing cytokine stimulation. All patient’s primary cell showed a
rent Fusarium proliferatum sinusitis. She had neutropenia, significative increase in activation and expression of STAT1
monocytopenia and severe B cell lymphopenia. Bone marrow as compared to normal donors. Patients’ cell lines either of
was hypocellular without neutrophil precursors. hematopoietic or somatic origin showed STAT1 signaling and
Haploidentical HSCT from her healthy sibling led to neutro- expression alterations only in AGS derived cell lines.
phil engraftment on day +19, 100 % donor T cell and myeloid Similarly, gene expression induced by type I IFN via STAT1
engraftment by day 30 with B and NK cell engraftment after is altered in all patients in primary cells, while only in the AGS
1 year. Whole exome sequence identified a novel, homozy- we demonstrated a constitutive activation maintaining a high
gous change in CECR1, encoding ADA2 (c.794C>G, IFN score. Although these diseases share a high production of
p.Q268X). Sanger sequencing confirmed this and identified type I IFN, they differ in pathogenesis and given the results
298 J Clin Immunol (2016) 36:235–334

2
obtained, we can consider these assays useful in differential Fungal Pathogenesis Unit, Laboratory of Clinical Infectious
diagnosis of patients with suspected Interferonopathies and Diseases, National Institute of Allergy and Infectious
therapeutic effects monitoring. Diseases, National Institutes of Health, Bethesda, MD,
3
Division of Blood and Marrow Transplantation and Cellular
Therapies, Children’s Hospital of Pittsburgh, Pittsburgh, PA,
4
4574: DOCK8 AND ITS GUANINE NUCLEOTIDE Division of Medicine - Pulmonary, Critical Care & Sleep
EXCHANGE ACTIVITY ARE REQUIRED FOR Medicine, North Shore University Hospital, New Hyde
REGULATORY T CELL HOMEOSTASIS AND Park, NY,
5
FUNCTION Division of Allergy & Immunology, Cohen Children’s
Medical Center of New York, Great Neck, NY,
6
Erin Janssen, MD, PhD, Sumana Ullas, MS, Mona Hedayat, Leidos Biomedical Research, Inc., NCI-Frederick, Frederick,
MD and Raif S. Geha, MD MD

Boston Children’s Hospital, Boston, MA A 37 year old woman was evaluated for CID,
hypogammaglobulinemia, pancytopenia, recurrent pneumo-
DOCK8 deficient patients have a tendency towards develop- nias, and bronchiectasis. Sputum had grown nontuberculous
ing autoimmunity. We previously demonstrated that DOCK8 mycobacteria and Aspergillus.
deficient patients have increased serum autoantibodies. They Whole exome sequencing identified a novel, de novo, het-
also have a defect in the peripheral B cell tolerance check- erozygous change in RAC2, p.E62K. Neutrophil studies
point, which was associated with a decrease in their peripheral showed intact chemotaxis but impaired chemokinesis, in-
blood regulatory T (Treg) cell percentage and in vitro suppres- creased specific and primary granule marker staining and
sive activity. To better understand this Treg cell defect, we low CD62L, all suggesting persistent activation.
generated Dock8−/− mice, which express no detectable Superoxide (O2-) was normal at baseline and after PMA
DOCK8 protein in their tissues. Like, DOCK8 deficient pa- treatment, but showed a prolonged response after fMLP.
tients, Dock8−/− mice have a peripheral CD4+ T cell lympho- Both fMLP and IL-8 dependent calcium flux were im-
penia. In addition, the percentage of CD25+Foxp3+ Treg cells paired regardless of dose. Electron microscopy showed
out of total CD4+ cells is decreased in their spleen and lymph large membrane bound vacuoles in the cytoplasm.
nodes. Furthermore, DOCK8 deficient Treg cells have de- Previous reports of mutations in the GTP binding pro-
creased in vitro suppressive activity, diminished expression tein, RAC2, include two young children with CVID homo-
of CD25 (IL-2Rα) on their surface, and increased apoptosis zygous for p.W56X who presented with pulmonary infec-
and cell death. We also examined the Treg cell compartment in tions, hypogammaglobulinemia and bronchiectasis. Two
Dock8pri/pri mice that express a DOCK8 protein with a other infants with heterozygous RAC2 p.D57N mutations
S1827P mutation in the DHR2 domain. This mutation abol- had severe neutrophil defects, lymphocytosis and
ishes the ability of DOCK8 to act as a guanine exchange factor neutrophilia. Our patient has a novel mutation at the highly
for CDC42. Dock8pri/pri mice had a similar Treg cell profile conserved glutamate 62, which is required for guanine nu-
with a decrease in percentage, in vitro activity, CD25 expres- cleotide exchange factor mediated nucleotide exchange;
sion, and increased apoptosis. These results suggest that this appears to confer some gains and some losses of func-
DOCK8, and, in particular, its CDC42 exchange activity, is tion. The patient has undergone unrelated donor HSCT and
required for proper Treg homeostasis and function. has engrafted post transplant.

4576: NOVEL HETEROZYGOUS RAC2 4577: DEFECTS IN HUMAN B-CELL

MUTATION PRESENTING AS COMBINED DEVELOPMENT AND DIFFERENTIATION DUE
IMMUNODEFICIENCY. TO DISEASE-CAUSING MUTATIONS IN THE
PI3K PATHWAY
Amy P Hsu, BA1, Muthulekha Swamydas, PhD2, Michail S.
Lionakis, MD, ScD2, Paul Szabolcs, MD3, Harry Steinberg, Stuart G. Tangye
MD4, Vincent R Bonagura, MD5, Douglas B. Kuhns, PhD6
and Steven M. Holland, MD1 Immunology Division, Garvan Institute of Medical Research,
Darlinghurst, Australia
1
Laboratory of Clinical Infectious Diseases, National Institute
of Allergy and Infectious Diseases, National Institutes of Gain of function (GOF) mutations in PIK3CD, encoding
Health, Bethesda, MD, p 110 d su bu n i t of P I 3- k i n as e, ca use s a pr i m ar y
J Clin Immunol (2016) 36:235–334 299

immunodeficiency characterized by recurrent respiratory bronchiectasis. Sanger sequencing of NEMO gene revealed a
tract infections, and increased susceptibility to herpes (EBV, novel missense variant c.860_862delAGG in IKBKG gene.
CMV, VZV) viruses, and B-cell lymphoma. These individuals MGF, not patient, was noted to be mosaic. Targeted sequenc-
exhibit clear defects in humoral immunity, evidenced by poor ing in MGF sorted cells is undergoing. Patient’s respiratory
Ab responses to both protein and polysaccharide Ags. To gain symptoms significantly improved with the addition of inhaled
a better understanding of defects in humoral immunity due to tobramycin and mycobacterial prophylaxis. Donor search
PIK3CD GOF, we performed detailed analysis of B-cell de- identified no fully matched donors for SCT.
velopment, differentiation and function in these individuals. In The atypical disease course in the grandfather probably can be
peripheral blood, there was a stark increase in the proportion attributed to somatic reversion. Effect on prognosis and manage-
of transitional (CD20+CD10+CD27−) and a reduction in mem- ment is unknown. Further clinical and immunological follow-up
ory (CD20+CD10−CD27+) B cells; within the memory subset of patients over time may provide valuable information, espe-
the proportion of IgG+ cells was also dramatically reduced. cially in those not considered good candidates for SCT.
Strikingly, the phenotype of naïve B cells with PIK3CD GOF
mutations resembled that of normal transitional B cells, indi-
cating aberrant arrest of developing B cells. In vitro functional 4580: CTLA-4 MISSENSE MUTATION LEADS
analyses revealed an intact ability of naïve PIK3CD GOF B TO EXPANDED GERMINAL CENTERS WITH
cells to initiate differentiation to the plasma cell lineage, but a INCREASED T-FOLLICULAR HELPER CELLS
selective impediment in in undergoing class switching and AND DECREASED T-FOLLICULAR
secretion of IgG. These results indicate that intrinsic defects REGULATORY CELLS IN A PATIENT WITH
in B-cell development and differentiation underlie poor hu- AUTOIMMUNE LYMPHOPROLIFERATIVE
moral immune responses that are characteristic of individuals SYNDROME-LIKE DISEASE
with PIK3CD GOF mutations.
Louis-Marie Charbonnier, PhD1, Talal A Chatila, MD,
M.Sc.1, Richard McMasters, MD2, Jack J. Bleesing, MD,
4578: GERMLINE MUTATION WITH SOMATIC PhD3 and Zeynep Yesim Kucuk, MD3
1
REVERSION IN A PATIENT WITH A NOVEL Division of Immunology, The Children’s Hospital, Boston,
MISSENSE VARIANT IN IKBKG GENE MA,
2
CAUSING X- LINKED ECTODERMAL Division of Pathology, Cincinnati Children’s Hospital
DYSPLASIA WITH IMMUNE DEFICIENCY Medical Center,
3
Division of Bone Marrow Transplantation and Immune
Manar Abdalgani, MD1, Ashley Brazil, MS2, Christopher Deficiency, Cincinnati Children’s Hospital Medical Center,
Towe, MD 3, Jack J. Bleesing, MD, PhD 1 and Zeynep Cincinnati, OH
Yesim Kucuk, MD1
CTLA-4 haploinsufficiency is found in patients with
1
Division of Bone Marrow Transplantation and Immune hypogammaglobulinemia, recurrent infections, cytopenia
Deficiency, Cincinnati Children’s Hospital Medical Center, and lymphocytic infiltrations.
Cincinnati, OH, We describe a patient with autoimmune lymphoproliferative
2
Division of Genomics and Human Genetics, syndrome (ALPS), found to have CTLA-4 haploinsufficiency
3
Division of Pulmonology, Cincinnati Children’s Hospital with expanded germinal centers and increased T-follicular
Medical Center helper (TFH) and decreased TF-regulatory (TFR) cells.
Patient is 15 year old female with a history of recurrent sto-
We report a case of XL-EDA-ID with a family history of an matitis, intermittent lymphadenopathy and multi-lineage auto-
affected maternal grandfather (MGF), who showed somatic immune cytopenia, referred for ALPS. Ig levels and titers
reversion of the same NEMO mutation in the proband. were normal. She had increased double-negative T cells, de-
A 10 year old male with a former diagnosis of CVID and creased isotype-switched CD27+ memory B cells and in-
recurrent sinopulmonary infections complicated by septic creased CD19 + CD21 − CD38 − B cells. ALPS markers
shock due to pseudomonas infections, despite SQIG replace- Vitamin-B12, IL-10, and sFASL were normal, while IL-18
ment, good IgG levels and antibiotic prophylaxis, was noted to levels were elevated. NextGen ALPS panel remained nega-
have conical teeth. His MGF, with a similar teething pattern tive. Histopathology revealed expanded germinal centers and
has demonstrated infections, clustered in ages <12 and bet- marked chronic inflammation and fibrosis. BCL6 staining
ween 40 and 70. MGF has never been on antibiotic prophy- demonstrated follicular center cells in germinal centers.
laxis. Patient’s immune work-up revealed elevated inflamma- CTLA-4 sequencing revealed a previously shown pathologic
tion markers, decreased memory B cells. HRCT demonstrated variant, c.223C>T (p.R75W). In vitro studies revealed
300 J Clin Immunol (2016) 36:235–334

increased TFH cells with decreased TFR cells, and defective Rosen, BS1, Tatyana Tavella, Elise Ferrer6, Christa S. Zerbe,
Treg suppression. M.D.1, Michail Lionakis7 and Steve M. Holland, MD1
These results confirm the need to screen for CTLA4 deficien-
1
cy in patients with ALPS-like clinical presentations and high- Laboratory of Clinical Infectious Diseases, NIAID/NIH,
light the essential role of CTLA4 in regulation of the human Bethesda, MD,
2
germinal center response. Laboratory of Clinical Infectious Diseases, National Institute
of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD,
3
4581: A NOVEL NFKB2 MUTATION Fungal Pathogenesis Unit - LCID / NIAID,
4
INTERFERES WITH THE ACTIVITY OF Computational Biology Section - OCICB- NIAID / NIH,
5
CANONICAL AND NONCANONICAL NF Laboratory of Clinical Infectious Diseases (LCID),
6
KAPPA B SIGNALLING PATHWAY Fungal Pathogenesis Unit - Laboratory of Clinical Infectious
Diseases, NIH
Yiwen Liu1 and Mohammad A. A. Ibrahim2
We found the novel STAT1 gain of function (GOF) mutation
1
Viapath at King’s College Hospital, London, United c.2114A>T, p.E705V in a patient with disseminated
Kingdom, Rhodococcus infection, Norwegian scabies, CMC, hypothy-
2
Faculty of Life Sciences & Medicine, Division of Asthma, roidism and esophageal squamous cell carcinoma. The muta-
Allergy & Lung Biology, King’s College London, King’s tion is located in the tail segment within the motif
Health Partners, King’s College Hospital NHS Foundation 702IKTE705 and is predicted to disrupt STAT1 sumoylation.
Trust, London, United Kingdom Mutation at the adjacent residue, L706S, is clearly loss of
function. Post-translational modification by SUMO (small
Common variable immunodeficiency (CVID) is a heteroge- ubiquitin-related modifier) is an important regulator of protein
neous primary immunodeficiency disorder. A few single gene function. Functional impact of the mutation was evaluated in
defects have been associated with CVID in approximately transfected cells. Co-immunoprecipitation experiments con-
20 % of patients. Recently we identified a germline mutation firm absent STAT1 sumoylation for E705V, while it is present
within the c-terminal region of NF KB2gene, which leads to with WT STAT1, as well as the LOF mutants L706S and
defective processing of NFκB2 protein. Here, we investigated Y701C. Assays performed in U3C STAT1-deficient cells evi-
effects of this mutation on the interaction of canonical and denced delayed tyrosine dephosphorylation, following stimu-
noncanonical NFκB signalling. lation with IFN-gamma, enhanced DNA binding, and in-
EBV-transformed lymphoblastoid cell lines (LCLs) from both creased IFN-gamma target gene expression in the E705V
patient and her healthy sibling were used to study the NFκB transfected cells compared with WT STAT1. Modeling anal-
pathway. We demonstrated that nuclear levels of p52 and Rel B ysis of STAT1 shows that Y701 is mostly buried and unavail-
from patient’s LCLs were markedly decreased compared to able for phosphorylation with the L706S, whereas it is more
control, before and after CD40L stimulation. Nuclear level of exposed with the E705V mutation. This is the first report of a
c-Rel from patient’s LCLs was increased compared to control. mutation in the STAT1 sumoylation motif associated to clin-
However, unlike control, there was no further nuclear c-Rel ical disease. Such finding indicates that sumoylation is impor-
induction in patient’s LCLs after CD40L stimulation. With tant in STAT1 signaling and points to a novel regulatory
TransAM analysis, we confirmed that basal level of DNA- mechanism in GOF STAT1.
binding capacity of p52 and Rel B from patient’s LCLs were
significantly reduced to 39 ± 9 and 24 ± 8 %, respectively, com-
pared to control. However, c-Rel DNA-binding capacity in pa- 4583: GENETIC DIAGNOSIS USING WHOLE
tient’s LCLs was significantly decreased compared to control. EXOME SEQUENCING IN SEVERE CVID
Interestingly, IkBα level was significantly reduced in patient’s PHENOTYPES
LCLs, compared to control. These findings partially account for
the characteristic phenotype of patients with this mutation. Patrick Maffucci, BA1, Charles A. Filion, MD, FRCPC1,
Bertrand Boisson, PhD2, Yuval Itan, PhD2, Jean-Laurent
Casanova, MD, PhD2 and Charlotte Cunningham-Rundles,
4582: NOVEL STAT1 GOF MUTATION MD, PhD1
AFFECTING PROTEIN SUMOYLATION
1
Division of Clinical Immunology, Department of
1 2
Elizabeth P. Sampaio, MD, PhD , Li Ding, MD , Stacey Medicine, Icahn School of Medicine at Mount Sinai,
Rose3, Phillip Cruz, Ph.D4, Amy P Hsu, BA2, Lindsey B. New York, NY,
J Clin Immunol (2016) 36:235–334 301

2
St-Giles Laboratory of Human Genetics of Infectious controls. We utilized an Electronic Health Record (EHR) to
Diseases, Rockefeller University, New York, NY estimate the rate of dysgammaglobulinemias in patients diag-
nosed with TS or OCD.
Purpose: Whole Exome Sequencing was used to survey the Using the EHR we identified children diagnosed with the
landscape of mutations in a cohort of patients with Common following conditions: OCD, TS, Anxiety disorders,
Variable Immune Deficiency (CVID) with severe clinical phe- ADHD, Autism Spectrum Disorders, and Celiac Disease.
notypes. We sought to provide a framework for clinicians These populations were queried for diagnosis of IgA de-
seeking to dissect the etiology of unknown antibody deficien- ficiency and IgA levels. Least square means, adjusting for
cies in their patients. age at blood draw, were performed to observe differences
Methods: Massively parallel whole exome sequencing in immunoglobulin levels between groups. ANCOVA
(WES) was performed on genomic DNA. Exomes were were performed to examine the difference in rates of im-
screened for mutations in 279 genes reported to cause mune deficiency.
Primary Immunodeficiencies (PIDs). Patients with OCD had significantly lower (p < 0.05) mean
Results: We performed WES on 50 patients with charac- IgA levels than patients with anxiety disorders or ADHD.
teristics of CVID who demonstrate a positive family histo- There was a higher rate of IgA deficiency in OCD than in
ry, onset under age 15, absence of B cells, and/or severe TS (OR 3.5), autism (OR 2.9), ADHD (OR 2.0), or non-
autoimmunity. Heterozygous mutations were identified in OCD anxiety disorders (OR 2.46). There was no significant
32 genes, including STAT3, CTLA4, PIK3CD, and difference in IgA deficiency or mean IgA levels between OCD
NFKB1. 23 of these mono-allelic mutations have been re- and celiac disease.
ported to be rare (<0.1 %) while 20 are novel. We also Compared to controls, patients with pediatric-onset OCD may
identified two sets of rare compound heterozygous muta- display higher rates of IgA deficiency, than children with other
tions in LRBA in two of our patients. All the mutations are psychiatric conditions.
predicted to severely impact protein function and are likely
to cause immunodeficiency in the affected patients.
Overall, potential causative mutations were identified in 4585: CLINICAL SPECTRUM AND OUTCOME
22 of our highly selected 50 patients (44 %). OF TREATMENT FOR AUTOIMMUNE
Conclusion: The approach of using WES combined with CYTOPENIAS IN RAG DEFICIENCY
targeted screening of the 279 genes offers a simplified ap-
proach to clinicians wishing to use WES to determine the Zsofia Foldvari, MD 1,2 , Boglarka Ujhazi 3,4 , Hassan
genetic cause of PIDs in their patients. Abolhassani, MD, PhD5, Roshini Abraham, PhD6, Mehdi
Adeli, MD7,8,9, Asghar Aghamohammadi, MD, PhD 10,
Waleed Al-Herz, MD 11 , Aia Assaf-Casals 1 2 , Alice
4584: IgA DEFICIENCY IS ASSOCIATED WITH Bertaina, MD, PhD13, Jack J. Bleesing, MD, PhD14,15,
PEDIATRIC OBSESSIVE COMPULSIVE Claire Booth, PhD 16 , David Buchbinder, MD, MS 17 ,
DISORDER Caterina Cancrini 18 , Karin Chen, MD 19 , Janet Chou,
MD20, Beatriz Tavares Costa-Carvalho, MD21, Ghassan
Kyle A. Williams, MD, PhD1, Leah Shorser-Gentile, BA2, Dbaibo, MD12, Suk See DeRavin, MD PhD22, Meredith
Suraj Sarvode, MPH2, Mark S. Pasternack, MD3, Daniel A. A Dilley, MD23,24, Cullen M Dutmer, MD25, Martha M
Geller, MD1 and Jolan Walter, MD, PhD4 Eibl 26 , Polly J Ferguson, MD 27, Christoph B Geier 26 ,
Raif S. Geha, MD 20 , Erwin W. Gelfand, MD 28 , Rima
1
Psychiatry / Child Psychiatry, Massachusetts General Hanna-Wakim 12 , Steven M. Holland, MD 29 , Avni Y
Hospital, Boston, MA, Joshi, MD, MSc 3 0 , Maria Kanariou, MD 31 , Franco
2
Psychiatry, Massachusetts General Hospital, Boston, MA, Locatelli 32, E Lykopoulou, MD 33, Michel J. Massaad,
3
Pediatric Infectious Disease, Massachusetts General PhD20, Sarah Kogan Nicholas, MD34,35, Paolo Palma36,
Hospital, MA, Turkan Patiroglu, MD 37,38 , Jennifer M. Puck, MD 39 ,
4
Department of Pediatrics, Division of Allergy & Andreas Reiff, MD40, Catharina Schuetz, MD, MSc 41,
Immunology, Massachusetts General Hospital, Boston, MA John Sleasman, MD 42 , Ekrem Unal, MD 43 , Hermann
Wolff26, Luigi D Notarangelo, MD44 and Jolan E. Walter,
Neuronal inflammation and brain-based autoimmunity are hy- MD PhD3,4,45
pothesized etiologies of pediatric onset obsessive-compulsive
1
disorder (OCD) and tic disorders. Pilot studies have revealed Department of Immunology, Faculty of Medicine,
decreased concentrations of immunoglobulins in both University of Debrecen, Debrecen, Hungary,
2
Tourette syndrome (TS) and OCD compared to healthy Pediatric Allergy and Immunology and the Center for
302 J Clin Immunol (2016) 36:235–334

23
Immunology and Inflammatory Diseases, Massachusetts Department of Immunology, Boston Children’s Hospital,
General Hospital, Harvard Medical School, Boston, MA, Boston, MA.,
3 24
Division of Pediatric Allergy/Immunology, Massachusetts Harvard Medical School, Boston, MA,
25
General Hospital for Children, Boston, MA, Division of Allergy & Immunology, Children’s Hospital
4
Center for Immunology and Inflammatory Diseases, Colorado, University of Colorado School of Medicine,
26
Massachusetts General Hospital, Harvard Medical Immunology Outpatient Clinic, Vienna, Austria,
27
School, Boston, MA, Department of Pediatrics, University of Iowa Carver
5
Research Center for Immunodeficiencies,, Pediatrics College of Medicine; Iowa City, IA, USA,
28
Center of Excellence, Children’s Medical Center, Tehran Department of Pediatrics - Division of Pediatric Allergy and
University of Medical Sciences, Tehran, Iran., Clinical Immunology, National Jewish Health, Denver, CO,
6 29
Laboratory Medicine and Pathology, Mayo Clinic, Laboratory of Clinical Infectious Diseases, NIAID/NIH,
Rochester, MN, Bethesda, MD,
7 30
Pediatrics, Weill Cornell Medical College in Qatar, Doha, Division of Pediatric Allergy/Immunology, Mayo Clinic,
Qatar, Rochester, Minnesota,
8 31
Allergy and Immunology, Sidra Medical and Research Department of Immunology-Histocompatibility,
Center, Doha, Qatar, Doha, Qatar, Specialized Center and Referral Center for Primary
9
Hamad Medical Corporation, Hamad Medical Immunodeficiencies-Pediatric Immunology, Aghia Sophia
Corporation, Doha, Qatar, Children’s Hospital, Athens, Greece, Athens, Greece,
10 32
Research Center for Immunodeficiencies, Pediatrics Department of Pediatric Hematology and Oncology,
Center of Excellence, Children’s Medical Center, Tehran Ospedale Pediatrico Bambino Gesu’, Roma, Italy,
33
University of Medical Sciences, Tehran, Iran, Tehran, Iran Department of Pediatric Hematology and Oncology, IRCCS
(Islamic Republic of), Bambino Gesù Children’s Hospital, Rome, Italy,
11 34
Pediatrics Department, Faculty of Medicine, Kuwait Department of Pediatrics, Baylor College of Medicine,
35
University, Section of Allergy and Immunology, Texas Children’s
12
Department of Pediatrics and Adolescent Medicine, Hospital, Houston, TX, USA.,
36
Center for Infectious Diseases Research, American Department of Pediatrics, Bambino Gesù Children’s
University of Beirut, Beirut, Lebanon, Hospital and University of Tor Vergata School of Medicine,
13
Stem Cell Transplant Unit Department of Onco- Rome, Italy.,
37
Hematology, Bambino Gesù Children’s Hospital, Rome, Department of Pediatric Hematology and Oncology, Erciyes
Italy, University School of Medicine, Kayseri, Turkey.,
14 38
Division of Bone Marrow Transplantation and Immune Department of Pediatric Immunology, Erciyes University
Deficiency, Cincinnati Children’s Hospital Medical Center, School of Medicine, Kayseri, Turkey,
39
Cincinnati, OH, Pediatric Immunology and Bone Marrow Transplantation,
15
Cincinnati Children’s Hospital Medical Center, University of California, San Fransisco, San Fransisco, CA,
16 40
Department of Paediatric Immunology, Great Ormond Children’s Hospital Los Angeles, USC Keck School of
Street Hospital, London, United Kingdom of Great Medicine, Los Angeles, CA, USA,
41
Britain and Northern Ireland, Department of Pediatrics and Adolescent Medicine,
17
Pediatrics / Hematology, CHOC Children’s Hospital - University Hospital Ulm, Ulm, Germany,
42
UC Irvine, Orange, CA, Division of Allergy and Immunology, Duke University
18
Department of Pediatrics, Children’s Hospital Bambino School of Medicine, Durham, NC,
43
Gesù and University of Rome Tor Vergata School of Department of Pediatric Hematology and Oncology, Erciyes
Medicine, Rome, Italy, University School of Medicine, Kayseri, Turkey,
19 44
Division of Allergy, Immunology & Rheumatology, Division of Immunology, Boston Children’s Hospital,
Department of Pediatrics, University of Utah, Salt Lake Harvard Medical School,
45
City, UT, Division of Immunology, Boston Children’s Hospital,
20
Immunology Division, Department of Pediatrics, Boston Harvard Medical School, Boston, MA
Children’s Hospital, Harvard Medical School, Boston, MA,
21
Department of Allergy, Clinical Immunology and The clinical presentation of patients with hypomorphic RAG
Rheumatology, Federal University of Sao Paulo, Sao Paulo, mutations is diverse with autoimmunity being associated with
Brazil, delayed diagnosis, complications and death. Out of our cohort
22
Laboratory of Host Defenses, National Institute of Allergy of over 50 patients with RAG mutations, we identified 31
and Infectious Diseases, National Institutes of Health, patients with autoimmunity (62 %) with average age of
Bethesda, MD, 11 years. One third of the patients with autoimmunity
J Clin Immunol (2016) 36:235–334 303

deceased, mainly secondary to infections (at mean age of (p = 0.0072) between patients who were subsequently treated
16 years). with immunoglobulin replacement (n = 7) based on their IgG
Autoimmune cytopenias were found in 77 % of the cases, level and response to immunization, and those who were not
and involved multiple lineages (Evans syndrome, 29 %). (n = 5).
Autoimmune hemolytic anemia (AIHA) (61 %) was the CONCLUSION: A pneumococcal assay, which includes
most frequent autoimmune complication in our cohort. complement fixation, may provide a useful tool to assess func-
The average onset of AIHA, autoimmune neutropenia tional antibacterial antibody. Standardizing the test in a larger
(AN), idiopathic thrombocytopenic purpura (ITP) was cohort of patients will be the next step.
4.3, 4.78, 3.7 years, and lasted for 2.2, 1.5 and 2.8 years
respectively. Data on effective treatment is was available
for over 50 % of patients. Successful treatment of AIHA 4587: STAT3 GOF MUTATION MIMICKING
was achieved with hematopoietic HSCT in 15.79 %, IVIG AUTOIMMUNE LYMPHOPROLIFERATION
in 10.53 %, IVIG-steroid 10.53 %, IVIG-rituximab, IVIG- SYNDROME (ALPS)
CSA, 6MP-rituximab, steroid alone in 5.26 % of the
cases, each. Rituximab was effective in 12.5 % of AN Olaf Neth1, Peter Olbrich, MD1, Carsten Speckmann, MD2,
patients but 50 % recovered only after HSCT. 12.5 % of Paola Cura Daball2, Anne Rensing-Ehl2, Paula Sanchez
the patients died neutropenic, before HSCT. A variable Moreno1, Marta Benavides Nieto1, Marta Melon1, Jose
response of ITP was observed with steroids, IVIG, ritux- Manuel Lucena Soto3, Berta Sanchez3 and Stephan Ehl, MD2
imab and HSCT.
1
Cytopenias are common among RAG deficient patients, in Pediatric Infectious Diseases and Immunodeficiency,
some cases with full resolution only after HSCT. Hospital Universitario Virgen del Rocio, Seville, Spain,
2
Center of Chronic Immunodeficiency, University Freiburg
Medical Center, Freiburg, Germany,
3
4586: EXPLORING COMPLEMENT Immunology, Hospital Universitario Virgen del Rocio
PNEUMOCOCCAL SPECIFIC ANTIBODY
BINDING FUNCTION IN PATIENTS WITH Chronic benign lymphoproliferation and autoimmune cytope-
SPECIFIC ANTIBODY DEFICIENCY AND nias are hallmarks for autoimmune lymphoproliferation syn-
IgG/SUBCLASS DEFICIENCY drome (ALPS). Elevated sFASL, DNTs and Vitamin B12
levels are further suggestive for ALPS. Patients fulfilling these
Charles A. Filion, MD, FRCPC, Paul J. Maglione, MD, criteria without mutations in the ALPS genes are considered
PhD, Lin Radigan, BMed and Charlotte Cunningham- as ALPS-like.
Rundles, MD, PhD A 2-year-old caucasian girl of non-consanginous par-
ents presented with type I Diabetes mellitus. Two years
Division of Clinical Immunology, Department of Medicine, later she received IVIG treatment for an autoimmune
Icahn School of Medicine at Mount Sinai, New York, NY thrombocytopenia. During follow-up she developed
generalized lymphoproliferation (follicular hyperplasia)
PURPOSE: Patients with specific antibody deficiency (SAD), with marked splenomegaly, autoimmune hemolytic ane-
IgG deficiency or IgG subclass deficiency may present with mia and a significant undefined interstitial lung disease
infections of different severities. Based on IgG level and re- with acropachy. Immunologic work up included eleva-
sponse to immunization, some of these patients with recurrent ted DNTs (4.5 %) and raised Vitamin B12 levels.
infections benefit from immunoglobulin replacement therapy. Lymphocyte apoptosis assay and expression of FAS
As an attempt to identify these patients, we measured the and FASLG were normal and the patient was consid-
ability of immune complexes to fix complement in patients. ered as probable ALPS, and mycophenolate mofetil,
METHOD: 96-well plates were coated with capsular polysac- MMF (600 mg/m2/12 h/vo) was initiated, resulting in
charides from S. pneumoniae (serotypes 4, 14, and 23F) or a significant improvement of lymphoproliferation,
C3a antibody. The polysaccharide coated-plate was incubated cytopenias and lung disease. Later she developed
with serum from patients and controls supplemented with hu- hypogammaglobulinemia with decreasing memory B
man complement. Serum was then transferred to the C3a- cells whilst transitional B cells increased. Multicentric
coated plate. The plate was incubated with biotinylated C3a reevaluation revealed a reported STAT3 GOF mutation
antibody. After incubation with streptavidin-HRP and devel- (p.R152W).
opment, absorbance was measured at an OD of 450 nm. STAT3 GOF mutations should be considered in patients with
RESULTS: Among a cohort of 12 patients with SAD, IgG ALPS-like phenotype. MMF may be an effective therapy op-
deficiency or subclass deficiency, the assay could distinguish tions in this patient group.
304 J Clin Immunol (2016) 36:235–334

4589: INFECTION FREQUENCY OF Foruraghi, CRNP1, Alexandra F Freeman, MD1, Daphne

INTRAVENOUS AND SUBCUTANEOUS Mann, RN, BSN2, Betty Marciano, MD1, Cindy Palmer,
IMMUNOGLOBULIN FOR PRIMARY RN, BSN3, Joy Peterson, BSN, RN2, Amy Rump, CRNP2,
IMMUNODEFICIENCY WITHIN THE IDEAL Laquita Snow, RN, BSN3, Amanda Urban, CRNP2, Gulbu
PATIENT REGISTRY Uzel, MD1, Lynne Yockey, RN, BSN3, Steve M. Holland,
MD1 and Christa S. Zerbe, MD1
Angela Tsuang, MD, MSc1, Elizabeth Feuille, MD2, Sean
Kearns, Ph.D3 and Shradha Agarwal, MD2 1
Laboratory of Clinical Infectious Diseases, NIAID/NIH,
Bethesda, MD,
1 2
Division of Clinical Immunology, Department of Medicine, Clinical Monitoring Research Program/Frederick National
Icahn School of Medicine at Mount Sinai, New York, NY, Laboratory, Leidos Biomedical Research, INC support to
2
Division of Clinical Immunology, Icahn School of Medicine NIAID/LCID, Bethesda, MD,
3
at Mount Sinai, New York, NY, Department of Nursing, NIH Clinical Center, Bethesda, MD
3
IDEaL Patient Registry, Coram Clinical Trials, Denver, CO
The NIH Clinical Research Nursing Model of Care provides a
Introduction framework for the delivery of clinical care to research partic-
Studies comparing efficacy of immunoglobulin (Ig) replace- ipants and the support of research protocols. The primary clin-
ment via subcutaneous (SC) and intravenous (IV) routes are ical research nurse/case manager (CM) is central to this deliv-
limited. We report dosing and infection rates from immuno- ery model with expertise in clinical research implementation.
deficient subjects enrolled in the IDEal Patient Registry from a The tenets of practice are: expertise in clinical research and
home infusion company. specialty clinical nursing, accountability for coordination of
Methods research participant plan of care in collaboration with the pa-
Data on diagnosis, route, dose, frequency of infections, tient, family, interdisciplinary and research teams, continuity
were obtained from pharmacy/nursing reports and patient of care based on consistency in care providers and approach
surveys. to care, and advocacy for the research participant and family.
Results The Laboratory of Clinical Infectious Diseases, NIAID, NIH
Three hundred seventy-six subjects in IDEal are receiving Ig uses this model in the outpatient setting. Using an interdisci-
for immune deficiency (ICD-9 279.xx). Data was available for plinary approach, medical teams—attending physician, nurse
207 subjects; 159 (77 %) received SCIg, 37 (18 %) IVIg, and 11 practitioner, and 1–2 CMs—care for patients with specific
(5 %) received both. Baseline mean IgG (SCIg 709 mg/dL, primary immune deficiencies. These focused teams provide
IVIg 647 mg/dL, p = 0.37) and IgM (SCIg 154 mg/dL, IVIg both expertise and continuity of care. Each CM follows ap-
123 mg/dL, p = 0.80) levels were similar, however mean IgA proximately 100 patients. The CM serves as the central point
levels were higher for subjects on SCIg (144 mg/dL) compared of contact for the patient and coordinates care. The amount of
to IVIg (67 mg/dL), (p = 0.008). Mean protective pneumococ- contact per patient varies from annual to weekly, depending
cal serotypes was similar, 29 % for SC and 23 % for IV on complexity and illness. Communication is made through
(p = 0.51). Average dose of SCIg was 124 mg/kg/week versus Medical Secure Email, phones calls, or in person clinic visits.
485 mg/kg/month for IVIg (p = 0.74). Average number of in- Objective measures have been obtained and will be presented.
fections was comparable between the two routes; 2.9 infections/
year for SC versus 2.7 infections/year for IV (p = 0.61).
Conclusion 4592: REGULATION OF IMMUNITY TO
The majority of these subjects had mild-moderate decline in NEUROBLASTOMA VIA POLYAMINE
antibody levels. Clinicians prescribe comparable doses of SC BLOCKADE
versus IV. At these doses, both SC and IV Ig replacement for
subjects in this cohort provided similar rates of protection Adriana D. Benavides, Ph.D.1, Annette Vu, B.S.2, Jennie B.
against infection. Altman, B.A. 3, Gabrielle M. Ferry, B.A. 1 , Michael D.
Hogarty, M.D.2 and Hamid Bassiri, MD, PhD1

1
4591: PATIENT SATISFACTION USING THE NIH Division of Infectious Diseases, Children’s Hospital of
CLINICAL RESEARCH NURSING CARE Philadelphia, Philadelphia, PA,
2
DELIVERY MODEL Department of Pediatrics, Children’s Hospital of
Philadelphia, Philadelphia, PA,
3
Samantha A Kreuzburg, RN, BA1, Dawn Shaw, RN, MBA, Microbiology and Immunology, Mount Sinai School of
MN2, Dirk Darnell, MA, RN3, Janine Daub, CRNP1, Ladan Medicine, New York, NY
J Clin Immunol (2016) 36:235–334 305

High-risk neuroblastoma (NB), which accounts for a con- antigens (TSA) linked to GAg-loaded CD1d molecules. We
siderable portion of pediatric cancer-related mortalities, re- hypothesize that these CD1d-GAg:anti-TSAmAb (BCAb^)
sults from MYCN-amplification and alterations in Myc- conjugates will accumulate in tumors and activate direct and
regulated pathways. Despite improvements in therapy, indirect iNKT cell-mediated anti-tumor responses in situ.
long-term survival rates remain poor. High-risk NBs have Consistent with this hypothesis, in preliminary studies we ob-
elevated polyamine (PA) levels due to Myc’s targeting of serve that: 1) CAbs induce directed lysis of various tumors by
ornithine decarboxylase, the rate-limiting enzyme for PA human or murine iNKT and NK cells in vitro; 2) adminis-
synthesis. It has been shown that in vivo PA blockade tration of CAbs to mice induces rapid activation and intra-
using the drug DFMO lead to a greater reduction in NB cellular production of IFN-γ by iNKT cells and activation
growth than that seen in vitro, suggesting a tumor-cell ex- of NK cells; 3) CAbs retard tumor growth in lymphocyte-
trinsic effect. Elevated PAs can drive the differentiation of deficient NSG mice repleted with small numbers of iNKT
immune suppressive cells, while blockade can reverse this and NK cells. Ongoing studies will help develop novel
by increasing tumor-infiltrating leukocytes (TILs). platforms of cellular cancer immunotherapy employing
However, previous studies investigating immune effects CAbs and iNKT cells.
of DFMO on the tumor microenvironment (TME) are in-
complete. Therefore, we sought to characterize the NB
TME in a spontaneous MYCN-driven NB mouse model 4595: EXPRESSION, ACTIVATION AND
with and without DFMO. Terminal disease tumors were ASSEMBLY OF TACI ISOFORMS IN HUMAN B
dissociated, and the frequencies of various TILs were CELLS
assessed. We observe that DFMO reproducibly alters the
NB TME by increasing frequencies of DCs and NK cells Yolanda Garcia-Carmona, PhD1, Thomas Kraus, PhD2,
while maintaining CD4-negative invariant NKT cells and Thomas Moran, PhD2 and Charlotte Cunningham-Rundles,
granulocytic-MDSCs. These data support our hypothesis MD, PhD1
that PA blockade induces distinct immune changes in the
1
TME that could allow for a more efficient anti-tumor re- Division of Clinical Immunology, Department of Medicine,
sponse to NB. Icahn School of Medicine at Mount Sinai, New York, NY,
2
Center for Therapeutic Antibody Development (CTAD),
Icahn School of Medicine at Mount Sinai, New York, NY
4594: NOVEL INVARIANT NATURAL KILLER T
CELL-BASED CANCER TACI, is a cell-membrane receptor for APRIL and BAFF. Its
IMMUNOTHERAPEUTICS activation in B cells leads to antibody isotype switching, and T
cell–independent antibody production. Mutations in TACI
Gabrielle M. Ferry, B.A.1, Jennie B. Altman, B.A.2, Adriana have been found in 8 to 10 % of patients with CVID. TACI
D. Benavides, Ph.D.1 and Hamid Bassiri, MD, PhD1,3 has 2 isoforms, TACI-S and TACI-L. We previously described
that in humans, TACI short isoform signals for plasma cell
1
Division of Infectious Diseases, Children’s Hospital of differentiation. Marginal zone B cells expressed the short
Philadelphia, Philadelphia, PA, TACI isoform suggesting that this isoform is important to
2
Microbiology and Immunology, Mount Sinai School of antibody secreting capacity. TACI isoforms mRNA levels
Medicine, New York, NY, were measured by qPCR in PBMCs cultured in the presence
3
Center for Childhood Cancer Research, Children’s Hospital or absence or TLR9 ligand, anti-CD40/ IL21 and anti-IgM.
of Philadelphia, Philadelphia, PA TACI-L expression is increased after stimulation and main-
tained in time. TACI-S isoform show an expression peak at 5 h
Invariant natural killer T (iNKT) cells are innate-like lympho- after TLR stimulation. TACI-L protein is mostly detected, on
cytes that recognize glycolipid antigens (GAgs) presented by B cells surface. TACI-S surface levels are low. However, is
CD1d molecules. Engagement of iNKT cell TCRs by CD1d/ mostly located in the cytoplasm. Transiently transfected 293
GAg complexes result in rapid and robust production of cyto- cells with TACI-L or S and analyzed by confocal microscopy,
kines that subsequently promote NK and CD8+ T cell anti- show colocalization with transferrin and Rab7, suggesting that
tumor immunity. In addition to this indirect mechanism, iNKT TACI is internalized from the surface into the cytoplasm.
cells directly kill CD1d+ tumor cells in a TCR- and perforin- Receptor assembly was analyzed measuring FRET signal by
dependent fashion, and under certain conditions, also alter the FACS. TACI-L and TACI-S can assemble in complexes with
tumor microenvironment. To harness these myriad iNKT cell- each other, and this association is not altered when TACI is
mediated mechanisms of tumor control, we developed conju- mutated or even in the presence of ligands BAFF or APRIL.
gate molecules composed of mAbs against tumor-specific However, TACI mutants are not capable of signaling.
306 J Clin Immunol (2016) 36:235–334

4596: SUCCESSFUL TREATMENT OF Jack A Gilbert6, Naseer Sangwan, PhD6, Duane Wesemann,
FULMINANT INFANTILE HEMOPHAGOCYTIC MD PhD7, Alessio Fasano, MD3, Luigi D Notarangelo, MD8
LYMPHOHISTIOCYTOSIS (HLH) REQUIRING and Jolan E. Walter, MD PhD1,2,8
VENO-ARTERIAL EXTRACORPOREAL
1
MEMBRANE OXYGENATION (ECMO) AND Division of Pediatric Allergy/Immunology, Massachusetts
CONTINUOUS RENAL REPLACEMENT General Hospital for Children, Boston, MA,
2
THERAPY (CRRT) Center for Immunology and Inflammatory Diseases,
Massachusetts General Hospital, Harvard Medical School,
Angela C Weyand, MD1, Kelly Walkovich, MD1, James Boston, MA,
Connelly, MD1, David Selewski, MD2 and David Frame, 3
Center for Celiac Research, Mucosal Immunology and
PharmD3 Biology Research Center, Massachusetts General Hospital
and Division of Pediatric Gastroenterology and Nutrition,
1
Pediatrics and Communicable Diseases, Pediatrics- Massachusetts General Hospital for Children, Boston, MA,
4
Hematology/Oncology, University of Michigan, Ann Department of Medical Oncology, Dana-Farber Cancer
Arbor, MI, Institute/Harvard Medical School, Boston, MA;,
2 5
Pediatrics and Communicable Diseases, Nephrology, Division of Rheumatology, Immunology and Allergy,
University of Michigan, Ann Arbor, MI, Department of Medicine, Brigham and Women’s Hospital
3
Pharmacy, University of Michigan, Ann Arbor, MI and Harvard Medical School, Boston, MA,
6
Department of Surgery, University of Chicago. Bioscience
Hemophagocytic lymphohistiocytosis (HLH) is an immune Division, Argonne National Laboratory, Chicago, IL,
7
dysregulatory syndrome defined by severe inflammation and Division of Rheumatology, Immunology and Allergy,
consequent organ damage. Infants with HLH often have sig- Department of Medicine, Brigham and Women’s
nificant organ dysfunction requiring support in the form of Hospital and Harvard Medical School, Boston, MA,
extracorporeal membrane oxygenation (ECMO) and continu- Boston, MA,
8
ous renal replacement therapy (CRRT). These modalities Division of Immunology, Boston Children’s Hospital,
complicate diagnosis, dosing of therapies (corticosteroids Harvard Medical School, Boston, MA
and etoposide), and outcomes.
We present two cases of infantile HLH requiring ECMO and Inflammatory enteropathy is a serious complication of
CRRT. Patient 1 presented at 2 months of age with respiratory many primary immunodeficiencies (PID) and mecha-
failure and status epilepticus. ECMO and CRRT were initiated nisms are highly determined by the underlying genetic
and continued for a total of 26 days. He received treatment per defect, secondary immune dysregulation and changes in
HLH 1994 protocol with dose adjustments, dexamethasone the microbiome.
(20 mg/m2) and etoposide (75 mg/m2). Treatment was suc- In a model of inflammatory enteropathy in the Rag1S723C/
S723C
cessful and he is now >17 months post hematopoietic stem mouse model of leaky SCID, histological evidence of
cell transplant. Patient 2 presented at day 9 of life with fever. enteric inflammation with increased Marsh score and in-
She was adenovirus positive and quickly developed cardiore- creased small intestinal permeability was noted as compared
spiratory failure, requiring ECMO and CRRT. Due to concern to wild type mice.
for uncontrollable infection, treatment was started with dexa- In contrast to the lymphopenia observed in peripheral
methasone alone (20 mg/m2). She is currently stable, requir- blood and secondary lymphoid tissues, an increased pres-
ing ECMO and CRRT with improvement in her ferritin from ence of T cells was observed in the small intestine and in
>19,000 to <2000 ng/ml. the colon lamina propria, associated with increased pro-
These cases demonstrate the ability to treat HLH while on duction of inflammatory cytokines. Expansion of
ECMO and CRRT. While special dosing needs to be considered, Foxp3+T cells was also noted in the small and large bowel,
it should not preclude the use of traditional HLH therapies. although it is not clear whether they can mediate suppres-
sive function. 16S ribosomal RNA sequencing showed an
altered composition of gut microbiota. In the setting of
4597: FEATURES AND MECHANISMS OF increased gut barrier permeability in the small intestine,
MUCOSAL IMMUNE DYSREGULATION IN A we demonstrated occurrence of bacterial translocation
MOUSE MODEL OF LEAKY SCID DUE TO from the gut to lymph nodes.
HYPOMORPHIC RAG MUTATIONS We propose that in our model inflammatory enteropathy is the
result of synergistic effects of inflammation secondary to in-
Boglarka Ujhazi 1,2 , Krisztian Csomos, PhD 1,2 , Craig nate and adaptive immune dysregulation, altered microbiome
Sturgeon3, Francisco Beca4, Jared Nathan Silver, MD PhD5, and increased gut permeability.
J Clin Immunol (2016) 36:235–334 307

2
4598: COMMON VARIABLE Department of Pediatrics, Sultan Qaboos University, Muscat,
IMMUNODEFICIENCY CAUSED BY A Oman
HOMOZYGOUS MISSENSE MUTATION IN
TRNT1 Background: ORAI1 is the pore-forming subunit of the cal-
cium release-activated calcium (CRAC) channel. Stromal in-
Glynis Frans, MPharm1, Leen Moens, PhD1, Ann Janssens, teraction molecule 1 (STIM1) senses the depletion of calcium
MD, PhD2, Isabelle Meyts, MD, PhD3 and Xavier Bossuyt, in the endoplasmic reticulum and interacts with ORAI1 to
MD, PhD1 facilitate the calcium entry important for lymphocyte function.
All but one known human ORAI1 mutation abrogate protein
1
Microbiology and Immunology, KU Leuven, Leuven, expression.
Belgium, Methods: Whole exome sequencing (WES) was performed
2
Hematology, University Hospitals Leuven, Leuven, Belgium, on the patient’s DNA. Flow cytometry was used to assess
3
Childhood Immunology, University Hospitals Leuven, lymphocyte subsets and calcium flux. Transient transfection
Leuven, Belgium of HEK293T cells was used to assess expression of Myc-
tagged ORAI1 constructs.
We identified a 23-year old male patient with mental retarda- Results: The patient is a female with a history of hypotonia,
tion, dysmorphic features, bilateral cataract, Crohn’s disease, CMV viremia, and respiratory failure due to Pneumocystis
and low levels of IgG, IgA, IgM. He was classified as having jiroveci. She had normal numbers of B cells, slightly de-
common variable immunodeficiency and has been treated creased T and NK cells, and absent T cell proliferation to
with immunoglobulin substitution since the age of 12 months. anti-CD3 stimulation. WES identified a homozygous non-
Initially, the total lymphocyte count, B- and NK-cell numbers sense mutation in ORAI1 (p.R270X) predicted to eliminate
were normal but dropped significantly after age 21. Whole the C-terminal residues important for the interaction between
exome sequencing identified a homozygous missense muta- ORAI1 and STIM1. HEK293T cells transfected with either
tion (NP_886552.2: exon 3, c. C295T, p. R99W) in the Myc-tagged ORAI1R270X or Myc-tagged ORAI1WT construct
TRNT1 gene. His parents were consanguineous (second cous- showed expression of a truncated ORAI1. CD3+ T cells from
in marriage) and carried the variant in a heterozygous state, the patient exhibited absent SOCE, indicating that the
indicating autosomal recessive inheritance. expressed protein is non-functional.
Biallelic mutations in TRNT1 are the cause of sideroblastic Conclusions: This study demonstrates the in vivo importance
anemia with B-cell immunodeficiency, periodic fevers and of the C-terminus of ORAI1 in host immunity.
developmental delay (SIFD) [Chakraborty et al. 2014].
Microcytic hypochromic anemia was demonstrated on some
occasions but the patient never required blood transfusions. 4601: PARACOCCIDIOIDOMYCOSIS AS A NEW
Expression of the TRNT1 protein was normal in patient skin- (AND AWAITED) INFECTIOUS DISEASE IN
derived fibroblasts. Additional investigations into the func- GATA2 DEFICIENCY
tional impact of the mutated TRNT1 variant are ongoing.
Our case further expands the clinical spectrum associated with Dewton Moraes-Vasconcelos1, Nathalia Moreira2, Antonio
TRNT1 mutations. The milder phenotype and longer survival Lancha Ruiz3, Luciana Nardinelli3, Noac Chuffi Barros4,
of our patient could possibly be explained by the variants’ Zarifa Khoury5 and Israel Bendit3
location in the less conserved N-terminal region.
1
Laboratory of Dermatology and Immunodeficiencies –
LIM56, Faculdade de Medicina da Universidade de São
4600: A NOVEL MUTATION IN ORAI1 Paulo, São Paulo, Brazil,
2
RESULTING IN THE EXPRESSION OF Instituto do Coração, Faculdade de Medicina da
A NONFUNCTIONAL C-TERMINALLY Universidade de São Paulo, São Paulo, Brazil,
3
TRUNCATED PROTEIN Hematology, Hospital das Clínicas da Faculdade de
Medicina da USP, Brazil,
Yousef R. Badran, MD1, Michel J. Massaad, PhD1, Wayne 4
Immunodermatology, Hospital das Clínicas da Faculdade de
Bainter, BS1, Salem Al-Tamemi, MD2, Shafiq Ur Rehman Medicina da USP, Brazil,
Naseem, MD2, Hashim Javad, MD2, Raif S. Geha, MD1 and 5
Infectology of fungal diseases, Instituto de Infectologia
Janet Chou, MD1 Emílio Ribas, Brazil

1
Immunology Division, Department of Pediatrics, Boston An increasing number of primary immunodeficiencies un-
Children’s Hospital, Harvard Medical School, Boston, MA, derlie fungal infectious diseases in children and young
308 J Clin Immunol (2016) 36:235–334

adults. Among these, phagocyte defects are usually asso- nodes and progressive throat pain. A laryngoscopy revealed
ciated to invasive candidiasis and aspergillosis, inborn er- a friable ulcerative peri-vallecular lesion. He failed treatment
rors of IL-17 immunity are linked to mucocutaneous can- with oral prednisone and clindamycin. Three weeks later, he
didiasis, defects of IFN-g pathway are associated with deep presented to our facility. The patient was febrile with a tender
mycoses and GATA-2 deficiency usually presents with 3x3cm anterior cervical neck mass. Computer tomography
several opportunistic diseases beginning in the skin (warts scans of the neck and chest revealed multiple enlarged cervical
and molluscum) followed by non-tuberculous lymph nodes and diffuse micronodular pulmonary disease
mycobacteriosis, sometimes histoplasmosis, complicated with mediastinal adenopathy. Inpatient laryngoscopy was per-
by multilineage cytopenias, myelodysplastic syndrome formed, and the oral lesion was biopsied as was the cervical
and acute myeloid leukemia. lymph node. Staining showed organisms consistent with
We present the case of a young male (26 years old) who Histoplasma species. Urine and serum Histoplasma antigens
presented to our outpatient unit with a history of acute were positive. Cultures grew Histoplasma capsulatum. He
disseminated paracoccidioidomycosis 10 years ago. At was started on Amphotericin B and continued on itraconazole.
that time we searched for IFN-gamma axis defects with-
out success. The patient improved after aggressive therapy
and lost follow-up for 9 years, when he presented chronic 4606: ANTI-MADCAM-1 THERAPY DOES NOT
renal failure and pancytopenia and was evaluated at an- AFFECT IMMUNE SURVEILLANCE IN THE
other hospital. After being discharged he was sent for CENTRAL NERVOUS SYSTEM
investigation.
The careful examination of the previous laboratorial re- Geert D’Haens1, Walter Reimisch2, Séverine Vermeire3,
ports showed striking monocytopenia and T, B and NK Harald Vogelsang4, Matthieu Allez5, Pierre Desreumaux6,
lymphopenia. We therefore tried to look for GATA2 muta- Andre van Gossum7, Daniel Baumgart8, Mina Hassan9,
tions and an exonic mutation (A164T) was found at the John Cheng 10 , Yanhua Zhang 10 , William Sandborn 11 ,
exon 3 of GATA2 gene. Annamarie Kaminsiki12, Alaa Ahmad9, Vivek Pradhan9,
Fabio Cataldi9, Robert Clare12, Kenneth Gorelick13 and
Olaf Stuve14
4604: PAINFUL SWALLOWING IN A 20 YEAR
1
OLD WITH COMMON VARIABLE IMMUNE Inflammatory Bowel Disease Center, Academic Medical
DEFICIENCY Center, University of Amsterdam, Amsterdam, Netherlands,
2
Hamilton, Canada,
Leslie Cristiano, MD1, Alex K Bonnecaze2 and Jason W 3
Leuven, Belgium,
Caldwell, DO3 4
Vienna, Austria,
5
Paris, France,
1 6
Section of Pulmonary, Critical Care, Allergic and Lille, France,
7
Immunological Diseases, Wake Forest University School of Brussels, Belgium,
8
Medicine, Winston-Salem, NC, Berlin, Germany,
2 9
Internal Medicine, Wake Forest University School of Cambridge, MA,
10
Medicine, Winston-Salem, NC, Groton, CT,
3 11
Section of Pulmonary, Critical Care, Allergic and La Jolla, CA,
12
Immunologic Diseases, Wake Forest University School of Collegeville, PA,
13
Medicine, Winston-Salem, NC Newtown Square, PA,
14
Dallas, TX
A 20 year old male with Common Variable Immune
Deficiency (CVID) initially presented at 6 years of age with Blocking integrins can be associated with an increased risk of
sinopulmonary infections. Laboratory analysis revealed IgG progressive multifocal encephalopathy (PML). MAdCAM-1
538 mg/dl, IgA 23 mg/dl, and IgM 33 mg/dl. Post-vaccine is an adhesion molecule not constitutively expressed in
pneumococcal titers were non-protective. T cell, B cell, and healthy CNS and considered mostly gut-selective. However,
NK enumeration was performed: total lymphocytes 570 cells/ MAdCAM-1 is upregulated in choroid plexus epithelium dur-
μL, 33 % CD19 cells (190 cells/μL), 57 % CD3 cells (330 ing experimental autoimmune encephalomyelitis (EAE). PF-
cells/μL), 19 % CD4 cells (110 cells/μL), 22 % CD8 cells 00547659 is a fully human mAb highly selective for
(130 cells/μL), and 5 % NK cells (30 cells/μL). IgG declined MAdCAM-1. We investigated its effect on cellular elements
to 280 mg/dl and IVIG was started. In November of 2014, he of immune surveillance in the CNS and blood of patients with
complained of fever, chills, malaise, painful right cervical Crohn’s disease (CD). Methods were tested in a control
J Clin Immunol (2016) 36:235–334 309

Cohort 1 of volunteers with CD. Study patients (Cohort 2) had 4608: LESSONS FROM A SMALL IPEX-LIKE
CD and prior treatment with anti-TNF and immunosuppres- PATIENT COHORT: WHOLE EXOME
sant therapies. Patients underwent a lumbar puncture (LP1) SEQUENCING (WES) RESULTS IN HIGH HIT
followed by 3 monthly injections of 225 mg PF-00547659. RATE AND SUPPORTS FOCUSING ON THE
After the last dose, a LP2 was performed. CSF was analyzed USUAL SUSPECTS.
by flow cytometry. In Cohort 1, lymphocyte subset percent-
ages were the same at both time points. Cohort 2 consisted of David Hagin, MD PhD1, Eric J Allenspach, MD/PhD2,
30 patients. CSF lymphocytes (cells per mL) shown as geo- Stephanie J Anover-Sombke3, Hans Ochs4 and Troy R.
metric means (CV%). LP1: total lymphocytes 391 (140 %), Torgerson, MD PhD5
CD3+/CD4+ cells 246 (152 %), CD3+/CD8+ cells 100
1
(126 %), CD4:CD8 ratio 2.46 (57 %). LP2: total lymphocytes Allergy and Immunology, University of Washington / Seattle
513 (137 %), CD3+/CD4+ cells 332 (143 %), CD3+/CD8+ Children’s Hospital, Seattle, WA,
2
cells 123 (125 %), CD4:CD8 ratio 2.69 (56 %). This is the first Pediatric Rheumatology and Immunology, University of
evidence that a therapeutic dose of anti-MAdCAM-1 mAb Washington and Seattle Children’s Hospital, Seattle, WA,
3
does not affect the composition of CNS leukocytes. Department of Pediatrics, University of Washington and
Seattle Children’s Research Institute, Seattle, WA,
4
Center for Immunity and Immunotherapies, Seattle
4607: INSIGHTS FROM THE IGH AND TRB Children’s Research Institute, Seattle, WA,
5
REPERTOIRES TO UNDERSTAND THE Division of Immunology, Department of Pediatrics,
PHENOTYPIC AND MOLECULAR SPECTRUM University of Washington and Seattle Children’s Research
OF RAG DEFICIENCY Institute, Seattle, WA

Yu Nee Lee, Ph.D, Kerry Dobbs, Francesca Ververs and IPEX (Immune dysregulation Polyendocrinopathy
Luigi D Notarangelo, MD, Division of Immunology, Enteropathy X-linked) syndrome is caused by mutations in
Boston Children’s Hospital, Harvard Medical School, FOXP3, master regulator of regulatory T cell lineage. The
Boston, MA term IPEX-Like is used to describe patients with features of
IPEX syndrome and normal FOXP3 sequencing. Preliminary
Patients ranging from infants to early adulthood are suf- cohort of 15 individual IPEX-like patients was submitted for
fering not only from severe combined immunodeficiency, WES and data was analyzed in search for underlying mono-
but are affected by a broad spectrum of immune dysreg- genic defects. Potential causative mutations were identified in
ulation due to defects in Recombination Activating Gene 7/15 patients (46 %). Major clinical features included different
(RAG) proteins. The RAG1 and RAG2 proteins are cru- combinations of the following: Enteropathy w/wo villous at-
cial in generating the initial repertoire of the B and T cell rophy and lymphocytic infiltration, endocrinopathies, immune
receptors via VDJ recombination process. Based on our cytopenias, eczema and recurrent infections. Mutations iden-
observation that severity of clinical presentations correlate tified are summarized in Table I. Despite an obvious analysis
to the residual RAG1 activity, we hypothesize that im- bias, the high hit rate and high prevalence of known causative
mune repertoire in patients will show gradual restriction genes, support a two-step approach when studying a defined
of the B and T cell repertoires with the severity of the population, starting with targeted sequencing of relevant gene
disease. panel followed by trio WES of unsolved cases.
Thus, blood sample from 12 patients with various clini-
cal presentations with RAG deficiency were collected, Gene Mutation
and the IGH and TRB repertoires were determined from CTLA4 HT: c.410C>T/C, p.P137L
total RNA by using next generation sequencing. The LRBA HM: c.2617_2620delCTCT, p.L873fs
IGH and TRB repertoires are gradually restricted and STAT3 HT: c.1243G>C/G, p.E415Q
correlates with the severity of the disease, as depicted TTC7A CH:
by treemaps of CDR3 sequences and diversity indices. c.1817A>G/A, p.K606R
Furthermore, Shannon’s H diversity index of the reper- c.2086T>C/T, p.S696P
toires correlates best with the severity of clinical presen- MYO5B HM: c.946G>A, p.G316R
tations and RAG activity. Overall, our study demonstrate CTLA4 HT: c.436G>A/G, p.G146R
that the heterogeneity of clinical presentations of RAG FOXP3 Splice site: c.712G>C
deficiency is determined by RAG activity and nature of
the mutation, which shapes the initial repertoire of IGH Table 1: Pathogenic mutations identified. HT—Heterozygous,
and TRB in these patients. HM—Homozygous, CH—Compound Heterozygous
310 J Clin Immunol (2016) 36:235–334

4609: IMMUNE RECONSTITUTION IN HSCT besides having or not 100 % of chimerism this generally
PEDIATRIC PATIENTS WITH SEVERE shows the status of engrafment however it can not conclude the
COMBINED IMMUNODEFICIENCY AFTER presence of complete and incomplete IR
HEMATOPOIETIC STEM CELL
TRANSPLANTATION, A SINGLE CENTER
EXPERIENCE. 4610: NEONATAL HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS: A MULTI-CENTER
Kannelva Gomez Castillo, MD1, Nideshda Ramírez-Uribe, CASE SERIES HIGHLIGHTING THE UNIQUE
MD2, Edith González-Serrano3, Edgar Alejandro Medina- PHENOTYPIC PRESENTATION AND
Torres, PhD4, L Berrón-Ruiz, MSc5, Sara Espinosa-Padilla, CHALLENGES IN DIAGNOSIS AND
MD 6 , Francisco Espinosa-Rosales 7 , Gerardo Lopéz- MANAGEMENT
Hernández, MD8 and Alberto Olaya Vargas, MD, MSc9
Adam S DuVall, MD, MPH1, Courtney Palka2, David G
1
Immunodeficiency Research Unit, National Institute of Frame3, Michael Briones4, Christen L Ebens5, Michael S
Pediatrics, Mexico City, Mexico, Grimley6, Sarita A Joshi7, Mark T Vander Lugt8, James A
2
Hematopoietic stem cell transplant, Instituto Nacional de Connelly, MD9 and Kelly J Walkovich, MD9
Pediatría, Mexico City, Mexico,
3 1
Unidad de Investigación en Inmunodeficiencias, Instituto Department of Pediatrics, University of Michigan, Ann
Nacional de Pediatría, Mexico, Mexico, Arbor, MI,
4 2
Immunodeficiencies Research Unit, National Institute of University of Michigan, Ann Arbor, MI, (3)Department of
Pediatrics, Pharmacy, University of Michigan, (4)Children’s Healthcare
5
Immunodeficiencies Research Unit, National Institute of of Atlanta, Atlanta, GA,
5
Pediatrics, Distrito Federal, Mexico, University of Minnesota, Minneapolis, MN,
6 6
Research of Primary Immune deficiency Unit, Intituto Cincinnati Children’s Hospital Medical Center, Cincinnati,
Nacional de Pediatría, Mexico City, Mexico, OH,
7 7
Research Head and Jeffrey Modell Diagnostic Center, National Nationwide Children’s Hospital, Columbus, OH,
8
Institute of Pediatrics, Mexico D.F. C.P. 04530, Mexico, Children’s Hospital of Pittsburgh, Pittsburgh, PA,
8 9
HSCT Unit, Instituto Nacional de Pediatría, Mexico city, Pediatrics and Communicable Diseases, Pediatrics-
Mexico, Hematology/Oncology, University of Michigan, Ann Arbor, MI
9
Hematopoietic Stem Cell Transplantation Unit, National
Institute of Pediatrics, Mexico City, Mexico Hemophagocytic lymphohistiocytosis (HLH) is a life-
threatening syndrome characterized by excessive inflammation
Backgrounds SCID are a group of genetic conditions charac- and immune dysregulation. Familial HLH can present early in
terized by profound deficiency in the number and function of T life, but very little is known about development of HLH during
cells as well as variables changes according to the molecular the neonatal period. Thus, there are limited descriptions avail-
defect in NK and B cells the hematopoietic stem cell transplan- able of the most common phenotype, etiology, and the efficacy
tation is the curative treatment Immune reconstitution is the of therapy. We describe here the largest multi-center case series
process by which is reestablished in quantity and function the describing neonatal HLH to date. A review of the literature was
different immune cells lines after HSCT Objective describe also performed, and an additional 16 previously published
the immune reconstitution during the clinical monitoring pro- cases of neonatal HLH were identified. Symptoms were non-
cess of patients diagnosed with SCID post-transplanted at our specific and difficult to distinguish between other common
institute Methods: 5 SCID patients with HSCT were studied causes of critical illness in the neonate. Laboratory findings
Immunophenotyping lymphocytes immunoglobulins levels most commonly revealed hepatic failure with synthetic dys-
and lymphoproliferation of T cells were performed at 1, 3, 6, function, relatively mild hyperferritinemia, normal triglyceride
9 and 12 months post HSCT Results We report 5 male SCID levels, variable coagulopathy, and disproportionately low plate-
patienst post HSCT, the median age at diagnosis was 162 days let levels. Genetic causes of immune dysregulation were found
the immunophenotypes were T-B+NK- in four patients and T- in a minority of cases, but specific etiologies were commonly
B-NK- in one patient disseminated BCG was present in 3/5 unable to be identified. Mortality was high in this age group
patients, pneumonia in 4/5 patients and no patient has CMVor with survivorship highly dependent upon early therapy and
EBV infection The median age at HSCT was 9 months and the transition to hematopoietic cell transplant. Overall, neonatal
median time to neutrophil and platelet engraftment was 13 and HLH is a difficult to diagnose condition causing severe illness
7 days respectively Conclusions IR of CD8 presented and the in the neonate, which requires prompt identification in order to
T cells response to mitogens were normal at 3 months post institute life-saving therapy early.
J Clin Immunol (2016) 36:235–334 311

2
4612: A PATIENT WITH A MUTATION IN CD40L Division of Infectious Disease, Ann & Robert H. Lurie
PRESENTING WITH Children’s Hospital of Chicago, chicago, IL,
3
PANHYPOGAMMAGLOBULINEMIA AND Division of Allergy & Immunology and Jeffrey Modell
NATURAL KILLER CELL LYMPHOPENIA Diagnostic Center for Primary Immunodeficiencies, Ann
& Robert H. Lurie Children’s Hospital of Chicago,
Safa Baris, MD1, Elif Karakoc-Aydiner, MD1, Ayca Kiykim, Chicago, IL
MD1, Ercan Nain, MD1, Ahmet Ozen, MD1, Rodrigo Hoyos-
Bachiloglu, MD2, Mustafa Bakir, MD3, Raif S. Geha, MD4, We report a 20 month old female with right upper lobe
Janet Chou, MD4 and Isil Barlan, MD1 infiltrative findings with lymph node necrosis, sputum pos-
itive for growth of acid fast bacilli, and a positive PPD but
1
Immunology, Marmara University, Istanbul, Turkey, indeterminate quantiferon gold serologic study. Prior infec-
2
Immunology, Boston Childrens Hospital, Boston, MA, tious history is notable for mycobacterium foruitum cervi-
3
Pediatric Allergy&Immunology, Marmara University School cal adenitis, recurrent stomatitis, and varicella infection
of Medicine, Istanbul, Turkey, 10 days after receiving her first Varivax immunization.
4
Immunology Division, Department of Pediatrics, Boston Quantitative immunoglobulin levels and lymphocyte sub-
Children’s Hospital, Harvard Medical School, Boston, MA sets were normal. Lymphocyte proliferation in response to
mitogens was normal, but lymphocyte proliferation in re-
Mutations in CD40L result in diverse clinical presentations sponse to antigens and NK cell function were sub-optimal.
beyond classical X-linked hyper-IgM syndrome. Natural kill- The IFN-gamma level was normal. Genetic testing re-
er cell lymphopenia has been described in one patient with a vealed two different heterozygous mutations in the IFN-
mutation in CD40L. We now report a patient with acute re- gamma receptor one gene confirming a defect in the IL-
spiratory distress syndrome, panhypogammaglobulinemia 12/IFN- gamma axis. The patient remains on IFN-gamma
and NK cell lymphopenia at 5 months of age. T cell prolifer- replacement, antimicrobial therapy for treatment of pulmo-
ation to anti-CD3 stimulation was intact, as was B cell pro- nary MAC, and antiviral therapy for recurrent HSV infec-
liferation to anti-CD40+IL4/IL-21 stimulation. CD40L ex- tions. While the mechanism of this disease process does
pression was normal. He subsequently developed recurrent not support the use of interferon gamma therapy, our pa-
CMV infections in the setting of persistent NK cell lympho- tient remains on replacement therapy in the event that sup-
penia, which was confirmed three times through 2.5 years of plemental interferon gamma is augmenting some minimal
age. Whole exome sequencing revealed a hemizygous muta- function that she may have.
tion in exon 5 of CD40L (p.T147N) in the C-terminal TNF
homology domain important for ligand binding. This mis-
sense mutation has been previously reported to preserve 4616: IMMUNOGLOBULIN REPLACEMENT
CD40L expression, but abrogate binding of CD40-Ig. The THERAPY IN A PATIENT WITH
clinical phenotype associated with this mutation has not been HYPOGAMMAGLOBULINEMIA AFTER
detailed previously. This patient’s NK cell lymphopenia may CARDIOPULMONARY BYPASS.
be due to defective signaling downstream of CD40L
expressed by bone marrow dendritic cells, thereby impairing Edna Venegas-Montoya1, Mónica Rodríguez-González1,
IL-15 secretion important for NK cell proliferation. NK cell Selma Scheffler-Mendoza2, Marco Antonio Yamazaki3,
lymphopenia may represent an atypical feature of CD40L de- Miriam Martinez-Perez1, Giovanni Sorcia-Ramírez4 and
ficiency, leading to increased susceptibility to viral infections. Edith González-Serrano5

1
4614: PNEUMONIA IN A 20 MONTH OLD GIRL C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C
WITH HISTORY OF MYCOBACTERIAL ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS,
CERVICAL ADENITIS, VARICELLA MEXICO CITY, Mexico,
2
INFECTION AFTER VACCINATION AND Pediatric Allergy and Immunology, Instituto Nacional de
RECURRENT STOMATITIS Pediatria, MEXICO, Mexico,
3
Instituto Nacional de Pediatría, Coyoacán, Mexico,
Jenna R.E. Bergerson, MD, MPH1, Bessey E Geevarghese, 4
C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C
DO2 and Ramsay L Fuleihan, MD3, ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS,
Mexico City, Mexico,
1 5
Division of Allergy and Immunology, Ann & Robert H. Unidad de Investigación en Inmunodeficiencias, Instituto
Lurie Children’s Hospital of Chicago, Chicago, IL, Nacional de Pediatría, Mexico, Mexico
312 J Clin Immunol (2016) 36:235–334

Male 4 months old. Parents and 2 sisters, healthy. No consan- interstitial lung disease (ILD) in one, and Multiple Sclerosis-
guinity, no inbreeding. Started at 12 h of life, with cyanosis like disease, autoimmune cytopenias and ILD in the second.
and respiratory distress, diagnosis of transposition of the great The father of these siblings had a remote history of transient
arteries was made. Admitted to emergency procedure thrombocytopenia and autoimmune thyroiditis but is other-
Rashkind with cardiopulmonary bypass time of 3 h 50 min. wise doing well. Targeted sequencing of CTLA4 revealed a
Bad outcome with Gram-negative sepsis after surgical proce- +6 heterozygous intronic mutation at the end of exon 3
dure with linfopenia and hypogammaglobulinemia. A first (GTGAGT>GTGAGA). Amplification and sequencing of
2grkg dose of intravenous immunoglobulin was administered. the CTLA4 cDNA showed two splice products, one of normal
Subsequently with septic shock, procalcitonin 28 ng/mL, re- full length transcript, and a second, joining exon 2 to exon 4
quiring new dose of IVIG 1grkg. while skipping exon 3, which encodes the CTLA4 transmem-
Immunologic profile: subpopulations of lymphocytes and brane domain. Thus, an intronic mutation affecting the vari-
lymphocyte proliferation reported normal, CBC without able residues in the splice donor sequence downstream of
linfopenia. Primary immunodeficiency was discarded. exon 3 are predicted to cause a loss of cell surface protein
Discharged after 98 days. Last appointment, asymptomatic, expression from one allele and lead to abnormal cell surface
without requiring antibiotic therapy or gammaglobulin, serum levels of CTLA4. In addition, stem cell transplant offers a
level of immunoglobulins reported normal. curative treatment for CTAL4 haploinsufficiency.
Hypogammaglobulinemia occurs in half of infants after cardio-
pulmonary bypass. Our patient had hypogammaglobulinemia
after the average of 7 days reported in literature, which in- 4618: A PROSPECTIVE ALEMTUZUMAB
creased morbidity secondary to serious infections. We observed PHARMAKOKINETIC (PK) STUDY REVEALS
improvement with IVIG replacement therapy, so it is important THAT PERI-TRANSPLANT ALEMTUZUMAB
to evaluate serum immunoglobulin levels in patients who LEVELS DEPEND ON ABSOLUTE
underwent cardiopulmonary bypass with poor outcome, be- LYMPHOCYTE COUNT AND UNDERLYING
cause IVIG can prevent infections in CPB-induced PRIMARY IMMUNE DEFICIENCY
hypogammaglobulinemia.
Rebecca Marsh, MD1, Tsuyoshi Fukuda, Alexander Vinks
and Parinda A Mehta, MD3
4617: A NOVEL DONOR SPLICE-SITE
MUTATION CAUSING CTLA4
1
HAPLO-INSUFFICIENCY AND SEVERE Cincinnati Children’s Hospital, Cincinnati, OH,
2
AUTOIMMUNITY D i v i s i o n o f B o n e M a r r o w Tr a n s p l a n t a t i o n a n d
Immunodeficiency, Cincinnati Children’s Hospital Medical
David Hagin, MD PhD1, Matthew C Altman, MD2, Hans Center, Cincinnati, OH
Ochs3 and Troy R. Torgerson, MD PhD4
Background
1
Allergy and Immunology, University of Washington / Seattle We recently defined an optimal range for Day 0 alemtuzumab
Children’s Hospital, Seattle, WA, concentration of 0.2–0.4 ug/mL to potentially balance the
2
Allergy and Immunology, University of Washington, Seattle, risks of acute GVHD and mixed chimerism, and maximize
WA, lymphocyte recovery following alemtuzumab, fludarabine,
3
Center for Immunity and Immunotherapies, Seattle and melphalan RIC HCT. The aim of this study was to study
Children’s Research Institute, Seattle, WA, alemtuzumab pharmacokinetics (PK) in PID patients.
4
Division of Immunology, Department of Pediatrics, Methods
University of Washington and Seattle Children’s Research Seventeen patients received 1 mg/kg alemtuzumab sc divided
Institute, Seattle, WA over 5 days, starting on day −14, as part of alemtuzumab,
fludarabine, and melphalan RIC HCT. Alemtuzumab levels
CTLA4 haplo-insufficiency was recently described as a cause were measured pre-dose, 30 min and 8 h after each dose,
for Type V Autoimmune Lymphoproliferative disorder. We and then daily. Absolute lymphocyte counts were recorded.
describe a family with variable presentation of immune dys- PK analysis was conducted.
regulation and antibody deficiency. In this family, two affected Results
siblings underwent successful matched unrelated stem cell Fourteen of 17 patients had alemtuzumab concentrations
transplant due to severe uncontrolled immune dysregulation >0.4 ug/mL at day 0. Day 0 levels correlated negatively with
with significant improvement. Major symptoms included ar- pre-HCT ALC. A trend towards decreased levels in patients
thritis, autoimmune cytopenias, lymphocytic colitis and with HLH was observed (p = 0.07). The median terminal t ½
J Clin Immunol (2016) 36:235–334 313

was 124 h (range 33.8–1088.6 h). Day 0 concentrations cor- amphotericin and antibiotics should be considered in STAT3
related positively with concentrations at Day −7 and AUC, deficiency for refractory aspergillomas. The safety and effica-
and inversely with ke. cy of this approach may be different in STAT3 deficiency than
Conclusion in other causes of aspergilloma with hemoptysis.
Most patients have persistence of lytic levels of alemtuzumab
beyond day 0, in excess of that needed to reduce the risk of
acute GVHD. Levels correlate with pre-transplant ALC, and 4621: SUBTLE PHENOTYPIC FINDINGS
also diagnosis, likely due to ALC differences in patients with IN A PATIENT WITH RMRP MUTATION
diagnoses associated with lymphocyte expansion vs lympho-
penia. Precision dosing trials are warranted. Maria A Slack, MD1,2 and Peter J Mustillo, MD2

1
4619: INTRACAVITARY AMPHOTERICIN FOR Allergy Immunology and Rheumatology, University of
ASPERGILLOMAS IN STAT3 MUTATED HYPER Rochester Medical Center, Rochester, NY,
2
IgE SYNDROME Allergy and Immunology, Nationwide Children’s Hospital,
Columbus, OH
Amanda Urban, CRNP1, Richard Chang, MD2, Kenneth
Oliver, MD3, Dirk Darnell, MA, RN4, Kamille West, MD5, Introduction
Michael Kolf6, George Grimes6, Steve M. Holland, MD7 and Cartilage hair hypoplasia (CHH) is a disorder characterized by
Alexandra F Freeman, MD7 metaphyseal chondrodysplasia, sparse hair, increased risk of
malignancy, and variable immunologic expressivity. Those
1
Clinical Monitoring Research Program/Frederick National affected have features ranging from hypogammaglobulinemia,
Laboratory, Leidos Biomedical Research, INC support to lymphopenia, neutropenia, to severe combined immunodefi-
NIAID/LCID, Bethesda, MD, ciency, but few have isolated CD8 lymphopenia as the predom-
2
Radiology and Imaging Sciences, NIH Clinical Center, inant laboratory finding.
Bethesda, MD, (3)NHLBI, Bethesda, MD, Case Description
4
Department of Nursing, NIH Clinical Center, Bethesda, MD, We report a 7 year-old girl with history of severe varicella
5
Department of Transfusion Medicine, NIH Clinical Center, pneumonia, and failure to thrive, referred for chronic cough,
Bethesda, MD, recurrent pneumonias, and bronchiectasis. On exam she had
6
Pharmacy Department, NIH Clinical Center, Bethesda, MD, fine hair, mild facial dysmorphism, but no evidence of dwarf-
7
Laboratory of Clinical Infectious Diseases, NIAID/NIH, ism. Laboratory evaluation showed normal IgG 1520, IgM 126,
Bethesda, MD IgA 46, & good post vaccination diphtheria, tetanus & pneu-
mococcal titers. Lymphocyte subsets revealed lymphopenia
STAT3 mutated Hyper IgE Syndrome is frequently complicat- (ALC 1343), CD8 count 86 (range 370–1100), CD3 839 (range
ed by pneumatoceles, which become secondarily infected 1200–2600), CD4 676 (range 650–1500), CD19 284 (range
with Aspergillus, often leading to life-threatening hemoptysis. 270–860), CD56/16 of 15.9 % (range 4–17), CD45/RO
Resection of infected pneumatoceles is often complicated by 80 %, CD45/RA 22 %. Long bone X-ray revealed metaphyseal
prolonged bronchopleural fistulae. We describe 2 patients dysplasia. Mutation was found in the RMRP Allele 1 n.70A>G.
with aspergillomas complicated by hemoptysis despite sys- Conclusion
temic antifungal therapy who were treated successfully with CHH due to RMRP mutations can present with both subtle
intracavitary Amphotericin. phenotypic and laboratory abnormalities. This case empha-
Patient 1 had recurrent pneumonias, multiple pneumatoceles sizes the importance of heightened awareness for CHH, even
with Aspergillus, and developed life-threatening hemoptysis in the absence of dwarfism, in those with severe infections and
at 35 years. Patient 2 had recurrent pneumonias and a prior isolated CD8 lymphopenia.
right upper lobectomy. At 23 years he had recurrent hemop-
tysis from a right aspergilloma. We injected a mixture of
amphotericin, antibiotics, cryoprecipiate and thrombin (to fa- 4624: IDENTIFICATION OF TYPE I
cilitate solidification) into the aspergilloma under general an- INTERFERONOPATHIES IN CHILDREN WITH
esthesia, with resolution of the hemoptysis. These patients are EARLY-ONSET SLE AND VASCULOPATHY
now 10 and 1.5 years post procedure, respectively, on main-
tenance posaconazole. Stefano Volpi, PhD1,2, Elettra Santori3, Paolo Picco4, Claudia
Aspergilloma-associated hemoptysis is a major cause of mor- Pastorino4, Roberta Caorsi4, Gillian Rice5, Alberto Martini6,
tality in STAT3 deficiency. Intracavitary instillation of Yanick Crow5,7, Marco Gattorno4 and Fabio Candotti3
314 J Clin Immunol (2016) 36:235–334

1 1
Division of Immunology and Allergy, University Hospital of Department of Allergy and Immunology, University of
Lausanne, Laboratory Center of Epalinges (CLE), Epalinges, Florida/All Children’s Hospital, Saint Petersburg, FL,
2
Switzerland, Epalinges, Lausanne, Switzerland, Division of Bone Marrow Transplantation and Immune
2
Department of Neuroscience, Rehabilitation, Ophthalmology, Deficiency, Cincinnati Children’s Hospital Medical Center,
Genetics, Maternal and Child Health (DINOGMI), University Cincinnati, OH,
3
of Genoa and Istituto Giannina Gaslini, Genoa, Italy, University of Florida, Department of Pediatrics, Division of
3
Division of Immunology and Allergy, University Hospital of Gastroenterology Washington University,
4
Lausanne, Laboratory Center of Epalinges (CLE), Epalinges, Departments of Pediatrics and Internal Medicine, St. Louis,
Switzerland, Missouri,
4 5
Pediatria 2, Istituto Giannina Gaslini, Genoa, Italy, Pediatrics, Division of Rheumatology, and Pathology and
5
Genetic Medicine, Manchester Academic Health Science Immunology, Washington University in St. Louis, St. Louis,
Centre, University of Manchester, Manchester, United MO,
6
Kingdom, University of South Florida, Tampa, FL
6
Pediatria 2 and Department of Pediatrics, Istituto Giannina
Gaslini and University of Genoa, Genoa, Italy, Objective: Germline gain of function (GOF) mutations in
7
Institute Imagine, University Paris Decartes, Paris, France signal tranducer and activator of transcription 3 (STAT3) lead
to early onset autoimmunity, infections, growth failure, and
Defective regulation of Type I interferon pathway may result lymphoproliferation. Interleukin (IL)-6 is a key inflammatory
in an excessive α/β-IFN immunity presenting with severe cytokine that utilizes STAT3. Tocilizumab is a humanized
inflammatory phenotypes. Some of these conditions have an monoclonal antibody directed at the IL-6 receptor. We
underling genetic defect and have been grouped under the assessed the efficacy of tocilizumab to treat autoimmunity in
name of type I interferonopathies. Diseases such as STING 3 patients with GOF-STAT3 mutations.
associated vasculopathy with onset in infancy (SAVI) and Methods: Three GOF-STAT3 patients from 3 different cen-
familial inflammatory syndrome with systemic lupus erythe- ters were treated with tocilizumab. Retrospective chart re-
matosus (SLE)-like manifestations, clinically overlap with views were performed.
paediatric rheumatic syndromes. Results: All 3 have missense mutations that confer gain of func-
To test the hypothesis that severe or atypical presentations of tion in transcriptional activity of the mutant STAT3 proteins.
paediatric rheumatic diseases with features of SLE and vascu- Patient 1 is a 13 year old female with severe growth failure,
lopathy, interstitial lung disease or panniculitis, might have a autoimmune hepatitis, enteropathy, myelodysplasia, and lym-
genetic origin, we screened a cohort of patients using periph- phoproliferative disease. Patient 2 is an 11 year old male with
eral blood interferon signature and molecular analysis in se- polyarticular juvenile idiopathic arthritis, autoimmune hepatitis,
lected cases. scleroderma-like skin and autoimmune hemolytic anemia.
29 out of 38 patients had a positive signature with an IFN Patient 3 is a 7 year old male with growth failure, autoimmune
score ranging from 0.9 to 28. Based on the clinical pre- thyroiditis, arthritis, severe eczema, and diarrhea. All 3 patients
sentation and the result of the IFN score we further ana- failed multiple immunosuppressants and had significant im-
lyzed 3 patients for mutations affecting known type I provement in disease manifestations with tocilizumab.
interferonopathy-related genes: 2 patients presented dis- Conclusions: IL-6 blockade is effective in treating the severe
ease causing mutations in TMEM173 and 1 patient pre- autoimmunity associated with GOF-STAT3 mutations.
sented a mutation in DNASE1L3. Molecular screening for
all other patients is ongoing.
With the present study we anticipate that testing blood for an 4626: IPEX SYNDROME: A MOROCCAN CASE
interferon signature is a valuable screening tool for the iden-
tification of type I interferonopathies. Imne Zineb1, Asmae alaoui Mdaghri2, Alai Hattersley3,
Amina Balafrej4 and Naima Elhafidi4

1
4625: TREATMENT WITH IL-6 BLOCKADE IN pediatrics department, university mohamed VI, Rabat,
PATIENTS WITH GAIN OF FUNCTION STAT3 Morocco,
2
MUTATIONS pediatrics departement, university mohamed VI, Rabat,
Morocco,
Johana B Castro-Wagner, MD1, Ashish R. Kumar, MD 3
Department of Molecular Genetics,, Royal Devon and Exeter
PhD2, Christopher Jolley, MD3, Tiphanie P Vogel, MD, Hospital NHS, london,
PhD 4 , Megan A. Cooper, MD, PhD 5 and Jennifer W. 4
peadiatric department, university mohamed VI, Rabat,
Leiding, MD6 Morocco
J Clin Immunol (2016) 36:235–334 315

Introduction: IPEX is a rare pediatric syndrome secondary to Nine pediatrics patients from 6 families with STAT1 muta-
a mutation in the FOXP3 gene on chromosome X (Xp 23.11 tions are currently followed at the NIH. The median age is
region-q 13.3). We report the case of an infant suffering from 16 years (range 5–20 years). Seven have decreased STAT1
IPEX syndrome. Observation : male sex infant was hospital- dephosphorylation, consistent with a gain of function pheno-
ized at the age of 5 days with acute dehydration and metabolic type. The first clinical manifestation (age 0.2–6 years) includ-
acidosis, and whose diagnosis of diabetes mellitus was made ed mycobacterial osteomyelitis (1); persistent diarrhea (4),
at day 11 to life. Insulin therapy was then started. Laboratory pulmonary infections (2), mucocutaneous candidiasis
tests found hyperglycemia, a C-peptide levels undetectable (CMC) (3), and one asymptomatic (twin brother).
anti-GAD negative, normal liver function tests and eosino- Progression of the disease included cerebral aneurysm (2),
philia. The genetic study has excluded common mutations hypothyroidism (2), and insulin dependent diabetes (3).
responsible for neonatal diabetes. The patient developed atop- Infections included CMC (4), mycobacterium (6), viral (4),
ic eczema then hospitalized twice for dehydration in acute and bacterial sinopulmonary (3). One received BMT prior to
diarrhea . The child died at 8 months in an array of dehydration. diagnosis for a severe IPEX-like phenotype. All are main-
The review of his case, suggested the IPEX syndrome . The tained on continuous antimicrobial prophylaxis and 3 receive
search of the FOXP3 gene mutation has returned positive. immunoglobulin replacement.
Discussion: IPEX is a Deregulation immune Pediatric presentations of STAT1 mutations are varied with a wide
polyendocrinopathies, autoimmune enteropathy X-linked, range of infectious and inflammatory complications. Earlier
which often manifests itself in a boy in the early neonatal period diagnosis may help to prevent severe clinical manifestations.
or before the age of 4 months for insulin-dependent diabetes, a
profuse secretory diarrhea responsible for a significant failure to
thrive, eczema, thrombocytopenia, anemia, thyroid dysfunction 4630: EMERGING ROLE OF TYPE-2 INNATE
and recurrent infections. Conclusion: IPEX is rare but one LYMPHOCYTES (ILC2) IN TH2 SKEWING
should think before a boy with neonatal diabetes that develops OF LEAKY SCID/OMENN SYNDROME
later any autoimmune disorder.
Krisztian Csomos, PhD1,2, Boglarka Ujhazi1,2, Sanhong Yu,
PhD3, Benjamin Causton, PhD2, Benjamin Medoff, MD2,
4627: BROAD CLINICAL PHENOTYPE Dale T Umetsu, MD, PhD, Luigi D Notarangelo, MD5 and
IN PEDIATRIC PATIENTS WITH Jolan E. Walter, MD PhD1,2,5
HETEROZYGOUS STAT1 MUTATIONS

Betty Marciano, MD1, Peter Olbrich, MD2, Elizabeth P. 1

Division of Pediatric Allergy/Immunology, Massachusetts
Sampaio, MD, PhD1, Amy P Hsu, BA3, Ofer Zimmerman, General Hospital for Children, Boston, MA,
MD4, Gulbu Uzel, MD1, Christa S. Zerbe, M.D.1, Steven M. 2
Center for Immunology and Inflammatory Diseases,
Holland, MD3 and Alexandra F Freeman, MD1 Massachusetts General Hospital, Harvard Medical School,
Boston, MA,
3
Department of Medical Oncology, Dana-Farber Cancer
1
Laboratory of Clinical Infectious Diseases, NIAID/NIH, Institute and Harvard Medical School, Boston, MA,
4
Bethesda, MD, Division of Immunology, Boston Children’s Hospital,
2
Pediatric Infectious Diseases and Immunopathology, Seville, Harvard Medical School, Boston, MA
Spain,
3
Laboratory of Clinical Infectious Diseases, National Institute Introduction. Patients with Omenn syndrome (OS) have
of Allergy and Infectious Diseases, National Institutes of highly restricted T and B cell repertoires secondary to im-
Health, Bethesda, MD, paired V(D)J recombination with low RAG activity. Th2
4
Immunopathogenesis section, NIH, NIAID, LCID, skewing is a hallmark of OS but mechanisms that lead to
Bethesda, MD abnormal T helper cell polarization are not fully understood.
The homozygous Rag1S723C/S723C (mut/mut) mouse model of
STAT1 is a key molecule in the regulation of inflammation leaky SCID/OS provides a unique opportunity to investigate
and infection. The clinical spectrum of patients with hetero- mechanisms of Th2 skewing in the context of T cells and type-
zygous STAT1 mutations is complex, with fungal, bacterial 2 innate lymphoid cells (ILC2s).
and viral susceptibility as well as endocrine and vascular ab- Methods. ILCs, T cells and type-2 cytokine (IL-5, IL-13)
normalities. We reviewed our pediatric patients to better char- production were assessed in the lungs of mut/mut mice by
acterize the early presentation and course to avoid potential flow cytometry. Type-2 cytokines were measured in serum
diagnostic delays. with multiplex assay and with RT-qPCR from lung tissue.
316 J Clin Immunol (2016) 36:235–334

Results. Th2 skewing was observed in mut/mut mice was abolished in the absence of TLR9 stimulation (1.42 ±
and reflected in Th2 cell enrichment, elevated type-2 0.18). Finally, soluble CD40L signal could be replaced by
cytokine level and eosinophilia. In parallel, increased activated allogeneic CD4 T cells, shown by parallel level of
number of ILC2s was detected in lungs with elevated IgG class switch using healthy donor CD4 T cells (12.5 ±
type-2 cytokine production compared to wild type mice. 2.4), and only background IgG staining with X-HIGM CD4
T cells isolated from the lung had an activated effector T cells (1.92 ± 0.27). Thus, this assay could potentially
memory phenotype and produced significantly higher differentiate between extrinsic and intrinsic B cell CSR
amounts of IL-2. defects.
Conclusions. We propose that a dysregulated T cell com-
partment facilitates expansion of ILC2s in the lungs of mut/
mut mice through increased release of alarmins (IL-33, IL- 4632: AUTOIMMUNITY IN STAT3 MUTATED
25, TSLP) and IL-2. In return, ILC2s promote Th2 polar- HYPER IgE SYNDROME
ization via activation of dendritic cells (IL-13) and eosin-
ophilia (IL-5). Amanda K Urban, CRNP1, Niraj C Patel, MD2, Jennifer
Heimall, MD3, Dirk Darnell, MA, RN4, Joy Peterson, BSN,
RN1, Steve M. Holland, MD5 and Alexandra F Freeman, MD5
4631: IN-VITRO NAïVE B CELL CLASS SWITCH
ASSAY FOR EVALUATION OF B CELL AND
1
HELPER T CELL FUNCTION Clinical Monitoring Research Program/Frederick National
Laboratory, Leidos Biomedical Research, INC support to
David Hagin, MD PhD1, Nicholas W. Hubbard2, Hans Ochs3 NIAID/LCID, Bethesda, MD,
and Troy R. Torgerson, MD PhD4 2
Pediatrics, Carolinas Medical Center, Charlotte, NC,
3
Division of Allergy and Immunology, Children’s Hospital of
Philadelphia, Philadelphia, PA,
1 4
Allergy and Immunology, University of Washington / Seattle Department of Nursing, NIH Clinical Center, Bethesda, MD,
5
Children’s Hospital, Seattle, WA, Laboratory of Clinical Infectious Diseases, NIAID/NIH,
2
Center for Immunity and Immunotherapies and the Program Bethesda, MD
for Cell and Gene Therapy, Seattle Children’s Research
Institute, Seattle, WA, Rationale: STAT3 signaling, Th17 cells, and IL-6 have been
3
Center for Immunity and Immunotherapies, Seattle implicated in the pathogenesis of inflammatory autoimmune
Children’s Research Institute, Seattle, WA, disorders but are markedly impaired in STAT3 mutated Hyper
4
Division of Immunology, Department of Pediatrics, IgE Syndrome. Therefore, a paucity of autoimmune disease
University of Washington and Seattle Children’s Research would be expected in HIES.
Institute, Seattle, WA Methods: We retrospectively reviewed the 125 patients with
HIES followed at the NIH for signs of autoimmunity.
A feature of many combined immunodeficiency syn- Results: Four females were identified with systemic lupus
dromes is abnormal Class Switch Recombination (CSR) erythematosus (SLE), all receiving hydroxychloroquine ther-
and antibody deficiency. This could be the result of either apy. Three had nephritis treated with prednisone, and myco-
intrinsic B cell defects or impaired extrinsic CD4 T cell phenolate mofetil in one. One patient requires dialysis. One
helper function. An assay to differentiate between the two male patient had alopecia and Raynaud’s with a positive ANA
could direct further investigation to focus on either B cell and anti-dsDNA. One patient was identified with a systemic
or T cell pathways in an attempt to reveal underlying erosive inflammatory polyarthritis consistent with rheumatoid
defects. We developed an in vitro assay to induce class arthritis (RA), with others partially filling RA criteria. One
switch of naïve IgG IgA double negative B cells. For this male and one female had hypothyroidism. One girl developed
purpose naive B cells were isolated and incubated for ITP after a viral illness; she received steroids, IVIG and ritux-
5 days in the presence of IL21 (100 ng/mL), TLR9 agonist imab before resolution. One patient had a self-limited episode
(1 nM), soluble CD40L (3 μg/mL) ± anti IgM (1 μg/mL). of ulcerative proctitis, but no other patients had inflammatory
On day 5, Golgi plug was added and cells were stained bowel disease.
intracellularly for IgG. While B cells incubated with IL21 Conclusions: Autoimmune disease appears to occur with in-
alone showed only background staining, significant increase creased frequency in HIES despite defective Th17 cell differ-
in percent of IgG+ cells was seen following incubation with entiation and decreased IL-6 signaling. The pathogenesis of
either soluble CD40L (9.07 ± 0.17), anti IgM (7.6 ± 0.34) or autoimmunity, with a predominance of lupus symptoms, in
both (14.3 ± 0.1). TLR9 signal was obligatory as class switch this cohort warrants further investigation.
J Clin Immunol (2016) 36:235–334 317

4633: UNDERSTANDING AUTOIMMUNE plaquenil, rituximab, and steroid taper with noted improve-
PATHOLOGY IN ACTIVATION-INDUCED ments in malar rash and cytopenias with repeat cardiac cath-
CYTIDINE DEAMINASE (AID) DEFICIENCY, eterization pending. To our knowledge, this is a novel case
A CASE REPORT OF SYSTEMIC LUPUS description of biopsy-proven pathogenic autoreactive IgM in a
ERYTHEMATOSUS (SLE) WITH EVIDENCE patient with SLE and underlying AID deficiency.
OF PATHOGENIC AUTOREACTIVE IgM.

Jocelyn Farmer, MD, PhD1, Sara Barmettler, MD1, Amar 4634: HEMOPHAGOCYTIC SYNDROME IN A
Oza, MD2, Jean-Nicolas Schickel, PhD3, Joel Sng3, Alex TEENAGER WITH RECURRING
Subtelny4, Ghulam Abbas Kharal, MD5, Maya Srikanth, AUTOINFLAMMATORY EPISODES: CASE
MD, PhD5, Richard Channick, MD6, Josanna Rodriguez- REPORT
Lopez, MD6, Rosalynn M Nazarian, MD7, Eric Meffre,
PhD3, John H Stone, MD2, Waleed Al-Herz, MD8 and Jolan Walter Flausino Fidelis Junior, MD1, Frederico da Costa Val
Walter, MD, PhD9 Barros, MD2, Antônio Vaz de Macedo, MD3, Maria Vitória
Pádua de Quintero, MD4, Camila Caetano daSilva, MD1,
Bernadete Barreto de Assis, MD1, Thalita Rodrigues Dias,
1
Department of Allergy & Immunology, Massachusetts MD5 and Luciana Araújo Oliveira Cunha, MD, PhD1,5
General Hospital, Boston, MA,
2 1
Department of Rheumatology, Massachusetts General Pediatrics, Hospital da Polícia Militar de Minas Gerais, Belo
Hospital, Boston, MA, Horizonte, Brazil,
3 2
Department of Immunobiology, Yale University School of ICU, Hospital da Polícia Militar de Minas Gerais, Belo
Medicine, New Haven, CT, Horizonte, Brazil,
4 3
Harvard Medical School, Boston, MA, Hematology, Hospital da Polícia Militar de Minas Gerais,
5
Department of Neurology, Massachusetts General Hospital, Belo Horizonte, Brazil,
4
Boston, MA, Rheumatolgy, Santa Casa de Misericórdia de Belo
6
Department of Pulmonary & Critical Care Medicine, Horizonte, Belo Horizonte, Brazil,
5
Massachusetts General Hospital, Boston, MA, Immunology, Hospital das Clínicas da Universidade Federal
7
Pathology Service, Dermatopathology Unit, Massachusetts de Minas Gerais, Belo Horizonte, Brazil
General Hospital, Boston, MA,
8
Pediatric Department, Faculty of Medicine, Kuwait Case report: A 14 year-old female who had had reccuring
University, Kuwait, Kuwait, febrile episodes during her childhood, including a treatment
9
Department of Pediatrics, Division of Allergy & for leishmaniasis because of febrile hepatosplenomegaly. She
Immunology, Massachusetts General Hospital, Boston, MA had also recently been treated for asseptic meningitis and hy-
potension. In October 2015 she presented to the emergency
Autoimmunity can occur in AID deficiency in association department with a 4-day history of persisting high grade fever,
with autoreactive B cells. To-date, a single case of SLE in diffuse abdominal pain, splenomegaly and delirium. Her lab-
AID deficiency has been reported, and the role of IgM auto- oratory exams were remarkable for anemia, neutrophilia, and
antibodies in disease pathogenesis is unclear. Herein we pres- increased inflammatory markers, with no overt signs of infec-
ent seven affected family members with AID deficiency, in- tion. Having infectious foci been initially excluded, she was
cluding one member seen at the Massachusetts General started on colchicine for the abdominal pain, and a bone mar-
Hospital. In the year prior to presentation, he uniquely devel- row examination was performed. This showed a slightly
oped a cerebral subarachnoid hemorrhage, pancytopenia, a hypocellular marrow, with neutrophil phagocytosis. After
malar facial rash, and pulmonary arterial hypertension. At 2 days, there was worsening of the fever, aswell as diarrhea
presentation, he had hyper IgM (3140 mg/dL) and normal and vomiting, followed by respiratory distress and hemody-
IgG on replacement therapy. Serology was notable for auto- namic instability necessitating Intensive Care support for the
antibodies (ANA; dsDNA; IgM to cardiolipin and B2 glyco- management of SIRS. This was accompanied by persistent
protein). Cardiac catheterization showed precapillary pulmo- anemia (demanding red cell support), fever and hepatic dys-
nary arterial hypertension. MRIs of the cerebral and pulmo- function, which prompted initiation of treatment for
nary vasculature were without clear evidence of vasculitis. Macrophage Activation Syndrome with pulsed systemic
However, biopsy of the malar rash confirmed perivascular dexametasone, followed by methylprednisolone, cyclosporine
lymphocytic infiltrates and granular immunoreactivity at the and immunoglobuline. This resulted in gradual improvement
basement membrane to IgM, IgG, IgA, and C3. A diagnosis of of symptoms and laboratory markers. She was well at last
SLE was made, and the patient was started on a course of follow-up.
318 J Clin Immunol (2016) 36:235–334

4638: INFLAMMATORY BOWEL DISEASE IN Neonatal screening programs for severe combined immuno-
X-LINKED AGAMMAGLOBULINEMIA deficiency (SCID) using the T cell receptor excision circles
assay have shown a tremendous success of newborn diagnos-
Iris M Otani, MD1, Sara Barmettler, MD2, Zuhair K Ballas, tics for the detection and initiation of life-saving treatment for
MD3, Francisco Bonilla, MD PhD4, Hans Ochs5 and Jolan E. PID patients. The limitations of other established cellular, ge-
Walter, MD PhD6 netic and functional tests however so far prevented a broad
application in newborn screening (NBS) for PID other than
1
Massachusetts General Hospital, Boston, MA, SCID. Combined immunodeficiencies with normal peripheral
2
Department of Allergy & Immunology, Massachusetts T/B cell counts, defects of phagocyte number and function,
General Hospital, Boston, MA, complement deficiencies, as well as diseases of immune
3
Allergy and Immunology, University of Iowa Hospitals and dysregulation or intrinsic immune defense with a reduc-
Clinics, Iowa City, IA, tion of characteristic cellular subsets are currently not
4
Childrens Hospital Boston, Boston, MA, covered in NBS programs for PID, as there is a lack of
5
Center for Immunity and Immunotherapies, Seattle suitable screening tools and evidence for their efficacy.
Children’s Research Institute, Seattle, WA, Although increasingly becoming appreciated as a future
6
Center for Immunology and Inflammatory Diseases, NBS concept, whole-exome or PID panel sequencing still
Massachusetts General Hospital, Harvard Medical School, does not meet the technical and ethical requirements for
Boston, MA routine implementation as a first-tier test in neonatal diag-
nostics. We will present novel diagnostic tests for new-
Aside from infections, patients with X-linked agamma- born screening of PIDs, including phagocytic and comple-
globulinemia (XLA) may present with autoimmune or in- ment deficiencies, as well as high-throughput epigenetic
flammatory complications. We follow a 71-year-old patient assays for the enumeration of lymphocyte subsets, and
initially diagnosed with Crohn’s disease at 35 years of age transcriptome (RNAseq) approaches for dried blood spot
and partially treated with prednisone and 5-amino salicy- samples currently undergoing investigation in European
lates. In his 40s, for history of chronic lung disease, he was pilotal trials.
investigated and diagnosed with hypogammaglobulinemia
and placed on intravenous Ig (IVIG). Only recently, when
his 3 year-old grandchild presented with absent IgG, were 4640: A CASE REPORT OF CTLA-4 DELETION
both patients diagnosed with XLA. Interestingly, while he AND COMMON VARIABLE
continues to have mild gastrointestinal (GI) complaints, he IMMUNODEFICIENCY.
has not required active treatment or hospitalization since
starting IVIG replacement. Hannah Laure Elfassy, M.D.1, Marie-Soleil Masse, M.D.1,2,
IVIG therapy has recently been gaining recognition as a po- Isabel Fernandez, PhD3,4, Françoise Le Deist, MD PhD2,3,4
tentially beneficial treatment for Crohn’s disease. Possibly, and Hugo Chapdelaine, M.D.1,2
IVIG use in the XLA patient population is preventing progres-
sion of IBD. We queried the USIDNET registry for patients
1
with XLA and GI disease. Of 19 patients, eight (50 %) had a Division of Allergy and Clinical Immunology, Department of
history of a chronic GI infection, 17 patients (89 %) were Medicine, Centre Hospitalier Universitaire de Montréal,
treated with immunoglobulin replacement therapy. Montreal, QC, Canada,
2
Immunomodulatory treatment for IBD was reported in two Department of Pediatrics, CHU Sainte-Justine, Montreal,
cases, however 14 patients (73 %) required parenteral nutri- QC, Canada,
3
tion. Longitudinal studies are needed to investigate GI pathol- Department of Microbiology and Immunology, University of
ogy and progression of IBD in XLA patients and to identify Montreal, Montreal, QC, Canada,
4
treatment strategies. Laboratory of Immunology, CHU Sainte Justine, Montreal,
QC, Canada

4639: NOVEL DIAGNOSTIC TESTS FOR CVID is a complex and heterogeneous primary immune defi-
NEWBORN SCREENING OF PIDs ciency, which is associated with autoimmune manifestations.
The CTLA4 is an essential regulator of immune responses as
Stephan Borte, MD, PhD, illustrated by autoimmune disease associated with mutation in
CTLA4 gene.
Dept. of Pediatrics, ImmunoDeficiencyCenter Leipzig, We report a case of a patient with an established diagnosis of
Leipzig, Germany CVID and a CTLA4 deletion.
J Clin Immunol (2016) 36:235–334 319

She had refractory lymphocytic interstitial lung disease, sero- despite clinical improvement. Whole exome sequencing of the
negative polyarthritis and apoptotic enterocolitis dependent of CD3−CD4+ clonal population identified several mutations not
parenteral nutrition and corticosteroids. Opportunistic infec- found in the patient’s normal CD3+CD4+ T cells. L-HES is
tions prompted immunological work-up which revealed grad- associated with angioimmunoblastic lymphoma; further char-
ual hypogammaglobulinemia. Replacement IGIV therapy was acterization of these somatic mutations may give insight into
initiated. Following genetic analysis, abatacept has been the origins of eosinophilia and oncogenesis in this disorder.
introduced.
Serial lymphocyte immunophenotyping showed gradual de-
crease of B cells (CD19+) and very low T reg cells (CD4+ 4642: FATAL HYPERINFLAMMATION IN
CD25+ FOXP3+ CD27- T cells). Expression of intracellular MURINE MODEL OF LEAKY SCID/OMENN
CTLA4 after 3 days stimulation of whole blood with anti-CD3 SYNDROME: INNATE OVERACTIVATION
antibody (OKT3) or ConA was normal. LOCALIZED IN SMALL AND LARGE
Array comprehensive genomic hybridation revealed heterozy- INTESTINES
gous 2q33.2q33.3 deletion, which resulted in complete
CTLA4 gene deletion. Krisztian Csomos, PhD1,2, Boglarka Ujhazi1,2, Katalin Kis-
Mutations in CTLA4 result in a disrupted T and B cell homeo- Toth, PhD3, Attila Szanto, MD PhD4, Stefano Volpi, PhD5,
stasis as well as a complex immune dysregulation syndrome. Frederick Alt, PhD6, Mike Recher, MD PhD7, Luigi D
Screening of CTLA4 expression by flow cytometry might Notarangelo, MD5 and Jolan E. Walter, MD PhD1,2,5
miss the detection of defective CTLA4, a diagnosis that might
offer specific treatment for the patient condition.
1
Center for Immunology and Inflammatory Diseases,
Massachusetts General Hospital, Harvard Medical School,
4641: CHILDHOOD ONSET LYMPHOCYTIC Boston, MA,
2
VARIANT HYPEREOSINOPHILIC SYNDROME Division of Pediatric Allergy/Immunology, Massachusetts
WITH TENOSYNOVITIS, ABNORMAL T CELL General Hospital for Children, Boston, MA,
3
PROLIFERATION, AND CLONAL CD3-CD4+ T Division of Rheumatology, Beth Israel Deaconess Medical
CELLS Center, Boston, MA,
4
Department of Molecular Biology, Massachusetts General
Christina Yee, MD, PhD1, Mindy Lo, MD, PhD1, Erdyni Hospital, Boston, MA,
Tsitsikov, PhD1, Serine Avagyan, MD, PhD1,2, Alan Cantor, 5
Division of Immunology, Boston Children’s Hospital,
MD, PhD1,2 and Andrew Lane, MD, PhD2 Harvard Medical School, Boston, MA,
6
Immune Disease Institute, Harvard Medical School, Boston,
MA,
1 7
Boston Children’s Hospital, Boston, MA, Clinic for Primary Immunodeficiency, Medical Outpatient
2
Dana Farber Cancer Institute, Boston, MA Unit, University Hospital Basel Switzerland

An 11 year old girl presented with new onset severe tenosyn- Hypomorphic mutations in recombination activating genes
ovitis involving the hands, wrists, and ankles. She was found (RAGs) result in a restricted T and B cell repertoire and fea-
to have eosinophilia (7570 cells/mcl) and elevated IgE (17, tures of autoimmunity and hyperinflammation beyond infec-
874 IU/mcl). She had normal T cell proliferation to mitogens, tions. Previously the pathomechanism was solely contributed
but poor response to anti-CD3, tetanus and Candida antigen. to the abnormal T and B cells and the role of innate system has
She had no history of opportunistic infections. Immune eval- not been fully examined. Prior reports suggest viral infections
uation identified an abnormal population of as triggers of hyperinflammation.
CD4+CD5+CD7−CD8− T cells with absent cell surface CD3 Utilizing a homozygous Rag1S723C/S723C (mut/mut) mouse
but expression of intracellular CD3, consistent with model of leaky SCID, myeloid and T cell subsets were
Lymphocytic-variant Hypereosinophilic Syndrome (L-HES). assessed in multiple organs at baseline and after high dose
The abnormal population represented 12.5 % of total CD4+ T i.v. poly(I:C) treatment mimicking acute viral infection. Pro-
cells. Deep sequencing of the TCR beta chain showed that the inflammatory cytokine production was determined by ELISA,
population was composed of 3 very closely related clones. RT-qPCR and mRNA flow cytometry assay.
The patient was treated with prednisone and methotrexate Against T cell lymphopenia, CD4 T cells accumulated in mul-
with partial improvement of her joint symptoms. The tiple organs along with infiltration of myeloid cells. High dose
CD3−CD4+ population remained present after treatment. poly(I:C) treatment, sublethal to wt/wt mice, induced an in-
Peripheral eosinophilia and elevated IgE levels also persisted flammatory cytokine surge and was fatal in all mut/mut mice.
320 J Clin Immunol (2016) 36:235–334

Mut/mut was rescued when crossed with either mda5 or tlr3 4644: AUTOINFLAMMATORY SYNDROME:
deficient mice. Gut and infiltrating myeloid cells appear to be CASE REPORT OF PROBABLE
potent source of pro-inflammatory cytokines as determined by CRYOPYRINOPATHIE
cytokine expression in our model.
In murine model of leaky SCID we propose that Thalita Rodrigues Dias, MD1, Rhaianny Gomes Souza,
hyperinflammation is driven by innate cells infiltrating the MD1, Luciana Araújo Oliveira Cunha, MD, PhD1 and Jorge
intestine and significantly contributes to the fatal cytokine Andrade Pinto, MD, PhD2
surge after acute viral infections.

1
Immunology, Hospital das Clínicas da Universidade Federal
4643: A NOVEL IL-10 RECEPTOR B GENE de Minas Gerais, Belo Horizonte, Brazil,
2
MUTATION CAUSING SEVERE NEONATAL Universidade Federal de Minas Geria, Belo Horizonte, Brazil
INTESTINAL INFLAMMATION
Case report: A male child, 3 months old, son of a
Jenna R.E. Bergerson, MD, MPH1, Aaruni Khanolkar, nonconsanguineous parentes, admitted to the Odilon
MBBS2, Valeria Cohran, MD3 and Ramsay L Fuleihan, MD4 Behrens Hospital of Belo Horizonte since birth. The patient
presents scattered rash since 1 week of life after exposure to
cold, besides, he has tachypnea, tachycardia, irritability and
1
Division of Allergy and Immunology, Ann & Robert H. limb pain. The child’s father also has rash and joint pain after
Lurie Children’s Hospital of Chicago, Chicago, IL, exposure to cold, undiagnosed. He was empirically treated for
2
Department of Pathology, Ann and Robert H. Lurie sepsis unfocused on several occasions, without improvement,
Children’s Hospital of Chicago, Chicago, IL, no growth of microorganisms. Laboratory data: investigations
3
Division of Gastroenterology, Hepatology and Nutrition, demonstrated persistent leukocytosis and increased of reactive
Ann & Robert H. Lurie Children’s Hospital of Chicago, C protein. Them, was started canaquinumabe (inhibitor IL-1?)
Chicago, IL, 2 months ago and showed significant improvement in symp-
4
Division of Allergy & Immunology and Jeffrey Modell toms. The genetic study was not performed until now, how-
Diagnostic Center for Primary Immunodeficiencies, Ann & ever, the symptoms ant clinical response to medication makes
Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL cryopyrinopathie a probable diagnosis.

We report a 2 month old, former full term male who presented

in the neonatal period with persistent diarrhea, failure to 4646: BTK MUTATIONS IN A PERUVIAN
thrive, hepatomegaly, recurrent febrile illnesses despite nega- AGAMMAGLOBULINEMIA COHORT.
tive cultures, and lymphopenia. Imaging studies were consis-
tent with inflammatory colitis and the patient was diagnosed Guisela Adriana Alva Lozada, MD1, Gesmar Segundo,
with very early onset inflammatory bowel disease (VEOBID). MD2, Enrique Cachay, MD3, Roman Angulo Vigo, MD4,
Family history was notable for consanguinity and multiple Jesus Lopez-Guisa, PhD5, Stephanie J Anover-Sombke6,
early infantile deaths. Laboratory evaluation demonstrated a Hans Ochs 7 , Juan Carlos Aldave, MD 8 and Troy R.
normal neutrophil oxidative burst assay, persistent Torgerson, MD PhD9
hypergammaglobulinemia, decreased T cell subsets with nor-
1
mal numbers of B cells and NK cells, but borderline elevated Edgardo Rebagliati Martins National Hospital, Lima, Peru,
2
memory T cells and decreased memory B cells. Lymphocytes Immunology Diagnostic Laboratory, Seattle Children’s
proliferated normally to mitogen stimulation and there was Institute Research, Seattle, WA,
3
normal diversity of T cell receptors. Immunologic testing re- Allergy and Clinical Immunology, Hospital Nacional
vealed an absence of the IL-10 mediated STAT3 phosphory- Edgardo Rebagliati Martins, LIMA, Peru,
4
lation, compatible with a defect in the IL-10 signaling path- Hospital Edgardo Rebagliati Martins, Lima, Peru,
5
way. Molecular analysis revealed a defect in the IL-10RB Immunology Diagnostic Laboratory, Seattle Childrens
gene. This patient has had persistence of febrile episodes Institute and Research, Seattle,
6
and severe colitis flares refractory to oral steroids and Department of Pediatrics, University of Washington and
anti-TNF therapies, and is currently undergoing hemato- Seattle Children’s Research Institute, Seattle, WA,
7
poietic stem cell transplantation. Our case highlights the Center for Immunity and Immunotherapies, Seattle
importance of the IL-10 signaling pathway for the Children’s Research Institute, Seattle, WA,
8
maintenance of intestinal homeostasis and intestinal Allergy and Clinical Immunology, Hospital Nacional
inflammation. Edgardo Rebagliati Martins, Lima, Peru,
J Clin Immunol (2016) 36:235–334 321

9
Division of Immunology, Department of Pediatrics, INTRODUCTION: CD25 deficiency is an autosomal reces-
University of Washington and Seattle Children’s Research sive complex disorder of immune dysregulation. Affected in-
Institute, Seattle, WA dividuals present in infancy with recurrent infections, lymph-
adenopathy, and variable autoimmune features. CASE
Introduction: X-linked agammaglobulinemia (XLA) is a rare REPORT: The patient was a 14 year-old boy of first-cousin
genetic disorder caused by a mutation in the Bruton’s tyrosine healthy parents. At 10 months of age, he presented chronic
kinase (BTK) gene. We report the first molecular investigation diarrhea, anemia and failure to thrive, and started presenting
of an agammaglobulinemia patient cohort from Peru. episodes of eczema. At 4 year old, was diagnosed with auto-
Methods: Patients were diagnosed by clinical history, pres- immune hemolytic anemia, and received oral prednisone for
ence of hypogammaglobulinemia (IgG,IgA, and IgM), and 7 years. Around 11 year old, he started presenting recurrent
low levels of CD19+ B cells (less than 2 %). DNA samples bacterial pneumonias, hypogammaglobulinemia and started
were evaluated for mutations in the BTK gene on the X chro- intravenous immunoglobulin monthly. No other infections
mosome. BTK protein expression was also performed on have been reported. At age 12, he received GH treatment for
some patients. Results: Twelve patients with diagnosis of 8 months without response. He had recently presented numer-
agamaglobulinemia were included. The mean age of onset ous admissions and blood transfusions due to autoimmune
symptoms was 12 months (3–31); the mean age of diagnosis hemolytic anemia. In immunological evaluation, he presented
was 60 month (13–125). The patients presented with recurrent low IgG (even under IVIg), low IgM, undetectable IgA and
airway infections, in particular recurrent pneumonias. IgE. Immunophenotyping showed normal number of CD4
Mutations in the BTK gene were identified in 9 (75 %) of and CD8 lymphocytes with inversion of CD4/CD8 ratio,
patients. The mutations were distributed throughout the gene: low numbers of memory T cells and B lymphopenia. A
One mutation in the TH domain, 1 in the SH3 domain, 2 in the whole-exome sequencing showed a homozygous mutation
PH domain, 2 in the SH2 domain, 2 in the TK domain, and 1 in the IL2RA gene (exon 4:c.398A>C,p.N133T).
involving both the SH2 and TK domains. Two patients had CONCLUSION: This work illustrates the phenotypic vari-
novel mutations (one base pair substitution, one splicing mu- ability of CD25 deficiency and points to the possible involve-
tation) and 2 patients had large deletions, one encompassing ment of B cells in these patients.
the downstream TIMM8A gene compatible with deafness-
dystonia-optic neuropathy (Mohr-Tranebjærg) syndrome.
Conclusion: BTK mutations were identified in 75 % and 4648: AUTOINFLAMMATORY SYNDROME:
two novel mutations were identified in this report. CASE REPORT OF TRAPS

Rhaianny Gomes Souza, MD1, Luciana Araújo Oliveira

4647: HYPOGAMMAGLOBULINEMIA Cunha, MD, PhD1,2, Thalita Rodrigues Dias, MD1, Maria
AND B CELL LYMPHOPENIA AS PHENOTYPE Vitória Pádua de Quintero, MD3, Ana Lúcia Nogueira Diniz,
ASSOCIATED WITH CD25 DEFICIENCY MD4, Fernanda Gontijo Minafra Silveira Santos, MD, MS1
and Jorge Andrade Pinto, MD, PhD5

Diogo C Soares, MD1, Bruna Aquilante, MD2, Antonio

Carlos Pastorino, MD, PhD3, João Bosco Oliveira, MD, 1
Immunology, Hospital das Clínicas da Universidade Federal
PhD4, Chong Ae Kim, MD, PhD5 and Magda Carneiro- de Minas Gerais, Belo Horizonte, Brazil,
Sampaio, MD, PhD6 2
Pediatrics, Hospital da Polícia Militar de Minas Gerais, Belo
Horizonte, Brazil,
1 3
Clinical Genetics Unit, Hospital das Clinicas da Universidade Rheumatolgy, Santa Casa de Misericórdia de Belo
de São Paulo, Sao Paulo, Brazil, Horizonte, Belo Horizonte, Brazil,
2 4
Allergy and Immunology Unit, Hospital das Clinicas da Infectious Diseases, Centro de Treinamento e Referência em
Universidade de São Paulo, São Paulo, Brazil, Doenças Infecto Parasitárias Orestes Diniz, Belo Horizonte,
3
Allergy and Immunology Unit - Department of Pediatrics, Brazil,
5
Universidade de São Paulo, São Paulo, Brazil, Universidade Federal de Minas Geria, Belo Horizonte, Brazil
4
Instituto de Medicina Integral Prof. Fernando Figueira, Recife,
Brazil, Case report: An 1 year and 5 month-old boy, admitted at
5
Clinical Genetics Unit, Hospital das Clinicas da Universidade Immunology Service Hospital of the Federal University of
de São Paulo, São Paulo, Minas Gerais and later to Children’s Rheumatology Service of
6
Department of Pediatrics, Universidade de São Paulo, São Santa Casa de Belo Horizonte - Minas Gerais, for the investiga-
Paulo, Brazil tion of autoinflammatory syndrome. Patient with recurrent fever
322 J Clin Immunol (2016) 36:235–334

frame from at age 3 months with no other associated symptoms. vaccine. At 1 year old, he evolved with weakness, spine de-
He was submitted at age of 6 months to an extensive workup to formations, no teeth and had a fracture in his right fist. Was
fever of unknown origin wich was unconclusive. Laboratory then diagnosed rickets. Being submitted to treatment with cal-
data without leukocytosis and acute phase reactants unchanged. cium and vitamin D. He was finally submitted to a bone mar-
Then started with colchicine at age 1 year and 6 months, how- row transplant at 1 and a half year of age, but weighting only
ever, patient remained persistent fever and developded an 6,5 kg and with lots of complications as pulmonary and
artrhalgia in the lower limbs. Administered canakquinumabe endocrinologics.
(inhibitor IL-1β), at age of 1 year and 7 months, with total
improvement of symptoms.
Held sequencing panel autoinflammatory syndromes and find 4650: IN-DEPTH DIAGNOSTIC
meaning uncertain variant (c.G362A: p.R121Q) in TNFRSF1A IMMUNE-PROFILING OF TWO X-LINKED
gene. The variant found in TNFRSF1A gene (c.362G>A: SCID SIBLINGS IDENTIFIED THROUGH THE
p.R121Q R92Q counted once), occurs in up to 1–2 % of cau- ILLINOIS NEWBORN SCID SCREENING
casians and is associated with the development TRAPS. PROGRAM

Aaruni Khanolkar, MBBS1, William Tse, MD, PhD2 and

4649: CLINICAL MANIFESTATIONS AND Ramsay L. Fuleihan, MD3
COMPLICATIONS BEFORE BONE MARROW
TRANSPLANT IN A SCID PATIENT
1
Department of Pathology, Ann and Robert H. Lurie
1
Fernanda Gontijo Minafra Silveira Santos, MD, MS , Children’s Hospital of Chicago, Chicago, IL,
2
Jorge Andrade Pinto, MD, PhD2, Livia Pierone B Cruz, Division of Hematology, Oncology and Stem Cell
MD 3 , Tiago Nunes Guimaraes, MD 4 , Luciana Araújo Transplantation, Ann & Robert H Lurie Children’s Hospital
Oliveira Cunha, MD, PhD1, Thalita Rodrigues Dias, MD1, of Chicago, Chicago, IL,
3
Rhaianny Gomes Souza, MD1 and Júlia Damasio Coutinho, Division of Allergy and Immunology and Jeffrey Modell
MD5 Diagnostic Center for Primary Immunodeficiencies, Ann &
Robert H Lurie Children’s Hospital of Chicago, Chicago, IL

1
Immunology, Hospital das Clínicas da Universidade Federal Immunophenotyping of cells from a male newborn with a
de Minas Gerais, Belo Horizonte, Brazil, TREC count of 0 revealed markedly reduced T and NK
2
Universidade Federal de Minas Geria, Belo Horizonte, cells but normal B cells, raising the possibility of SCID
Brazil, due to a mutation in either the common γ chain (CD132,
3
Immunology, Federal University of Minas Gerais, Belo X-SCID) or the Janus Kinase 3 genes (JAK3, AR-SCID).
Horizonte, Brazil, The few T cells present revealed a memory phenotype but
4
Division of Allergy and Immunology, School of Medicine, normal surface expression of CD132 and cytosolic expres-
Federal University of Minas Gerais, Belo Horizonte, Brazil, sion of JAK3. However, functional immune profiling dem-
5
Clinical Immunology Division, Universidade Federal de onstrated depressed PHA-induced proliferation and
Minas Gerais - Hospital das Clínicas, Belo Horizonte, Brazil marked hypo-phosphorylation of B cell-associated STAT6
following IL-4, suggestive of a signaling defect in the
Clinical manifestations and complications before bone mar- CD132-JAK3 axis. Sequencing revealed a non-sense mu-
row transplant in a SCID patient Case report: A supposedly tation in the CD132 gene (c.375C>A; p.Y125X), which
healthy boy until 2 months of age that presented eczema, predicts a protein lacking the transmembrane and intracel-
erytroderma and skin infections. Was hospitalized at 3 months lular domains, consistent with the immune profiling re-
of age due to periorbital cellulites. At the age of 4 months, he sults. The patient’s infant brother also had a newborn
presented a sepsis. After this episode, he developed diarrhea, screen with 0 TRECs and an almost identical immune pro-
dehydration and metabolic acidosis, requiring other hospital- file. The patients underwent unrelated donor stem cell
ization. He also presented failure to thrive and a persistent transplant following reduced-intensity conditioning with
cough. At 5 months of age he was referred to the service of fludarabine, busulfan and ATG. They are clinically well
Pediatric Immunology of Hospital das Clinicas de Minas with full donor engraftment and immune reconstitution.
Gerais, when he was diagnosed with Severe Combined In conclusion, functional immune profiling including
Immunodeficiency Disease with an Omen phenotype. Was phosphorylation studies of receptor signaling molecules,
started prophylactics antibiotics and antifungal, subcutaneous is a rapid and effective way to diagnose immunodeficiency
immunoglobulin and tuberculostatics as he had received BCG and should be considered in the work-up for SCID.
J Clin Immunol (2016) 36:235–334 323

4651: ALPHA TRYPTASEMIA TRAIT CAUSED abnormalities. A single linkage region mapping to the
BY ALPHA TRYPTASE COPY NUMBER tryptase locus was identified and monoallelic copy num-
VARIATION ber increases in alpha tryptase segregated with
affectation.
Jonathan J. Lyons, MD1, Xiaomin Yu, PhD1, Jason D. Conclusions: Elevated basal serum tryptase is commonly
Hughes, PhD2, Quang T. Le, PhD3, Ali Jamil, BS1, Yun Bai, caused by copy number increases in alpha tryptase and is
MS 1 , Ming Zhao, PhD 4 , Yihui Liu, PhD 1 , Michael P. associated with a complex mast cell activation phenotype with
O’Connell, PhD 1 , Celeste Nelson, CRNP 1 , Thomas variable penetrance, representing a previously unrecognized
DiMaggio, ADN1, Nina Jones, RN, BSN5, Katie Lewis, genetic trait.
ScM6, Peter Arkwright, FRCPCH, DPhil7, Celine Hong,
PhD6, Joshua McElwee, PhD2, Marc E. Rothenberg, M.D.,
Ph.D.8, Robert Hohman, PhD4, Kelly Stone, MD, PhD1, 4653: A SINGLE CENTER EXPERIENCE IN
Dean D. Metcalfe, MD 1 , Leslie G. Biesecker, MD 6 , ALLOGENEIC HEMATOPOIETIC STEM CELL
Lawrence B Schwartz, MD, PhD3 and Joshua D. Milner, TRANSPLANTATION FOR CHILDREN AND
M.D.1 YOUNG ADULTS WITH COMBINED IMMUNE
DEFICIENCY
1
Laboratory of Allergic Diseases, National Institute of Allergy
and Infectious Diseases, NIH, Bethesda, MD, Zeynep Yesim Kucuk, MD, Rebecca Marsh, MD,
2
Merck Research Laboratories, Merck & Co. Inc., Boston, MA, Ashish R. Kumar, MD PhD, Sharat Chandra, MD,
3
Virginia Commonwealth University, School of Medicine, Michael S Grimley, Alexandra H. Filipovich, MD and
Richmond, VA, Jack J. Bleesing MD, PhD
4
Protein Chemistry Section, RTB, National Institute of Allergy
and Infectious Diseases, NIH, Rockville, MD, Division of Bone Marrow Transplantation and Immune
5
Clinical Research Directorate/Clinical Monitoring Research Deficiency, Cincinnati Children’s Hospital Medical
Program, Leidos Biomedical Research, Inc., Frederick Center, Cincinnati, OH
National Laboratory for Cancer Research, Frederick, MD,
6
Genetic Disease & Research Branch, NHGRI, NIH, Bethesda, Introduction: Combined Immune Deficiency (CID) refers
MD, to a group of disorders, in which patients display clin-
7
Royal Manchester Children’s Hospital, Manchester, United ical and immunological findings consistent with defi-
Kingdom of Great Britain and Northern Ireland, ciencies of both humoral and cellular immunity. In con-
8
Division of Allergy and Immunology, Cincinnati Children’s trast to severe CID (SCID), there is limited experience
Hospital Medical Center, Cincinnati, OH with allogeneic hematopoietic stem cell transplantation
(SCT) for CID.
Background: While elevated basal serum tryptase is present Method: A retrospective chart review was performed. Thirty-
in 3–7 % of the general population the cause and significance seven patients with CID underwent SCT at our institution
of this finding is unknown. between 1998 and 2014.
Methods: A large cohort was referred to the NIH for Results: Thirty-seven patients (15 males and 22 females,
evaluation of mast cell associated diseases (MCAD). ages between 1 and 25) underwent 40 SCT (3 patients
Serum tryptase levels were obtained and bone marrow with 2 SCT) receiving 33 reduced intensity conditioning
biopsies were undertaken as indicated. Next generation and 7 myeloablative conditioning regimens prior to
sequencing and linkage analyses were performed. SCT. Donor source was unrelated bone marrow in 29
Tryptase genotyping was achieved by bioinformatics, transplants, sibling donor in 6, peripheral blood stem
and confirmed by Southern blot and ddPCR. Mast cells cell in 3, and cord blood in 2. All but 1 patient
were cultured from peripheral CD34+ cells, and tryptase engrafted. Sixteen patients died, 7/16 before day +100.
expression was characterized. Findings were validated in Twenty-one patients (57 %) are alive for a median of
independent cohorts undergoing genetic sequencing for 5.6 years (1–12 years) post-transplant. Immune reconsti-
reasons unrelated to MCAD. tution was complete in all but 2 patients who still re-
Results: Among all patients with elevated basal serum quire IgG replacement therapy.
tryptase, a dominant pattern of inheritance was identi- Conclusion: Our results suggest that SCT is a viable option for
fied. Segregating clinical features included episodic definitive treatment of CID; however, results appear less fa-
symptoms of mast cell mediator release, functional GI vorable than typically observed for other primary immunode-
and neurologic disorders, and connective tissue ficiencies, including SCID.
324 J Clin Immunol (2016) 36:235–334

4656: MCM4 DEFICIENCY: A RARE VARIANT 4657: IMMUNOLOGICAL MONITORING

OF IMMUNODEFICIENCY OF NK CELLS IN SMITH-MAGENIS SYNDROME
ASSOCIATED TO PROPORTIONATE NANISM
AND ADRENAL INSUFFICIENCY. Rahul Datta, MD-PhD1 and Elif Dokmeci, MD2
DESCRIPTION OF THE FIRST CASE IN BRAZIL

Dewton Moraes-Vasconcelos1, Roberto Ribeiro2, Paula 1

Department of Allergy and Immunology, Yale School of
Ordonhez Rigato3,4, Paula Pinichi3, Valeria Aoki5, Roberto Medicine, New Haven, CT,
Takaoka5, Alberto José da Silva Duarte6 and Ester Cerdeira 2
Pediatrics, Yale University School of Medicine, New Haven,
Sabino2 CT

We present a patient with Smith-Magenis syndrome (SMS).

1
Laboratory of Dermatology and Immunodeficiencies – She was diagnosed after suffering from seizures, intellectual
LIM56, Faculdade de Medicina da Universidade de São delay, deep-set eyes and a flattened nasal bridge. FISH con-
Paulo, São Paulo, Brazil, firmed a 3.4 Mb deletion on 17p11.2, consistent with the dis-
2
Infectious diseases, Hospital das Clínicas da Faculdade de ease. However, she had no history of recurrent respiratory, GI,
Medicina da USP, Brazil, or more serious infections, but did have recurrent warts. Given
3
ImmunoDermatology, Hospital das Clínicas da Faculdade de her predilection for immune deficiency with SMS as well as
Medicina da USP, Brazil, recurrent warts, we performed an evaluation revealing normal
4
Immunology, Instituto Adolfo Lutz, Brazil, levels of total IgM, IgG, IgA, but low levels of IgG2 and IgG4.
5
Dermatology, Hospital das Clínicas da Faculdade de She had low pneumococcal immunity with protective antibody
Medicina da USP, Brazil, production for 3 of 14 subtypes. She also lacked antibody pro-
6
Clinical Pathology, University of São Paulo School of duction to 3 out of the 4 serogroups for N. meningitides. The
Medicine, São Paulo, Brazil patient received boosters for both with robust responses. Flow
cytometry, mitogen, and NK function studies were all normal.
Natural killer (NK) cells are critical in defense against virally- We have since been monitoring her with annual evaluation of
infected cells and in tumor surveillance. general and specific antibody levels.
NK cell deficiency is extremely rare and presents severe, SMS is a complex disorder with numerous abnormalities due
recurrent, or atypical infections with viruses, sometimes to mutations or deletions in the RAI1 gene typically as a result
associated to neoplastic diseases. In the dermatology of a 17p11.2 deletion. It is characterized with facial
clinics, one of the predominant viral pathogens is HPV. dysmorphism as well as neurological deficits. From an immu-
There are several immunodeficiencies with HPV manifesta- nity standpoint, patients have an increased frequency of occult
tions. Among them there are: EVER1 and EVER2 deficiency, antibody deficiencies. In our case report, we propose regular
CXCR4 mutations associated with WHIM syndrome, monitoring for humoral deficiency, including subclass and
DOCK8 deficiency, idiopathic CD4 lymphopenia, GATA 2, specific antibody deficiencies.
serine-threonine kinase 4 (STK4), MagT1, RHOH and
MCM4 deficiencies, among others.
The patient is a 34 years old male, born to non- 4659: STRATIFICATION OF PATIENTS WITH
consanguineous parents, presenting with eczema since child- AUTOINFLAMMATORY DISEASES BY IFN
hood associated to giant molluscum contagiosum and warts. SCORE SUGGESTS A NEW GROUP OF IFN
The patient has proportionate nanism, microcephalia with MEDIATED DISEASES WITH OVERLAPPING
normal neurologic functions, and in the last 2 years began CLINICAL PHENOTYPES
to present diffuse skin hyperpigmentation.
The initial suspects were Bloom syndrome and DOCK8 Adriana A. Jesus, MD, PhD1, Yanfeng Hou, MD2, Zuoming
deficiency. Deng, PhD3, Stephen Brooks, PhD3, Hanna Kim, MD3, Yan
The laboratorial investigation showed mild lymphopenia with Huang3, Gina Montealegre, MD, MHs3, Dawn Chapelle3,
decreased T and NK cells and severely decreased NK cyto- Bernadette Marrero, PhD 2 , Louise Malle, BS 2 , Philip
toxic activity. Hashkes, MD, MSc4, Gulnara Nasrullayeva, MD5, Maria
With this phenotype in mind, we did a whole exome sequenc- Teresa Terreri, MD, PhD6, Bita Arabshahi, MD7, Marilynn
ing finding a compound heterozygous mutation of MCM4, Punaro, MD 8 , Vibeke Lilleby, MD, PhD 9 , L. Nandini
found in both parents in a heterozygous fashion. Morrthy, MD, MS, FAAP 10 , Adam Reinhardt, MD 11 ,
We believe that this is the first MCM4 deficient patient in the Raphaela Goldbach-Mansky, MD 12 and Kathleen M.
American continent. O’Neil, MD13
J Clin Immunol (2016) 36:235–334 325

1
Translational Autoinflammatory Diseases Section - NIAMS, 4660: T CELL IMMUNOSENESCENCE AND
National Institutes of Health, Bethesda, MD, PRIMARY IMMUNODEFICIENCY IN
2
Translational Autoinflammmatory Diseases Section, TELOMERASE MUTATION CARRIERS
NIAMS, NIH, Bethesda, MD,
3
NIAMS, National Institutes of Health, Bethesda, MD,
4
Shaare Zedek Unit of Pediatric Rheumatology, Shaare Zedek Christa L. Wagner 1,2 , Vidya Sagar Hanumanthu 1 ,
Medical Center in Jerusalem, Jerusalem, Israel, Christopher G. Kanakry 1, Carolyn D. Applegate 1,3 , C.
5
Department of Immunology, Azerbaijan Medical University, Conover Talbot Jr.4, Leo Luznik1 and Mary Armanios, MD3,5
Baki, Azerbaijan,
6 1
Pediatric Rheumatology, Federal University of Sao Paulo, Department of Oncology, Johns Hopkins University School
Sao Paulo, Brazil, of Medicine, Baltimore, MD,
7 2
Pediatric Rheumatology, Inova Medical Group, Fairfax, VA, Graduate Program in Cellular and Molecular Medicine,
8
Pediatric Rheumatology, Texas Scottish Rite Hospital for Johns Hopkins School of Medicine, Baltimore, MD,
3
Children, Dallas, TX, McKusick-Nathans Institute of Genetic Medicine, Johns
9
Rheumatology Research Group, Oslo University Hospital, Hopkins University School of Medicine, Baltimore, MD,
4
Oslo, Norway, Institute for Basic Biomedical Sciences, Johns Hopkins
10
Division of Pediatric Rheumatology, Rutgers Robert Wood University School of Medicine, Baltimore, MD,
5
Johnson Medical School, New Brunswick, Oncology/Johns Hopkins University School of Medicine,
11
Pediatric Rheumatology, Children’s Hospital & Medical Johns Hopkins Hospital, Baltimore, MD
Center and University of Nebraska, Omaha, NE,
12
National Institute of Health, National Institute of Arthritis Telomere syndromes (TS) are the most prevalent of premature
and Musculoskeletal and Skin Diseases, Bethesda, MD, aging disorders. They are caused by germline mutations in
13
Division of Pediatric Rheumatology, Indiana University, telomere maintenance genes and manifest as bone marrow
Indianapolis, IN failure, pulmonary fibrosis-emphysema and liver disease.
We identified primary immunodeficiency (PID) as a first pre-
Background: Monogenic Type I interferonopathies are sentation of TS in 22 % (4 of 18) telomerase (TERT, TR,
characterized by a chronic Type I Interferon signature DKC1) and telomere gene (RTEL1) mutation carriers under
(IFS) suggesting chronic IFN signaling. We hypothesize the age of 30. Patients were recruited to a Johns Hopkins
that the presence of IFS in peripheral blood may iden- Registry from 2007 to 2015. Life-threatening opportunistic
tify patients with interferon-mediated autoinflammatory infections were associated with severe CD4 lymphopenia
diseases. and skewed CD4/8 ratio. Immunophenotyping showed quan-
Method: RNA-seq from whole blood RNA was performed titative defects in naïve subsets, both CD4 and CD8, that were
using Illumina® platform. Heatmaps with 64 IFN response similar in severity to subjects five decades older (mean age 18
genes were assessed. vs. 73 years). T cells also expressed markers of
Results: We identified 26 patients with a blood IFS. Whole immunosenescence similar to elderly controls (CD95+ and
exome sequencing (WES) was performed in 21 patients. CD57+). After stimulation, T cells had increased rates of ap-
14/26 of the probands were female. The most frequent optosis, and, by both deep sequencing and
clinical manifestations were panniculitis (11/26), skin vas- immunophenotyping, showed a restricted T cell receptor rep-
culitis (11/26), myositis (7/26) and basal ganglion calcifi- ertoire. Gene expression microarray defined a distinct
cations (6/26). WES identified probably disease-causing immunosenescence program in effector memory CD45RA+
mutations in 7 probands. In one patient, we found a T cells (TEMRA). Our data indicate PID may be a first mani-
de novo and somatic mutation in TREX1. In one patient, festation of TS in young patients, and implicate short telo-
we identified compound heterozygous mutations in meres as a driver of T cell senescence with aging.
LRBA. In a third patient we detected a homozygous
9Kb deletion in SAMHD1. A fourth patient had com-
pound heterozygous mutations in PSMG2. 3 additional 4662: COMPREHENSIVE CLINICAL AND
patients had mutations in genes not yet associated with IMMUNOLOGICAL FEATURES OF ADULT
an autoinflammatory disease: a de novo mutation in PATIENTS WITH IgG SUBCLASS DEFICIENCY
DHX9; a X-linked mutation in TREX2; and a homozy-
gous variant in WRNIP1.
Conclusion: RNA-seq can be a tool for the identification of Amrita Khokhar, MD and Sudhir Gupta, MD, PhD, MACP,
patients with an IFN signature and guide the search for disease
causing variants in IFN signaling pathways by WES. University of California, Irvine, Irvine, CA
326 J Clin Immunol (2016) 36:235–334

Objectives: pulmonologist. Results showed an inconsistency in practice

The clinical and immunological features of IgG subclass de- related to therapies and follow-up care for management of
ficiency have not been well documented. Therefore, a com- CVID with interstitial lung disease (ILD) or bronchiectasis
prehensive analysis was conducted. (bronch) (see table). Oral steroids were used 64 % of the time
Methods: for patients with CVID w/ILD. For patients with CVID w/
A retrospective chart review of patients seen in the bronch, mucolytics were always/often used only 16 % of the
Immunology clinics at the University of California, Irvine time and ACT was always/often used only 41 % of the time.
was performed. Both immunological and clinical data prior Standards for management and follow-up care of CVID with
to replacement therapy were recorded. lung disease should be established to improve consistency and
Results: ultimately improve patient care.
Of 96 patients identified, data were analyzed so far for 44
patients. 14 had IgG1, 12 had IgG2, 25 had IgG3, and 7 had Practices for CVID w/Lung Disease
IgG4 deficiency. 15 patients were found to have a combined INITIALLY Ordered to Establish Lung Disease: %
subclass deficiency; 50 % had IgG1 and IgG3 deficiency. CT Chest w/Contrast 21
The clinical presentation included sinopulmonary infec- High Res CT 78
tions (60 %), urinary tract infections (7 %), fungal infec- PFT 43
tions (9 %), and chronic fatigue (26 %). 18 % of patients Sputum Culture 68
had associated allergic rhinitis or asthma, and 14 % had
Follow-up Frequency ILD % Bronch %
autoimmune disease. 50 % had poor specific antibody re-
Visit
sponse to pneumococcal vaccination. CD3+, CD4+, CD8+,
Yearly 3 4
and CD19+ lymphocyte counts were normal in the majority
Every 3 months 53 47
of cases. 17 % of patients had impaired mitogen response
Other 35 40
and 52 % had a decreased antigen specific response.
CT w/Contrast
Conclusion:
As clinically indicated 64 64
Patients with IgG subclass deficiency present predominantly
Yearly 9 10
with sinopulmonary infections and associated allergic and au-
Other 27 26
toimmune diseases. Approximately 50 % of patients have im-
paired specific antibody and antigen specific T-cell responses.

4663: MANAGEMENT FOR CVID W/ LUNG 4664: IMMUNODEFICIENCY SYNDROME

DISEASE: RESULTS FROM A JOINT CID & ASSOCIATED WITH HAPLOINSUFFICIENCY
ESID MEMBERSHIP SURVEY OF NFKB1 SUBUNIT p50: REPORT OF 5
IDENTIFIED CASES.
Javeed Akhter, MD1, Cheryl Lefaiver, PhD, RN2, Klaus
Warnatz3 and Christopher Scalchunes, MPA4 Elizabeth Feuille, MD1, Niloo Niloofar Anooshiravani,
MD 2 , Patrick Maffucci, BA 3 , Charles A. Filion, MD,
1
Pediatrics, Advocate Hope Children’s Hospital, Oak Lawn, FRCPC4, Bertrand Boisson, PhD5, Yuval Itan, PhD6, Jean-
IL, Laurent Casanova, MD, PhD5 and Charlotte Cunningham-
2
Advocate Center Pediatric Research, Advocate Children’s Rundles, MD, PhD3
Hospital, Oak Lawn, IL,
3 1
Centre for Chronic Immunodeficiency, Freiburg, Germany, Division of Clinical Immunology, Icahn School of Medicine
4
Immune Deficiency Foundation, Towson, MD at Mount Sinai, New York, NY,
2
New York, NY,
3
In a recent Immune Deficiency Foundation survey of allergy/ Division of Clinical Immunology, Department of Medicine,
immunologists, we evaluated current practice in regard to Icahn School of Medicine at Mount Sinai, New York, NY,
4
therapies for patients with common variable immune deficien- Division of Clinical Immunology and Allergy, Department of
cy (CVID) with lung disease. There were a total of 227 re- Medicine, Hôpital Maisonneuve-Rosemont, Montreal, QC,
sponses (ESID response rate = 17 %; CIS response Canada,
5
rate = 14 %); all of whom had treated a patient with CVID or St-Giles Laboratory of Human Genetics of Infectious
hypogammaglobulinemia (hypogam). Forty-three percent of Diseases, Rockefeller University, New York, NY,
6
their CVID/hypogam patients on average had been diagnosed Human genetics of infectious diseases, The Rockefeller
with lung disease, though only 2 % were co-managed with a University, New York, NY
J Clin Immunol (2016) 36:235–334 327

Haploinsufficiency of NFKB1 has been associated with CVID cousins. Shared features included frequent pulmonary infections,
in 3 multigenerational families. Using whole exome sequencing, enteropathy, and autoimmunity. Unique to this report is severe
we identified 5 subjects with 4 novel or rare heterozygous mu- loss of isotype switched memory B cells, opportunistic infec-
tations in NFBK1 out of 50 CVID patients. While all were tions suggesting T cell impairment, and for most, lack of family
considered Bsporadic^ CVID, patients 1 and 3 were second history.

Case 1 2 3 4 5
Age at diagnosis (y) n/a 24 25 9 30
Mutation c.1301-1G>A Y319X c.1301-1G>A F459Lfs*25 c.259-4A>G
IgG 624* n/a 59 393* 711*
IgA <7 7 5 10 <5
IgM 11 17 5 87 <5
B cells, /cu mm (3 %) 38 5 0 62
Isotype switched memory B cells 0 0 0 0 0
Opportunistic infection 0 PCP, MAI, PML 0 MAI 0
n/a – not available
*on Ig

4667: PIK3CD IMMUNODEFICIENCY WITH fat replacement. B cell predominant, but EBER nega-
COLITIS, PANCREATIC INSUFFICIENCY AND tive, non-clonal lymphocytic infiltration was found on
ASCITES liver biopsy and ascitic fluid cytology. He was started
and maintained on sirolimus following 4 doses of ritux-
Rakesh Kumar Goyal, MD1,2, Gulbu Uzel, MD3, Stefania imab and pancreatic enzyme supplements. While he
Pittaluga, MD, PhD4, Whitney Sunseri, MD5 and Douglas achieved significant weight gain, pubertal growth spurt
Lindblad, MD5 with the control of his extensive lymphoproliferative
state, 14 months after rituximab treatment his peripheral
1
Division of Blood and Marrow Transplantation and Cellular blood B cells gradually increased to 40 %, with in-
Therapies, Children’s Hospital of Pittsburgh of UPMC, creased percentage of transitional B cells in the absence
Pittsburgh, PA, of EBV viremia while patient remained symptom free.
2
Department of Pediatrics, University of Pittsburgh School of Our patient reflects unusual clinical and histopathological
Medicine, Pittsburgh, PA, findings with diagnostic and long-term therapeutic challenges
3
Laboratory of Clinical Infectious Diseases, NIAID/NIH, entertained in the setting of activated PI3K–AKT-mTOR
Bethesda, MD, pathway.
4
Hematopathology Section, NIH, Bethesda, MD,
5
Division of Gastroenterology, Hepatology and Nutrition,
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 4668: MULTI-LINEAGE ANALYSIS
OF X-INACTIVATION IN 54 FEMALES
Gain of function mutations in PIK3CD are associated with CARRIER OF GENETIC ALTERATIONS IN THE
lymphoproliferative disease, cytopenais, WISKOTT-ALDRICH SYNDROME PROTEIN
hypogammaglobulinemia and susceptibility to herpes group (WASP) GENE LOCUS
viruses with a predisposition to B cell lymphomas.
We describe the case of a 16-year -old boy with a novel het- Daniele Moratto1, Lucia Dora Notarangelo2, Cinzia Mazza3,
erozygous mutation in PIK3CD (E1025G), and manifesta- Luigi D Notarangelo, MD4, Fabio Candotti5 and Silvia
tions of fevers, generalized lymphadenopathy, chronic diar- Giliani6
rhea, malnutrition and ascites. In depth evaluation revealed
1
Crohns’ type colitis with avid cryptitis, lymphocytic A.Nocivelli Institute of Molecular Medicine, Dept. of
hepatitis, pancreatic insufficiency with near complete Pathology, University of Brescia, Brescia, Italy,
328 J Clin Immunol (2016) 36:235–334

2
Pediatric Clinic, Brescia University Hospital, cytokine production. We present a clinical case with a defect
3
A.Nocivelli Institute of Molecular Medicine, Dept. of in IL-12Rβ1 with a good clinical outcome using Thalidomide.
Pathology, University of Brescia, Clinical case. Female patient 1 year old with recurrent gas-
4
Division of Immunology, Boston Children’s Hospital, troenteritis, starts with an episode 3 months earlier character-
Harvard Medical School, Boston, MA, ized by fever, lymphadenopathy and abscesses. The cutaneous
5
Division of Immunology and Allergy, University Hospital of biopsy reported granulomas. A functional defect of IL-12Rβ1
Lausanne, Laboratory Center of Epalinges (CLE), Epalinges, was found and was treated with antifimic and recombinant
Switzerland, IFN-γ due to the biopsy findings. The patient continued fe-
6
Department of Molecular and Traslational Medicine, brile with nodule reduction and without an apparent infectious
Pediatrics Clinic and Institute for Molecular Medicine A. cause and Thalimomide was started as an immunomodulator.
Nocivelli,University of Brescia, Spedali Civili, Brescia, Italy Afebrile 1 day after with remission of nodules 3 weeks later.
Discussion. Mendelian susceptibility to mycobacterial in-
Since mutations in WASP are causative of a variety of X-linked fections is a rare illness that predisposes apparently
disorders spanning from Wiskott-Aldrich syndrome (WAS) to healthy individuals to weak mycobacteria like BCG
X-linked thrombocytopenia (XLT) we performed a flow cyto- and low virulent Salmonella strains. With these results
metric analysis of WASP expression in 54 females carrier of we conclude that Thalidomide should be an option of
WASP mutations aiming to detect the degree of lyonization in treatment in these patients, both corticosteroids and
different peripheral blood cell lineages. Thalidomide reduce inflammation but only Thalidomide
In the majority of cases we observed a nonrandom X-inactivation offers protective immunity.
favoring the wt allele independent from mutation types, clinical
manifestations of descendants and WASP expression already at
the level of circulating CD34+ cells; a phenomenon that becomes 4673: A CASE OF DISSEMINATED
more pronounced in cells involved in acquired immunity, espe- MUCO-CUTANEOUS MYCOBACTERIUM
cially when associated to mutations that abrogate WASP expres- HAEMOPHILUM IN A CHILD WITH A
sion and WAS in affected descendants. MUTATION IN NFKBIA
Within this cohort we have also found six carriers displaying a
pattern of X-inactivation in which the expression of the mu- Alison J Gibson, DO1, Mark Hannibal, MD2, Amy P Hsu,
tated allele was largely favored at the level of CD34+ precur- BA3, Steven M. Holland, MD3, Paul Harms, MD4, Amer
sors and myeloid derived cells. The five of them for whom we Heider, MD4 and R. Alexander Blackwood, MD, PhD1
had laboratory and clinical data displayed different degrees of
XLT suggesting that pathophysiological characteristics of af-
1
fected males may be found also in females with an atypical Pediatric Infectious Diseases, University of Michigan, Ann
lyonization. Arbor, MI,
2
Pediatrics - Genetics, University of Michigan, Ann Arbor, MI,
3
Laboratory of Clinical Infectious Diseases, National Institute
of Allergy and Infectious Diseases, National Institutes of
4672: USE OF THALIDOMIDE AS AN Health, Bethesda, MD,
4
IMMUNOMODULATOR IN A PATIENT WITH Pathology, University of Michigan, Ann Arbor, MI
MENDELIAN SUSCEPTIBILITY TO
MYCOBACTERIAL INFECTIONS Mycobacterium haemophilum can cause a spectrum of disease
from localized skin findings to disseminated systemic disease.
Yunuen R Huerta, We report the first case of disseminated muco-cutaneous M.
haemophilum in an otherwise healthy child. Previously, doc-
INER, INER, Mexico, Mexico umented cases in healthy children have been limited to local-
ized lymphadenitis. Disseminated cutaneous disease has been
Introduction. Thalidomide possesses immunomodulatory, reported in patients with known immunosuppression such as
anti-inflammatory and anti-angiogenic properties related to post-transplant or with use of immune modulating agents. Our
complex modulation of inflammatory cytokines. It enhances patient underwent functional testing for Mendelian
the immune effector cells, proliferation of the CD8+ T-cells, Susceptibility to Mycobacterial Diseases showing normal ex-
inhibits IL-6, IL-12, inactivates Caspase-1 and induces TH2 pression of CD119/IFN-γR on monocytes, normal activation
J Clin Immunol (2016) 36:235–334 329

of IFN-γ stimulated pSTAT1 in monocytes, and normal ex- 8 months into treatment showed significant improvement in his
pression of CD212/IL-12R on lymphocytes. Screening for GL-ILD.
anti-cytokine autoantibodies was negative. Sequencing of a Conclusion:
targeted set of 300 immune related genes revealed a variant Hydroxychloroquine may be an effective treatment in some
in NFKBIA, c.107C>A, p.Ser36Tyr. Mutation of this residue, patients with GL-ILD, especially if identified to have a muta-
p.Ser32Ile, has been previously reported in three unrelated tion in LRBA.
individuals (Courtois, 2003; Janssen 2004; Yoshioka 2013),
and changes a key regulatory phosphorylation site resulting in
altered NF-kappa-B activation. The current patient did show
evidence of impaired T cell proliferation in response to anti- 4675: UTILITY OF WHOLE EXOME
gens, but does not have typical features of an ectodermal SEQUENCING (WES): A NOVEL PATHOGENIC
dysplasia. VARIANT IDENTIFIED IN IFN-γ RECEPTOR 2
(IFNGR2) PRESENTING AS DISSEMINATED
MYCOBACTERIUM AVIUM
INTRACELLULARE (MAI) INFECTION
4674: RESPONSE TO
HYDROXYCHLOROQUINE IN CVID WITH Roxanne Carbonell Oriel, MD and Punita Ponda, MD,
GRANULOMATOUS INTERSTITIAL LUNG
DISEASE (GL-ILD) Division of Allergy & Immunology, Cohen Children’s
Medical Center of New York, North Shore Long Island
Peter J Mustillo, MD1 and Michael B Jordan, MD2 Jewish Health System, Great Neck, NY

Seven months F was admitted with disseminated MAI. After

1
Allergy and Immunology, Nationwide Children’s Hospital, prolonged hospital course on antimycobacterials, infection re-
Columbus, OH, solved and she was maintained on antimycobacterial prophy-
2
D i v i s i o n o f B o n e M a r r o w Tr a n s p l a n t a t i o n a n d laxis. At 12 months, she was re-admitted to the hospital for
Immunodeficiency, Cincinnati Children’s Hospital Medical multifocal PNA 2/2 MAI. Since then, she is stable on
Center, Cincinnati, OH antimycobacterial ppx and tobramycin for P. aeruginosa
found on BAL.
Introduction: Labs N CBC, T/B/NK cells, Igs, lymphocyte proliferation to
Approach to treatment in persons affected with Granulomatous mitogens, yet absent proliferation to CA and TT. Normal
Interstitial Lung Disease (GL-ILD) related to CVID is widely CH50, AH50, MBL; NADPH oxidase. Protective Ab titers
variable. This case describes a child with CVID & GL-ILD, to diphtheria, tetanus, Hib, and S. pneumoniae. Notably, high
with a mutation in LRBA (lipopolysaccharide beige-like an- IFN-γ (12.1 pg/mL, N < 2.0).
chor protein), who had significant improvement in GL-ILD Targeted gene analysis performed did not show defect in
following treatment with hydroxychloroquine. IFN-γ/IL-12 pathway but pointed to an uncharacterizable ab-
Case Description: normality on STAT3. Confirmation by sequencing failed to
A 10 y/o male presented with onset of headaches & marked replicate initial results.
fatigue. History was significant for recurrent sinus infections. WES obtained through GeneDx characterized a mutation in
Physical exam revealed splenomegaly, with subsequent imaging IFNGR2. Codon Thr was changed to Ile with consequent
by CT suggesting diffuse interstitial lung disease with hilar & creation of premature Stop codon of the new reading frame
mediastinal adenopathy. Lab evaluation demonstrated hypercal- (p.Thr168IlefsX33). Her parents were heterozygous for this
cemia. Immune workup revealed hypogammaglobulinemia. variant.
PFT’s, DLCO, & exercise challenge were normal. Lung biopsy A novel homozygous frameshift mutation encoding IFNGR2
path report showed granulomas with B & T-cell aggregates. gene was identified on WES. Here we exemplify the utility of
Further workup led to mutation identified in LRBA. WES since targeted analysis in our case failed to detect any
Discussions ensued regarding most appropriate treatment includ- abnormality in IFNGR2. WES is a powerful resource that may
ing continued monitoring, azathioprine, rituximab or the combi- in the future be used as a screening tool for clinicians. WES
nation, abatacept, or a trial of hydroxychloroquine. The decision was able to accurately identify a rare genetic etiology for PID
was made to trial hydroxychloroquine. A comparison chest CT in a short time frame.
330 J Clin Immunol (2016) 36:235–334

4677: INTRAVENOUS IMMUNOGLOBULIN IN Montoya 3 , Mónica Rodríguez-González 3 and Miriam

THE TREATMENT OF COMPLICATED Martinez-Perez3
PEMPHIGUS VULGARIS
1
Pediatric Clinical Immunology, National Institute of
1 1
Miriam Martinez-Perez , Mónica Rodríguez-González , Pediatrics, Mexico, Mexico,
Selma Scheffler-Mendoza2, MA Yamazaki-Nakashimada3, 2
Pediatric Allergy and Immunology, Instituto Nacional de
Edna Venegas-Montoya1 and Giovanni Sorcia-Ramírez4 Pediatria, MEXICO, Mexico,
3
C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C
1
C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS,
ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS, MEXICO CITY, Mexico
MEXICO CITY, Mexico,
2
Pediatric Allergy and Immunology, Instituto Nacional de Introduction
Pediatria, MEXICO, Mexico, There are numerous organisms that can cause infection
3
Immunology Department, National Institute of Pediatrics, in CGD Liver abscess occurred in 30 % of the cases.
Distrito Federal, Mexico, We describe 2 patients with CGD and refractory liver
4
C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C abscess who were successfully treated with systemic
ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS, corticosteroids in addition to antimicrobial agents, in
Mexico City, Mexico order to avoid surgery managment.
Case 1
INTRODUCTION A 11 year old boy with CGD- X linked with a 2-week
Pemphigus vulgaris (PV) is an autoimmune, blistering, muco- fever. An Hepatic US showed an abscess. Antimicrobial
cutaneous potentially fatal disease. The successful treatment and antifungal drugs were initiated. Surgical treatment
of severe PV has always been a challenge. We reported the use was contraindicated because the abcess was near to the
of intravenous immunoglobulin (IVIG) in complicated PV. inferior vena cava and the right hepatic vein. Prednisone
CASE REPORT was initiated. A control with CT scan showed complete
We report 13-years-old female, with family history of psoria- resolution of abscess.
sis. She was diagnosed with PV (clinical and histopathologi- Case 2
cal), treated with topical clioquinol and fluocinolone, antibi- A 11 year old girl with CGD- p22Phox with a 5-week of
otics, azathioprine and steroids, the treatment was abdominal pain, sickness and fever. She stopped main-
discontinued and she had reactivation of the disease. She pre- tenance therapy 6 months ago. An Hepatic US showed
sented fever and bullous lesions of 90 % of the body surface, multiple abscesses. Antimicrobial and antifungal drugs
including face, and oral mucosa. We started management were initiated. A liver puncture and drainage collection
based on antibiotics for sacral pressure ulcers and osteomye- were performed with a positive culture for S. Aureus
litis, scrubs and surgical flaps, methylprednisolone and cyclo- (MSSA) and Candida Glabrata. A new CT scan revealed
sporine. The patient had numerous active lesions but also with an increase in the abscesses after treatment, prednisone
a severe infection, we started adjuvant treatment with IVIG at was initiated. A control CT scan showed complete res-
2 g/kg/do, with excellent response. After infection resolution, olution of the abscesses
we added mycophenolate mofetil with improvement, the pa- Discussion
tient is doing well, without lesions. We suggest that the cautious addition of corticosteroids to
DISCUSSION optimal antimicrobial therapy should be considered for refrac-
Pemphigus vulgaris is potentially fatal disease; there have tory infections in patients with CGD.
been described different immunosuppressive treatments.
IVIG induces and maintains long-term clinical remission in
refractory cases; also help to reduce the dose of steroids and it 4679: CHANGING DISEASE SPECTRUM IN
is a safe therapy in the case of active PV and severe infections. ADULT X-LINKED AGAMMAGLOBULINEMIA
(XLA) PATIENTS

4678: USE OF STEROIDS AS AN ALTERNATIVE

SURGERY TREATMENT FOR LIVER ABSCESS Anahita Agharahimi, CRNP1, Ashleigh A Hussey, MSN,
IN CGD. RN1, Stefania Pittaluga, MD, PhD2, Mark Raffeld, M.D.3,
Katherine Calvo, M.D., Ph.D.4, Christopher Koh, M.D.5,
Giovanni Sorcia-Ramírez1, Selma Scheffler-Mendoza2, Theo Heller, M.D.5, Steven M. Holland, MD6, Gulbu Uzel,
Marco Antonio Yamazaki Nakashimada1, Edna Venegas- MD6 and Kathleen Sullivan, MD, PhD7
J Clin Immunol (2016) 36:235–334 331

1
Laboratory of Clinical Infectious Diseases, National Institute Introduction: We investigated long term complications of
of Allergy and Infectious Diseases/NIH, Bethesda, MD, XLA, focusing on manifestations of immunedysregulation
2
Hematopathology Section, NIH, Bethesda, MD, and inflammation in the adult XLA cohort followed at our
3
Laboratory of Pathology, National Cancer Institute, center, the National Institutes of Health.
Bethesda, MD, Methods: Retrospective review of clinical and laboratory data
4
Hematology Service of Department of Laboratory Medicine, from six XLA patients including lymphocyte subsets and T
Clinical Center, Bethesda, MD, cell clones, bone marrow, liver and GI biopsies, portal pres-
5
National Institute of Diabetes and Digestive and Kidney sures and chronic persistent infections.
Diseases, Bethesda, MD, Results: TABLE
6
Laboratory of Clinical Infectious Diseases, NIAID/NIH, Conclusion: Complications due to immunedysregulation, of-
Bethesda, MD, ten presenting with T cell infiltration of liver, intestines, mus-
7
Division of Allergy and Immunology, Children’s Hospital of culoskeletal system, secondary lymphoid tissues and bone
Philadelphia, Philadelphia, PA marrow are common in adult XLA patients.

Age (Y) HSM Portal HT Esoph varices NRH Inflam. Cond. Chr infec Cytopenia Lympho Bone marrow T cell clonality
Thrombo Anemia Neutro (BM) T-LGL Periph bld BM
29 + + + + Polyarthr + + + + +
24 + + + + Polyarthr myositis + + + +
26 +
27 Flexispira
51 colitis Campylo-bacter +
27 + + + + Inflam colitis Flexispira + + +

9
4680: ACCURATE COPY NUMBER VARIANT Division of Immunology, Department of Pediatrics,
(CNV) ANALYSIS OF IMMUNODEFICIENCY University of Washington and Seattle Children’s Research
GENES BY NEXT-GENERATION SEQUENCING. Institute, Seattle, WA

Gesmar Segundo, MD1, Ameet Thaker, MD2, Stephanie J Introduction: Next-generation sequencing offers an efficient
Anover-Sombke3, Stacey Rylaarsdam4, Karen Tsuchiya, means to screen panels of immunodeficiency genes. A com-
MD5, James Bennett, MD PhD6, Stephen S Salipante, MD mon weakness of this approach is an inability to accurately
PhD7, Jonathan Tait, MD PhD8, Colin Pritchard, MD PhD7 detect copy number variants (large deletions or duplications)
and Troy R. Torgerson, MD PhD9 in genes. We have developed a modified, targeted NextGen
sequencing approach that significantly improves the ability to
1
Immunology Diagnostic Lab, Seattle Childrens Ho, Seattle, detect copy number variants using the DOCK8locus as a
WA, model.
2
Department of Lab Medicine, University of Washington, Methods: Patients with suspected DOCK8 deficiency were
Seattle, WA, identified by clinical history and laboratory data. Targeted
3
Department of Pediatrics, University of Washington and capture of the entire DOCK8locus was performed using a
Seattle Children’s Research Institute, Seattle, WA, custom Agilent capture panel and samples sequenced to
4
Center for Immunity and Immunotherapies, Seattle >500x coverage. Data was analyzed using a custom analysis
Children’s Research Institute, Seattle, WA, pipeline. Flow cytometry was performed to evaluate DOCK8
5
Lab Medicine, Seattle Children’s Hospital, Seattle, WA, protein expression in patient cells.
6
Division of Genetics, Department of Pediatrics, Seattle Results: We demonstrate that targeted capture of the entire
Children’s Hospital, Seattle, WA, genomic locus of DOCK8 (both exons and introns) using a
7
Department of Lab Medicine, University of Washington, custom capture panel, followed by deep sequencing and anal-
School of Medicine, Seattle, WA, ysis using a customized pipeline, was able to accurately detect
8
Lab Medicine, University of Washington, School of both deletions and duplications in the DOCK8 locus. In one
Medicine, Seattle, WA, case, a DOCK8 deletion was detected that was missed by
332 J Clin Immunol (2016) 36:235–334

clinical array-based testing. Analysis of DOCK8 protein in Rao Koneti, MD6, Helen C. Su7, Anahita Agharahimi, NP8,
patient cells confirmed the sequencing results. Ashleigh A Hussey, MSN, RN9, Amy P Hsu, BA10, Eric
Conclusion: Detailed CNV analysis of immunodeficiency Meffre, PhD11 and Steven M. Holland, MD12
genes can be accurately performed by NextGen sequencing
1
using the described approach. NIAID, Laboratory of Clinical Infectious Diseases, National
Institute of Allergy and Infectious Diseases, Bethesda, MD,
2
Laboratory of Cell Biology, Division of Monoclonal
4681: STAT1 GOF MUTATION IN THE SH2 Antibodies, Office of Biotechnology Products, Center for
DOMAIN Drug Evaluation and Research, United States Food and
Drug Administration, Silver Spring,, MD,
Elizabeth P. Sampaio, MD, PhD1, Betty Marciano, MD1, 3
Hematopathology Section, NIH, Bethesda, MD,
Amy P Hsu, BA 2 , Nick Adamo 3 , Gulbu Uzel, MD 1 , 4
NINDS, NIH, Bethesda, MD,
5
Alexandra F Freeman, MD1, Christa S. Zerbe, M.D.1 and NIH, NIAID, LCID, Bethesda, MD,
Steven M. Holland, MD1 6
Laboratory of Clinical Infectious Diseases, National Institute
of Allergy and Infectious Diseases, NIH, Bethesda, MD,
1 7
Laboratory of Clinical Infectious Diseases, NIAID/NIH, Laboratory of Host Defenses, National Institute of Allergy
Bethesda, MD, and Infectious Diseases, National Institutes of Health,
2
Laboratory of Clinical Infectious Diseases, National Institute Bethesda, MD,
8
of Allergy and Infectious Diseases, National Institutes of National Institute of Allergy and Infectious Disease,
Health, Bethesda, MD, Bethesda, MD,
3 9
Laboratory of Clinical Infectious Disease, NIAID, NIH Laboratory of Clinical Infectious Diseases, National Institute
of Allergy and Infectious Diseases/NIH, Bethesda, MD,
10
Dominant gain-of-function (GOF) mutations in STAT1 are as- Laboratory of Clinical Infectious Diseases, National
sociated with chronic mucocutaneous candidiasis (CMC), Institute of Allergy and Infectious Diseases, National
squamous cell cancer, autoimmunity and disseminated fungal Institutes of Health, Bethesda, MD,
11
infections. To date GOF STAT1 mutations have been described Department of Immunobiology, Yale University School of
in the coiled-coil and DNA binding domains, respectively. We Medicine, New Haven, CT,
12
identified a novel missense mutation in STAT1 in the SH2 Laboratory of Clinical Infectious Diseases, NIAID, NIH,
domain, c.1859C>T, p.S620F, in a patient with severe pulmo- Bethesda, MD
nary M. abscessus infection associated with skin cancer, recur-
rent pneumonias, onychomycosis, and renal artery stenosis. Cytotoxic T lymphocyte antigen 4 (CTLA-4) has been a very
She had a history of frequent bronchitis, sinusitis, and mi- attractive target for immune mediated therapies due to its role
graines. She had pneumonia at 2 years old and primary varicella as a critical inhibitory co-receptor, carrying an essential role
at 22 years. At 50 years she presented with extensive pneumo- for regulatory T cell (Treg) function and control over effector
nia due to M. abscessus. This infection was unaffected by treat- T cell proliferation. Its mastery in immune regulation has been
ment with IFN gamma, but cleared rapidly on treatment with highlighted with the recent description of CTLA-4
IL-12 subcutaneous injections. STAT1-deficient cells haploinsufficiency in humans, in which heterozygous germ
transfected with STAT1:S620F demonstrated impaired STAT1 line CTLA4 mutations result in severe immune dysregulation.
dephosphorylation, enhanced DNA binding, and enhanced IFN Upon screening additional patients and families, we have
gamma-induced gene expression. The association of GOF mu- identified over 50 patients and 20 families with recurrent as
tations with pulmonary mycobacterial infections has been seen well as novel mutations leading to diminished function and
in pulmonary NTM suggests an overlap of mechanisms be- expression of CTLA-4. Our findings expanded our under-
tween GOF and loss of function mutations in STAT1. standing of the genetics, pathology of organ infiltrative dis-
ease and therefore resulting spectrum of manifestations in-
cluding CNS and lung disease, inflammatory colitis, bone
4683: MANY FACES OF CTLA-4 marrow failure, autoimmune cytopenia, endocrinopathy, skin
HAPLOINSUFFICIENCY; EXPANDING disease and arthritis. With an intend to treat approach, we have
DISEASE SPECTRUM WITH PATHOLOGIC, used immune modulation in affected patients when indicated
IMMUNOLOGIC AND MOLECULAR FINDINGS in order to control organ damage.
IN A LARGE COHORT A much wider perspective on autoimmunity, immu-
nedysregulation, immunodeficiency and predisposition to lym-
Gulbu Uzel, MD 1 , Weiming Ouyang, Phd 2 , Stefania phoma in CTLA-4 haploinsufficiency should help bridge mul-
Pittaluga, MD, PhD3, Matthew Schindler4, Hua Su, PhD5, tiple disciplines for diagnostic and treatment purposes.
J Clin Immunol (2016) 36:235–334 333

1
4684: FLOW CYTOMETRY ASSAY TO SCREEN C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C
FOR PRIMARY AND SECONDARY DEFECTS IN ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS,
STAT1 MEXICO CITY, Mexico,
2
Pediatric Allergy and Immunology, Instituto Nacional de
Sheree Poulton1, Stephanie Richards, BSc (Hons) MBBS2 Pediatria, MEXICO, Mexico,
and Sharon Choo3 3
Immunology Department, National Institute of Pediatrics,
Distrito Federal, Mexico,
1 4
Immunology Laboratory, Royal Children’s Hospital, C L I N I C A L I M M U N O L O G Y A N D P E D I AT R I C
Parkville, Victoria, Australia, ALLERGY, NATIONAL INSTITUTE OF PEDIATRICS,
2
Department of Laboratory Services, Royal Children’s Mexico City, Mexico
Hospital, Melbourne, Australia,
3
Department of Allergy and Immunology, Royal Children’s INTRODUCTION
Hospital, Parkville, Victoria, Australia Severe combined immunodeficiency (SCID) is character-
ized by a lack of protective T, B, and NK-cell responses
Background: Defects in STAT1 cause a broad spectrum of to infections, conferring susceptibility to pathogens.
disease, including susceptibility to mycobacterial and viral Chronic diarrhea and viral gastrointestinal infection can
infection, CMC and IPEX-like syndromes. be life threatening and difficult to treat. We reported two
Aim: To evaluate a rapid flow cytometry assay screening for patients successfully treated with enteral immunoglobulin
primary and secondary defects in STAT1 in a diagnostic im- for norovirus infection.
munology laboratory. CASE REPORTS
Method: 6 patients and 13 controls were assayed for We report two SCID patients, a female of 9 months with
intracellular phosphorylated STAT1 (pSTAT1) following immunophenotype (T-B+ NK-) and a male of 12 months with
stimulation with IFNg. To detect inhibition of pSTAT1 immunophenotype (T- B- NK +). Both patients presented se-
caused by IFNg autoantibodies, control cells were incu- vere malnutrition, chronic watery diarrhea with high fecal out-
bated with control or patient plasma prior to stimulation put from 6 to 8 g/Kg/day. Norovirus from stool was isolated.
with IFNg. pSTAT1 MFI was measured in unstimulated/ They not have improvement despite antidiarrheal medication
stimulated monocytes, and patients were compared to and intravenous immunoglobulin. We started treatment with
controls. enteral immunoglobulin (1,650 mg / 10 mL) by gastric tube at
Results: Patient 1 had confirmed homozygous loss-of- a dose of 45 mg / kg / day divided in 4 doses for 2 days with
function STAT1 mutations, patients 2 and 3 had con- adequate response, their fecal output decreased from 1.5 to
firmed heterozygous gain-of-function mutations in 3.5 g/kg/day.
STAT1and patients 4–6 had confirmed IFNg autoanti- DISCUSSION
bodies. pSTAT1 MFI of unstimulated/stimulated cells The norovirus gastrointestinal infection appears as a common
was 1.5/1.5 for patient 1, 2.6/18.6 and 2.3/23.3 in patient denominator in the two SCID patients, conditioning chronic
2 and 3, and 2.1/1.9, 1.9/1.8 and 2.1/2.3 for patients 4, 5 diarrhea and malnutrition. The norovirus infection also has
and 6. In controls, the median (range) pSTAT1 MFI in been reported in the context of other conditions with immu-
unstimulated and stimulated cells was 2.3 (1.6–2.9) and nodeficiency. We observed reduction in fecal output after en-
9.0 (7.0–14.8). teral administration of immunoglobulin, lowering the morbid-
Conclusion: Measurement of pSTAT1 in IFNg stimulated ity of these patients.
monocytes is a useful screening assay for primary and second-
ary defects in STAT1. This assay allows rapid testing in routine
diagnostic laboratories. 4687: X-LINKED CARRIERS OF CHRONIC
GRANULOMATOUS DISEASE

4685: ENTERAL IMMUNOGLOBULIN AS Betty Marciano, MD1, Christa S. Zerbe, M.D.1, Samantha A
TREATMENT OF CHRONIC NOROVIRUS Kreuzburg, RN, BA1, Lynne Yockey, RN, BSN2, Douglas B.
INFECTION IN SEVERE COMBINED Kuhns, PhD3, Gulbu Uzel, MD1 and Steven M. Holland, MD1
IMMUNODEFICIENCY
1
Laboratory of Clinical Infectious Diseases, NIAID/NIH,
Bethesda, MD,
Miriam Martinez-Perez1, Mónica Rodríguez-González1, 2
Department of Nursing, NIH Clinical Center, Bethesda, MD,
Selma Scheffler-Mendoza2, MA Yamazaki-Nakashimada3, 3
Leidos Biomedical Research, Inc., NCI-Frederick, Frederick,
Edna Venegas-Montoya1 and Giovanni Sorcia-Ramírez4 MD
334 J Clin Immunol (2016) 36:235–334

Chronic granulomatous disease (CGD) results from defects in %DHR+ of 43 % (n = 26, range 7–74 %). Those with both
the NADPH oxidase and is characterized by recurrent life- infections and autoimmunity had low %DHR+ of 3–14 %
threatening bacterial and fungal infections and aberrant in- (n = 6). %DHR+ <10 % was strongly associated with infec-
flammation. Mutations in CYBB cause X-linked CGD and tions (RR = 43.69; 95%CI 5.9 to 320); %DHR+ <20 % less so
account for 65–70 % of cases in most countries. (RR = 7.8; 95%CI 3.6 to 16.75). Autoimmunity was not
We retrospectively studied patients and samples from 162 associated with %DHR+. In two sets of identical twins the
affected females seen at the NIH and examined %DHR+ as %DHR+ populations tracked together over time. Further,
a marker of X inactivation. Clinical data were available for 93. the %DHR+ populations in sisters were strongly correla-
%DHR+ was 47 % (median)(SD = 24). 77 % of patients had ted, while there was no relationship between mothers and
levels of inactivation between 20 and 80 %, suggesting ran- daughters.
dom inactivation, independent of age. In contrast, carriers who %DHR+ is an important clinical variable in X-linked CGD
had CGD-type infections had %DHR+ 7 % (n = 9, range carriers but only predicts infection risk, while autoimmune
0.06–27 %); those with autoimmunity only had a median risk is independent of %DHR+.