HYPOTHESIS AND THEORY
published: 17 February 2021
doi: 10.3389/fimmu.2021.634544
TNFRSF13B Diversification Fueled by
B Cell Responses to Environmental
Challenges—A Hypothesis
Marilia Cascalho* and Jeffrey L. Platt
Department of Surgery and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI,
United States
Edited by:
Alessandro Camponeschi,
University of Gothenburg, Sweden
Reviewed by:
Paolo Casali,
University of Texas Health Science
Center at San Antonio, United States
Philip D. Hodgkin,
Walter and Eliza Hall Institute of
Medical Research, Australia
Pascal Schneider,
University of Lausanne, Switzerland
*Correspondence:
Marilia Cascalho
marilia@umich.edu
Specialty section:
This article was submitted to
B Cell Biology,
a section of the journal
Frontiers in Immunology
Received: 28 November 2020
Accepted: 21 January 2021
Published: 17 February 2021
Citation:
Cascalho M and Platt JL (2021)
TNFRSF13B Diversification Fueled by
B Cell Responses to Environmental
Challenges—A Hypothesis.
Front. Immunol. 12:634544.
doi: 10.3389/fimmu.2021.634544
B cell differentiation and memory are controlled by the transmembrane activator and
CAML interactor (TACI), a receptor encoded by TNFRSF13B. TNFRSF13B mutations
are frequently found in common variable immunodeficiency (CVID) and in IgA -deficiency;
yet, ∼98% of those with mutant TNFRSF13B are healthy. Indeed, TNFRSF13B is among
the 5% most polymorphic genes in man. Other mammals evidence polymorphism at
comparable loci. We hypothesize that TNFRSF13B diversity might promote rather than
detract from well-being by controlling key elements of innate immunity. We shall discuss
how extraordinary diversity of TNFRSF13B could have evolved and persisted across
diverse species of mammals by controlling innate and adaptive B cell responses in
apparently paradoxical ways.
Keywords: B-lymphocyte, TNFRSF13B, antibodies, T cell-dependent antibody response, T cell-independent
antibody responses
INTRODUCTION
B cell responses are often characterized as T cell-independent or T cell-dependent that differ on
how T cells are engaged. In “T-independent B cell responses” antigens with repetitive epitopes,
such as polysaccharides, engage B cell antigen receptors and/or toll-like receptors and in doing so
induce proliferation and plasma cell differentiation. The antibodies produced in T cell-independent
responses may appear relatively soon after introduction of antigen, but not immediately as in recall
responses. The Ig variable region genes encoding these antibodies typically lack extensive somatic
mutation (1). Repeated exposure to antigen that had generated a T cell-independent response does
not hasten and amplify the response [i.e., B cell memory is not manifest; (1)]. In contrast, the
T-dependent pathway requires T cell help and is associated with responses to protein antigens.
Proteins are processed and peptides presented on major histocompatibility class II molecules
expressed by antigen presenting cells that activate cognate CD4-positive T cells. These T cells
in turn, engage cognate B cells activated by the same antigen by binding peptide MHC class-II
complexes and co-receptors such as CD40. T cell-dependent responses induce long-lived memory
responses and are associated with high affinity binding antibodies produced by plasma cells
descending from the germinal centers in the secondary lymphoid organs (1). Naturally occurring
polymorphisms in the TNFRSF13B gene differentially control T-dependent and T-independent
pathways of antibody production.
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TNFRSF13B AND THE CONTROL OF
ANTIBODY PRODUCTION
variants corresponding to those in humans mount proficient
antibody responses and antibody-mediated defenses against
pathogenic bacteria (17). Still more puzzling is the relationship
between diversity of TNFRSF13B genotypes and phenotype.
We shall describe recent work that may have begun to clarify
apparently disparate aspects of the TNFRSF13B phenotype and
identify yet unsettled questions we think of importance.
Recent investigations in mice and human subjects have
clarified discrepancies concerning the impact of TNFRSF13B
on B cell responses to antigen. It is now apparent that
stimulation of TNFRSF13B is essential for T-independent- but
not for T-cell-dependent B cell responses. The requirement
for TNFRSF13B (TACI) function for mounting T-independent
antibody responses was first shown by von Bulow et al. (24),
who found that TACI-KO mice produce less antibodies in
response to immunization with pneumococcus. Failure of T cellindependent responses in tnfrsf13B-mutant mice was confirmed
by Wolf et al. (22) and Mantchev et al. (25), who showed
the defective T-independent responses were due to a block in
plasma cell differentiation. Tsuji et al. (12) found that defective
plasma cell differentiation was due to defective Blimp-1 synthesis.
Similarly, Grasset et al. (18) reported that production of gut IgA
by T-independent response depends on tnfrsf13B. In contrast,
human subjects with TNFRSF13B mutations, including those
with dominant negative phenotype and mice with tnfrsf13B
deficiency or dominant negative variants respond to antigen
when T cell help is provided. Tsuji et al. (12, 17) reported
that tnfrsf13B-deficient mice are quite proficient in responses
to polypeptide antigens associated with enteric organisms (or
purified therefrom), generating high affinity antibodies and
conferring protection against reinfection. Likewise, Grasset et al.
(18) found tnfrsf13B deficient mice quite effectively mount gut
IgA responses if T cell help is present.
The differential impact of TNFRSF13B on T cell-independent
and T-cell-dependent responses may reflect differences in how
Blimp-1 is induced. In T cell-independent responses, induction
of Blimp-1 depends absolutely on stimulation of TNFRSF13B by
BAFF or APRIL (12, 17). In T cell-dependent responses, double
strand DNA breaks generated by class-switch recombination (17)
and/or engagement of CD40 and IL21/STAT3 (26) signaling
can induce Blimp-1 independently of TNFRSF13B signaling.
Although TNFRSF13B may not directly impact on Ig isotype
class switching, changes of B cell development post-activation by
TNFRSF13B mutation, or deletion, that interfere with signaling
change the distribution of Ig isotypes in response to stimulation
and in the steady state (27).
How TNFRSF13B signaling contributes to the generation and
activation of memory B cells remains incompletely understood.
The increase in TNFRSF13B expression by memory B cells
suggests that TNFRSF13B signaling is important for memory B
cell differentiation, survival or function (28). Indeed memory
B cells from CVID subjects with monoallelic C104R or A181E
mutations fail to activate in response to BCR, TLR7, or TLR9
stimuli (28). Memory B cells of subjects with TNFRSF13B
hemizygosity (one null allele and one WT allele) mount a partial
response to activation to BCR, TLR7, or TLR9 stimuli suggesting
that signaling intensity is important in determining magnitude
TNFRSF13B encodes the tumor necrosis factor superfamily
member 13B, a transmembrane receptor of lymphocytes that
recognizes a proliferation induced ligand (APRIL) and B cell
activation factor (BAFF), members of the tumor necrosis ligand
family (2). TNFRSF13B also binds heparan sulfate chains
associated with syndecan-2 and−4 cores (3). The signaling
events initiated by TNFRSF13B are complex and intersect
with signaling by Toll-Like receptors (TLRs) and will be only
briefly summarized here. Binding of BAFF and APRIL to
the cysteine rich domain of the receptor closest to the cell
membrane (CRD2) engages TNFR—associated factors (TRAF 2,
5, and 6) and activates NF-kB, c-Jun NH2-terminal kinase (4)
and activator protein 1 (AP-1) (5). TNFRSF13B interacts with
calcium modulator and cyclophilin ligand (CAML), which in
turn activates calcineurin and nuclear factor of activated T cells
(NFAT) (6). TNFRSF13B is sometimes called “transmembrane
activator and CAML interactor” or TACI (6) reflecting this
series of interactions. TNFRSF13B potentiates signaling by
Toll-like family receptors in B cells (7) and in macrophages
(8). Accordingly, TNFRSF13B interacts with MyD88, recruits
mechanistic target of rapamycin (mTOR), activates mTORC1
and NF-kB (9–11). TNFRSF13B signaling in B cells generates
expression of BLIMP-1, a transcription factor that drives
differentiation of B cells into long-lived plasma cells (12).
The importance of TNFRSF13B and BLIMP-1 for
development of plasma cells and production of much of
the Ig in blood was suggested by investigation of genetic
basis of hypogammaglobulinemia, i.e., IgG-deficiency, IgMdeficiency, and IgA-deficiency observed in common variable
immunodeficiency (CVID) and in selective IgA deficiency
(13, 14). Consistent with this phenotype, TNFRSF13B-deficient
mice have few plasma cells in secondary lymphoid organs
and in the bone marrow and low concentrations of IgM, IgA,
and IgG in serum (12). However, TNFRSF13B governs more
than the machinery for long term-Ig production. Human
subjects with CVID have an increased risk of lymphoma and
gastro-intestinal cancer (15) and a propensity for development
of autoimmunity (16). Mice with deficient tnfrsf13b exhibit
pronounced expansion of follicular and germinal center B
cells, despite hypogammaglobulinemia, suggesting tnfrsf13B
may govern B cell differentiation and T and B cell interactions
(12, 17, 18).
Although some functions of TNFRSF13B, such as control
of plasma cell differentiation are understood, some puzzling
contradictions remain. One contradiction concerns the impact
of TNFRSF13B on the B cell response to antigen. TACI appears
more or less essential for natural immunity because humans and
mice lacking TACI (targeted deletion in mouse; expression of
dominant-negative variants in humans) have extremely low levels
of IgG, IgM, and IgA in blood (19) and produce little antigen
specific antibodies after exposure to antigen or foreign organisms
(20–22). However, most people with dominant negative TACI
variants do not manifest immunodeficiency (23) and TACI
knockout mice and mice expressing dominant negative TACI
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TNFRSF13B and B Cell Responses
cell activation (38). The short version of the receptor lacks
the cysteine rich domain 1 thought to mediate ligand binding
(38). However, absence of the CDR1 domain in the short form
does not appear to preclude assembly of the receptor trimer or
signaling. Garcia-Carmona et al. (10) showed that TNFRSF13BS and TNFRSF13B-L assembled receptor complexes composed
of one single S or L isoform, or of mixed complexes composed
of both S and L isoforms. TNFRSF13B-S requires a lower
ligand concentration to signal than TNFRSF13B-L, in part
owing to increased ligand binding affinity (10). In contrast,
certain mutated isoforms, C104R, A181E, and S194X, produced
receptors that had impaired or no signaling (10).
TNFRSF13B polymorphisms may be maintained by balancing
selection. Balancing selection is thought to occur when
multiple alleles (variants) are maintained in the population
in an equilibrium, at frequencies more evenly distributed
than expected under models of neutral evolution, because
selection favors the heterozygote. To measure the likelihood of
balancing selection at the TNFRSF13B locus we used a statistic,
the β index, which detects clusters in close proximity to a
site targeted by balancing selection [https://academic.oup.com/
mbe/article/34/11/2996/3988103; (39)]. TNFRSF13B manifests
balancing selection in four regions (two of them between exons
2 and 3, and the other two between exons 4 and 5) (39).
Research by Jagoda et al. (40) suggests that certain haplotypes
of TNFRSF13B may be of Neanderthal in origin and kept
in European/Eurasian populations as a result from adaptive
introgression. Thus, TNFRSF13B variants may have originated
by positive selection of archaic ancestry variants, maintained
thereafter by balancing selection.
What the selection pressures are that maintain TNFRSF13B
diversity is not known but our research and the research of others
connects these properties to the control of T-independent natural
IgA antibody production.
of response (28). Whether or not the phenotypic manifestations
of monoallelic dominant-negative mutations or haplo-deficiency
impact memory B cell responses to T-dependent stimuli and in
subjects who are healthy is not known.
TNFRSF13B POLYMORPHISMS
The diversity of TNFRSF13B, by some measures, equals or
exceeds that of genes encoding the major histocompatibility
complex (MHC) but the mechanisms contributing to
TNFRSF13B diversity are less apparent. Diversity of MHC
is generally ascribed to the function of housing a vast diversity
of microbial peptides for presentation to T cells (29) and while
some diversification likely reflects specificity for peptides, some
may also reflect non-effector functions such as recognition
leading to immune regulation for MHC-class II or controlling
NK cells for MHC class I (29).
Yet, TNFRSF13B encodes a polypeptide the sole function
of which may be recognition of several relatively nonpolymorphic agonists, BAFF and APRIL (30). Why then do
humans exhibit extreme genetic polymorphism of TNFRSF13B?
There are 951 TNFRSF13B missense and only 383 synonymous
mutations reported in compilations of more than 100.000
human genomes (https://useast.ensembl.org/index.html). Only 4
of the TNFRSF13B missense alleles are common (freq >0.05).
Unlike TNFRSF13B variants, nearly 20% of HLA-A variants are
found in 5% or more of the population (Genome Aggregation
Database, v2.1.1; http://exac.broadinstitute.org). TNFRSF13B has
a greater number of missense variants than it would be
predicted by a sequence-context-based mutational model as
reflected by a z score of −1.2, and TNFRSF13B has more
observed than expected loss of function variants (LoF) (stop
gain and splice site variants), which indicate a high tolerance
to these types of mutations (pLI = 0.00, where pLI of 1 is
the most intolerant) [Genome Aggregation Database, v2.1.1;
http://exac.broadinstitute.org; (31)]. Most common variants are
phenotypically dominant, either as dominant negatives or
causing haplo-insufficiency (32–34) but how exactly expression
of mutant alleles results in changes in TNFRSF13B signaling and
function is incompletely known (10). In contrast, the number
of missense mutations in the HLA-A gene is as expected by a
sequence-context-based mutational model as (z score of −0.1
according to the Genome Aggregation Database, v2.1.1; http://
exac.broadinstitute.org) and the HLA-A gene is less tolerant than
TNFRSF13B to loss of function mutations. Thus, TNFRSF13B
missense alleles appear to have been selectively retained and
recent analysis by the McDonald-Kreitman neutrality index
suggests the locus is under strong positive selection (35) in
contrast with prior analysis of smaller cohorts (36). This is in
contrast to genes encoding HLA which are under moderate
purifying pressure (35). Some TNFRSF13B polymorphisms are
conserved across mammalian species. As an example, mice have
17 missense alleles, 2 non-sense alleles, and 2 splice variants (37).
Adding to TNFRSF13B diversity the receptor is expressed as
two isoforms that differ by the presence (long, L) or absence
(short, S) of exon 2 that is alternatively spliced following B
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TNFRSF13B AND IgA
TNFRSF13B promotes IgA synthesis. In support, TNFRSF13Bdeficient animals and animals with dominant-negative
TNFRSF13B alleles are IgA deficient (12, 17, 20) and; selective
IgA deficiency in humans is often associated with mutant
TNFRSF13B alleles (41). We hypothesize that TNFRSF13B
polymorphisms may in part be driven by the receptor impact on
secretory IgA (sIgA).
First discovered in 1953, IgA is by some measures the most
abundant Ig in the body (42, 43). IgA exists as a monomer in
circulation and as a dimer in lumina of the respiratory, intestinal,
and genito-urinary system. Secretory IgA makes 2/3 of all IgA
produced in the body (44). An IgA monomer is, like other Ig
isotypes, a tetramer composed of two identical heavy chains
and two identical light chains united by covalent and noncovalent bonds. Each monomer contains two Fab domains and
one Fc region that includes C alpha 2 and C alpha 3 exons (44).
Humans, express IgA1 and IgA2, the later encoded by several
distinct alleles. IgA1 and IgA2 differ on the hinge region that
links constant domain alpha 1 to the constant domain alpha 2
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interaction with pIgR (55, 56). Serum IgA and secretory IgA are
differentially glycosylated presumably reflecting differences in the
glycosylation machinery in plasma cells of the spleen and bone
marrow vis a vis plasma cells in the mucosae (48).
The heavy-chain N-linked glycans help maintain the correct
IgA conformation and assist with dimer formation and secretion
(57, 58). Although the glycan composition of IgA HCs activate
the lectin complement activation pathway by binding mannose
binding lectin (MBL), the glycans are shielded by the secretory
component at physiologic pH and only become accessible
for binding at low pH and perhaps upon engagement with
bacterial adhesins which pull the secretory component away
from the IgA (48). Once uncovered, IgA HC glycans may also
directly bind mannose receptors on phagocytic cells promoting
internalization and antigen presentation (59). Secretory IgA
HCs are also extensively modified by O-linked glycans which
form highly complex structures that in addition to stabilizing
the hinge region also interact with bacterial adhesins (60).
Glycosylation-dependent IgA functions are likely due to low
affinity interactions and therefore critically dependent on IgA
concentration. Although there is no evidence in support of
TNFRSF13B direct influence on IgA glycosylation, by controlling
IgA secretion TNFRSF13B is likely to impact more on the nonspecific IgA functions than on the functions of IgA that depend
on high affinity interactions between mutated V regions and
their targets.
of the heavy chain, longer in IgA1 and shorter on IgA2. The
significance of the longer hinge region for the function of IgA1
is not completely known but modeling suggests that the longer
hinge region may afford greater flexibility to the variable region
relative to the Fc region at the cost of increased sensitivity to
proteolysis (44).
The secreted form of IgA is a complex comprised of an IgA
dimer linked by the joining (J) chain and a secretory component,
a fragment of the polymeric Ig receptor (PIgR). Secretion
and dimerization of IgA is made possible by two important
adaptations. In one, IgA has an 18 aa tail piece at the C-terminus,
highly homologous to another found at the C-terminus of IgM.
The tail piece allows IgA (and IgM) polymerization because it
binds to the J chain through 2 cysteine disulfide bonds (45, 46).
The J chain is a 137 amino-acid polypeptide and it is bound to IgA
before secretion. The second adaptation is the development of a
highly specific IgA transport system across the epithelium and
into secretions. The transport of IgA depends on the polymeric
Ig receptor (pIgR) that binds only polymeric Ig (IgA or IgM)
and is expressed on the basolateral surface of epithelial cells that
line mucosal surfaces of the gut, lung biliary tract, and lacrimal
glands. The pIgR has a 620 aa extra-cellular domain, a 23 aa
transmembrane domain and a 103 aa cytoplasmic domain (47).
Transcytosis of IgA from the submucosal region to the lumen
requires binding of dimeric IgA C alpha 3 to the pIgR at the
basolateral side of epithelial cells followed by internalization and
transport to the apical surface of the cell. IgA is released from
its attachment by cleavage of the pIgR ectodomain (secretory
component) at the apical surface. IgA, covalently bound to the
secretory component is released on to the mucosa, forming sIgA.
Bacterial and viral products induce heightened pIgR synthesis
by epithelial cells and hence increase transcytosis of IgA (47).
The secretory component confers resistance to proteolysis and
anti-microbial functions. In addition to binding to IgA, the
secretory component exists as a free protein and as such it binds
directly to a variety of microbes inhibiting adhesion to epithelial
cells, binds to mucus mediating immune exclusion of antigens
and pathogens, retains IL-8 and in this way, inhibits neutrophil
chemotaxis (48).
IgA complexed with J chain and the secretory component
is heavily glycosylated and glycosylation is necessary for many
of non-specific, variable region-independent IgA functions (49).
IgA complexes are modified by N-linked glycosylation at
Asn (N) residues and by O-linked sugars. Glycosylation of
the secretory component protects IgA from degradation (50)
and mediates some IgA immune functions. Glycans enable
secretory component binding to adhesins and lectins, to a wide
range of bacteria and to toxins [(48), and references therein]. Glycosylation of the secretory component determines the
distribution of IgA to specific areas of the epithelium (51) and the
secretory component is needed with IgA to neutralize rotavirus
(52). Furthermore, secretory component free or complexed
to IgA, binds to the lectin binding domain of Mac-1 (CR3,
CD11b/CD18) enhancing IgA receptor Fc alpha signaling and
augmenting phagocytosis and inflammation [reviewed in (53)].
J chain glycosylation is necessary for dimerization of IgA
(54) and for maintaining the correct conformation to facilitate
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DISCUSSION
One might expect that a cytokine receptor such TNFRSF13B
would exert straight forward functions that promote host defense
and/or immune regulation and accordingly polymorphism
should be rare and harmful. Yet, TNFRSF13B is as diverse as
MHC. Why?
Although the story is yet incomplete, the complexity of
TNFRSF13B gene and protein functions has been coming
more fully into focus. Although TNFRSF13B does not bind
antigen it controls response of B cells to T-independent and
to T-dependent antigens differently. TNFRSF13B promotes
T-independent antibody production in part by facilitating
differentiation of plasma cells. In contrast, TNFRSF13Bdeficiency does not inhibit and in some cases enhances IgG or
IgA responses to T-dependent antigens.
Most sIgA results from T-independent B cell responses. IgA
exerts protective functions by helping to eliminate pathogens
directly and/or through maintaining microbial homeostasis and
these functions are in a great extent independent of IgA
specificity (61–63). The equilibrium established between IgA,
microbes and pathogens results from anti-microbial functions
of IgA and microbial adaptations to IgA (49, 64). In one
example of a remarkable microbial adaptation, Nakajima et al.
(49) showed that highly glycosylated IgA of an irrelevant
specificity (specific to ovalbumin) bound to a human symbiont
Bacteroides thetaiotaomicron (B. theta) changing gene expression.
IgA induced transcription of B. theta polysaccharide utilization
loci (65) changing polysaccharide utilization and in this way
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TNFRSF13B and B Cell Responses
FIGURE 1 | Diversity of TNFRSF13B in host response to environmental challenges. TNFRSF13B encodes a receptor (TACI) through to support the maturation of B
cells, yet the gene is among the most polymorphic in the genome and polymorphism is maintained across mammalian species. The authors speculate that
polymorphism of TNFRSF13B reflects balancing selection—balancing benefits and disadvantages of signals the receptor delivers but also manifold intermediate
functions the protein and its neighbors in cell membrane confer. The figure depicts two hypothetically distinct regions of the protein that confer phenotypically distinct
properties. The balancing of complex sets of phenotypic properties that presumably impact all mammals could underlie extraordinary diversity of the gene across
species. CVID, Common Variable Immunodeficiency.
conferring competitive advantage (49). As another example,
Bacteroides fragilis capsule induces polysaccharide specific IgA
which in turn, increases its adherence to intestinal epithelial cells
by binding to mucus as well as to the capsule polysaccharides
(62). In these examples, commensal bacteria co-opt IgA to
colonize the gut.
We hypothesize TNFRSF13B polymorphisms are maintained
at least in part as the result of microbial adaptation to IgA
(Figure 1). We offer the following reasoning in support of
the hypothesis.
In a recent report Grasset et al. (18) showed that TNFRSF13B
is necessary for T-independent IgA responses to commensal
bacteria. These responses include secretion of polyreactive IgA
and represent the majority of secreted IgA. In contrast, T celldependent IgA responses occur independently of TNFRSF13B.
Thus, varying TNFRSF13B function changes the ratio between
highly-specific and polyreactive or non-specific IgA responses
which, in turn, may counteract pathogen adaptation to IgA
and facilitate specific elimination. In support, Grasset et al.
(18) showed that tnfrsf13b-KO mice generated mutated IgA
that specifically targeted a restricted subset of microbes. In
an earlier publication, Tsuji et al. (17) showed that tnfrsf13bKO produced highly mutated antibodies that rapidly cleared
C. rodentium. Whether changes of the properties and amount
of sIgA and/or varying the proportion of mixed polyreactive
and specific mono-reactive Ig in individuals or mice expressing
TNFRSF13B polymorphisms is protective awaits investigation.
For all the benefits of IgA, selective IgA deficiency is often
asymptomatic (41). TNFRSF13B polymorphisms are associated
with IgA deficiency (41), the most common immune-deficiency
(with frequencies varying between 1:143 in the Arabian peninsula
Frontiers in Immunology | www.frontiersin.org
to 1 in 500 Caucasian individuals) (66, 67). The limited
morbidity of IgA deficiency, suggests as one possibility that
benefits conferred by TNFRSF13B variants may outweigh the
detrimental impact of decreased IgA in the gut. Because tnfrsf13b
mutants maintain the ability to make “adaptive” IgA it is
possible that protective functions of IgA are maintained or
even enhanced. In accord, IgA-deficient patients were found to
have enhanced adaptive antibody responses to pneumococcal
vaccination (68). Perhaps it is this type of response that explains
the mild phenotype of many individuals with IgA deficiency
and the maintenance of the extreme polymorphism at the
TNFRSF13B locus.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding author/s.
ETHICS STATEMENT
Animal studies and human subject research that inspired some
of the hypotheses in the manuscript were reviewed and approved
by the Institutional Animal Care & Use Committee (IACUC)
or by the Institutional Review Board (IRB) at the University
of Michigan.
AUTHOR CONTRIBUTIONS
MC and JP wrote the manuscript. MC analyzed data. All authors
contributed to the article and approved the submitted version.
5
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TNFRSF13B and B Cell Responses
FUNDING
ACKNOWLEDGMENTS
This research was supported by NIH grants R01 AI51588 and
AI122369 (MC and JP), a grant from the State of Michigan,
CASE-283529 UM-MTRAC for Life Sciences (MC and JP), NIH
grant R21GM140359 (MC), and UM Michigan Institute for
Clinical & Health Research Accelerating Synergy Award.
The authors acknowledge the members of their laboratories for
valuable discussions and insights, and Drs. Siewert and Voigt at
the Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, who helped us interpret their statistics data on
the TNFRSF13B locus.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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