WAS is a severe X‐linked recessive disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. A six‐yr‐old boy with WAS diagnosed as B‐cell NHL (Stage III) localized in the liver who underwent successful HSCT from... more
WAS is a severe X‐linked recessive disorder characterized by microthrombocytopenia, eczema, and immunodeficiency. A six‐yr‐old boy with WAS diagnosed as B‐cell NHL (Stage III) localized in the liver who underwent successful HSCT from HLA‐one antigen mismatch sibling donor has been presented here. His conditioning regimen included ATG, busulfan, and fludarabine. He received 2.3 × 106/kg CD 34(+) stem cells and 11 × 108/kg nucleated cells at day 0. Neutrophil engraftment was achieved at day +14 and platelet engraftment at day +20. He has been in CR for more than two yr after transplantation. Thus, HSCT is an effective treatment for children with WAS even after development of lymphoma.
Research Interests: Pediatrics, Immunology, Treatment Outcome, Stem Cell, Medicine, and 15 moreTransplantation, Lymphoma, Humans, Child, Male, Siblings, Neutrophils, Hematopoietic Stem Cell Transplantation, Busulfan, Psychology and Cognitive Sciences, Vidarabine, Blood platelets, Liver neoplasms, Medical and Health Sciences, and Paediatrics and reproductive medicine
References 1 Koga M. Epidermal grafting using the tops of suction blisters in the treatment of vitiligo. Arch Dermatol 1988; 124: 1656–1658. 2 Kahn AM, Ostad A, Moy RL. Grafting following short-pulse carbon dioxide laser... more
References 1 Koga M. Epidermal grafting using the tops of suction blisters in the treatment of vitiligo. Arch Dermatol 1988; 124: 1656–1658. 2 Kahn AM, Ostad A, Moy RL. Grafting following short-pulse carbon dioxide laser de-epithelialization. Dermatol Surg 1996; 22: 965–967. 3 Lee DY, Park JH, Park HY, Lee JH. The use of suction blisters for the recipient area in epidermal grafting for vitiligo. J Eur Acad Dermatol Venereol 2009 (forthcoming). 4 Lee KJ, Choi YL, Kim JA et al. Combination therapy of epidermal graft and systemic corticosteroid for vitiligo. Dermatol Surg 2007; 33: 1002–1003.
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Research Interests: Adolescent, Medicine, France, Humans, Child, and 15 moreInternal Medicine, Female, Infection, Male, Infant, Monoclonal Antibodies, Prednisolone, Registries, Rituximab, Child preschool, Evans syndrome, Autoimmune hemolytic anemia, Disease Free Survival, Prednisone, and Cardiovascular medicine and haematology
Research Interests: Immunology, Biology, Stem Cell, Medicine, Transplantation, and 12 moreHumans, Male, Infant, Haematopoiesis, Recurrence, T lymphocytes, Retrospective Studies, Cell Proliferation, Postoperative Period, Hemophagocytic Lymphohistiocytosis, Hematopoietic Stem Cell Transplantation, and Cardiovascular medicine and haematology
Research Interests: Biology, Adolescent, Medicine, France, Phylogeny, and 15 moreDisease Outbreaks, Humans, Child, Blood sampling, Infant, Phylogenetic analysis, Clinical Sciences, Bone Marrow Transplantation, Genotype, Genotyping, Outbreak, Hematopoietic Stem Cell Transplantation, Child preschool, Nosocomial infection, and Cross Infection
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Human primary immunodeficiencies impairing Toll like receptor (TLR) signalling pathway have been recently described in patients with various infectious diseases. Germ line mutations in NEMO and IKBA impair NF-κB-mediated signalling, at... more
Human primary immunodeficiencies impairing Toll like receptor (TLR) signalling pathway have been recently described in patients with various infectious diseases. Germ line mutations in NEMO and IKBA impair NF-κB-mediated signalling, at least in response to TLRs, IL-1Rs, and TNFRs stimulation, and confer broad predisposition to infections; mutations in IRAK4 and MYD88 selectively impair TLRs other than TLR3 and most IL-1Rs
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There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes... more
There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.
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Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of... more
Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytoki...
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The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF... more
The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.
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Research Interests: Biology, Medicine, Signal Transduction, Toll Like Receptors, Endotoxin, and 14 moreHumans, Mutation, Infectious Disease, Gram Positive, Primary Immunodeficiency, NF-kappa B, Mitogen Activated Protein Kinase, Spectrum, In Vitro Studies, Autosomal Recessive, Ectodermal Dysplasia, Autosomal Dominant, Immunologic deficiency syndromes, and signalling pathway
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Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined.... more
Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such ...
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Research Interests: Immunology, Biology, Cytokines, Immunology of the Gut, Innate immunity, and 15 moreGene expression, Western blotting, Toll Like Receptors, Humans, Mutation, Male, NF-kappa B, The, Pedigree, Amino Acid Sequence, Myeloid Cells, Molecular Sequence Data, fibroblasts, innate immune response, and reverse transcriptase polymerase chain reaction
Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations... more
Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosp...
Research Interests: Flow Cytometry, Biology, Humans, Sequence alignment, Female, and 15 moreMale, Phosphorylation, Pedigree, Fluorescent Antibody Technique, DDC, Interleukins, Experimental Medicine, CHRONIC MUCOCUTANEOUS CANDIDIASIS, Base Sequence, Enzyme Linked Immunosorbent Assay, Interleukin, Interferon gamma, Immunoblotting, Molecular Sequence Data, and Medical and Health Sciences
This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to... more
This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.
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No abstract is available. To read the body of this article, please view the Full Text online. ... Supported by BNP-Paribas Fondation, Schlumberger Fondation, Institut Universitaire de France, the ANR, and the Rockefeller University Center... more
No abstract is available. To read the body of this article, please view the Full Text online. ... Supported by BNP-Paribas Fondation, Schlumberger Fondation, Institut Universitaire de France, the ANR, and the Rockefeller University Center for Clinical and Translational Science grant ...
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Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102... more
Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infec...
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Research Interests: Adolescent, Medicine, Biological Sciences, Humans, Child, and 15 moreMycobacterium, Primary Immunodeficiency, Female, Candida, Male, Candidiasis, Infant, Recurrence, Salmonella, Middle Aged, Adult, Clinical Infectious Diseases, Child preschool, Medical and Health Sciences, and Patient Outcome Assessment
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Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic... more
Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID–causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID–causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding–dependent receptors, the TNF and IL-1β receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations ...
Research Interests: Protein Folding, Biology, Medicine, Western blotting, Signal Transduction, and 13 moreUbiquitin, Humans, Female, Blood, Male, NF-kappa B, Young Adult, Pedigree, Clinical Sciences, Protein Binding, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, and Immunologic deficiency syndromes
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Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have... more
Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterize...
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Research Interests: Biology, Saudi Arabia, Medicine, Signal Transduction, Toll like receptor signaling, and 15 moreHumans, Sequence alignment, Female, Male, Infant, Pedigree, Genotype, Consanguinity, Amino Acid Sequence, Clinical Investigation, Interferon Alpha, Molecular Sequence Data, Child preschool, genetic heterogeneity, and Medical and Health Sciences
The NLRC4 inflammasome is part of the human immune innate system. Its activation leads to the cleavage of pro-inflammatory cytokines IL-1β and IL-18, promoting inflammation. NLRC4 gain-of-function (GOF) mutations have been associated with... more
The NLRC4 inflammasome is part of the human immune innate system. Its activation leads to the cleavage of pro-inflammatory cytokines IL-1β and IL-18, promoting inflammation. NLRC4 gain-of-function (GOF) mutations have been associated with early-onset recurrent fever, recurrent macrophagic activation syndrome and enterocolitis. Herein, we describe two new patients with NLRC4 mutations. The first case presented with recurrent fever and vasoplegic syndrome, gut symptoms and urticarial rashes initially misdiagnosed as a severe protein-induced enterocolitis syndrome. The second case had recurrent macrophage activation syndrome (MAS) and shock, suggesting severe infection. We identified two NLRC4 mutations, on exon 4, within the nucleotide-binding protein domain (NBD). After a systematic review of NLRC4 GOF mutations, we highlight the wide spectrum of this disease with a limited genotype–phenotype correlation. Vasoplegic shock was only reported in patients with mutation in the NBD. Diagno...
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Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses... more
Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-gen...
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Secondary use of data collected in Electronic Health Records opens perspectives for increasing our knowledge of rare diseases. The clinical data warehouse (named Dr. Warehouse) at the Necker-Enfants Malades Children's Hospital... more
Secondary use of data collected in Electronic Health Records opens perspectives for increasing our knowledge of rare diseases. The clinical data warehouse (named Dr. Warehouse) at the Necker-Enfants Malades Children's Hospital contains data collected during normal care for thousands of patients. Dr. Warehouse is oriented toward the exploration of clinical narratives. In this study, we present our method to find phenotypes associated with diseases of interest. We leveraged the frequency and TF-IDF to explore the association between clinical phenotypes and rare diseases. We applied our method in six use cases: phenotypes associated with the Rett, Lowe, Silver Russell, Bardet-Biedl syndromes, DOCK8 deficiency and Activated PI3-kinase Delta Syndrome (APDS). We asked domain experts to evaluate the relevance of the top-50 (for frequency and TF-IDF) phenotypes identified by Dr. Warehouse and computed the average precision and mean average precision. Experts concluded that between 16 an...
Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare... more
Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare lymphocyte syndrome type I, is a rare primary immunodeficiency disorder. We report a case of TAP1 deficiency revealed by skin lesions long before the occurrence of respiratory infectious manifestations.
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Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of... more
Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS. The proportion of CD25CD127 Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3CD4 T cells from ALPS patients and thus an abnormally low proportion of CD25FOXP3 Helios T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3CD45RA) and an unusual subpopulation (CD4CD127CD15sCD45RA). Despite this abnormal phenotype, the CD25CD127 Tregs' suppressive function was unaffected. Furthermore, conventional T cells from -mutated patients showed normal levels of sensitivity to Treg suppression. An abnormal Treg phenotype is observed in circulating lympho...
Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy... more
Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-t...
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V(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), its suboptimal activity, is associated with a broad spectrum of immune manifestations... more
V(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), its suboptimal activity, is associated with a broad spectrum of immune manifestations such as late onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, in particular when it involves myelo-ablative conditioning regimen for hematopoietic stem cell transplantation (HSCT). We aimed at developing biomarkers based on the analysis of TCRα repertoire to assist in the diagnosis of primary immunodeficient patients (PID) with V(D)J recombination and DNA repair deficiencies. We used flow cytometry (FACS) analysis to quantify TCR-Vα7.2 expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/NGS assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. The combined FACS and PROMIDISα analyses revealed specific...
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Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations... more
Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF...
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An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be... more
An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment. 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally. Molecular...
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Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including... more
Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD...
Research Interests: Hematology, Adolescent, Humans, Child, Mutation, and 14 moreFemale, Male, Polymerase Chain Reaction, Young Adult, Infant, Middle Aged, Adult, Immunocompromised host, Molecular Diagnostic Techniques, Perforin, DNA mutational analysis, Child preschool, Lymphoproliferative disorders, and Cardiovascular medicine and haematology
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in(APDS1) or(APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical... more
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in(APDS1) or(APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 A...
Store-operated Caentry (SOCE) through Carelease-activated Cachannels is an essential signaling pathway in many cell types. Carelease-activated Cachannels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction... more
Store-operated Caentry (SOCE) through Carelease-activated Cachannels is an essential signaling pathway in many cell types. Carelease-activated Cachannels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectoderm...
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Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune... more
Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to disting...