Pieper 2013

Mechanisms of allergic diseases
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD PhD
B-cell biology and development

Kathrin Pieper, MSc,a,b Bodo Grimbacher, MD,a and Hermann Eibel, PhDa Freiburg, Germany
B cells develop from hematopoietic precursor cells in an ordered

maturation and selection process. Extensive studies with many Abbreviations used
different mouse mutants provided fundamental insights into this AID: Activation-induced cytidine deaminase
process. However, the characterization of genetic defects APRIL: A proliferation-inducing ligand
causing primary immunodeficiencies was essential in BAFF: B-cell activator of the TNF-a family (aka BLYS)
BAFF-R: BAFF receptor
understanding human B-cell biology. Defects in pre–B-cell
BCMA: B-cell maturation factor
receptor components or in downstream signaling proteins, such BCR: B-cell antigen receptor
as Bruton tyrosine kinase and B-cell linker protein, arrest Blimp-1: B lymphocyte–induced maturation protein 1
development at the pre–B-cell stage. Defects in survival- BLNK: B-cell linker protein (aka Sark homology 2
regulating proteins, such as B-cell activator of the TNF-a family domain–containing leukocyte protein of 65 kDa [SLP65])
receptor (BAFF-R) or caspase recruitment domain–containing BM: Bone marrow
protein 11 (CARD11), interrupt maturation and prevent BTK: Bruton tyrosine kinase
differentiation of transitional B cells into marginal zone and CARD11: Caspase recruitment domain–containing protein 11
follicular B cells. Mature B-cell subsets, immune responses, and (aka CARMA1)
memory B-cell and plasma cell development are disturbed by CNR2: Cannabinoid receptor 2
CSR: Class-switch recombination
mutations affecting Toll-like receptor signaling, B-cell antigen
CVID: Common variable immunodeficiency
receptor coreceptors (eg, CD19), or enzymes responsible for DOCK8: Dedicator of cytokinesis 8
immunoglobulin class-switch recombination. Transgenic mouse GC: Germinal center
models helped to identify key regulatory mechanisms, such as GFP: Green fluorescent protein
receptor editing and clonal anergy, preventing the activation of H-chain: Heavy chain
B cells expressing antibodies recognizing autoantigens. HEL: Hen’s egg lysozyme
Nevertheless, the combination of susceptible genetic L-chain: Light chain
backgrounds with the rescue of self-reactive B cells by T cells MyD88: Myeloid differentiation primary response gene–88
allows the generation of autoreactive clones found in patients MZ: Marginal zone
with many autoimmune diseases and even in those with primary NBH: B-cell helper neutrophil
NF-kB: Nuclear factor k light chain enhancer of activated B cells
immunodeficiencies. The rapid progress of functional genomic
nur77: Nuclear receptor 77
research is expected to foster the development of new tools that S1P: Sphingosine-1-phosphate
specifically target dysfunctional B lymphocytes to treat SHM: Somatic hypermutation
autoimmunity, B-cell malignancies, and immunodeficiency. TACI: Transmembrane activator, calcium modulator, and
(J Allergy Clin Immunol 2013;nnn:nnn-nnn.) cyclophilin ligand interactor
TLR: Toll-like receptor
Key words: B cell, B lymphocyte, immunodeficiency, development, WAS: Wiskott-Aldrich syndrome
humoral immunity, autoimmunity, tolerance
From athe Centre of Chronic Immunodeficiency, University Medical Centre Freiburg,

and bthe Faculty of Biology, Albert-Ludwigs-Universit€at, Freiburg.
K.P. and H.E. are supported by the German Cancer Research fund through grant 108935. B cells and their antibodies are the central elements of humoral
B.G. and H.E. are supported by Federal Ministry of Education and Research through immunity and protect, as part of the adaptive immune system,
grant no. BMBF 01 EO 18 0803.
against an almost unlimited variety of pathogens. Defects in B-cell
Disclosure of potential conflict of interest: K. Pieper and H. Eibel have received grants
from the German Cancer Research Fund. B. Grimbacher has received a speaker’s development, selection, and function lead to autoimmunity, malig-
honorarium from the American Academy of Allergy, Asthma & Immunology and has nancy, immunodeficiencies, and allergy. Combined with the enor-
received grants from the European Community 6th and 7th Framework Programmes, mous increase in knowledge about gene function and the genetic
the Marie Curie Excellence Grant, and the German Cancer Research Fund. diversity of human subjects that has developed since the human
Received for publication December 10, 2012; revised January 21, 2013; accepted for
publication January 22, 2013.
genome was deciphered, primary immunodeficiencies are a still-
Corresponding author: Hermann Eibel, PhD, Centre of Chronic Immunodeficiency, Uni- growing source of mutations, providing unique opportunities to
versity Medical Centre Freiburg, Engesser Str 4, Freiburg 79106, Germany. E-mail: study the function of the human immune system. In addition, each
hermann.eibel@uniklinik-freiburg.de. newly discovered immunodeficiency represents a new challenge to
0091-6749/$36.00
develop the most optimal and personalized forms of treatment.
Ó 2013 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2013.01.046 In this review we discuss human B-cell development (Fig 1)
Terms in boldface and italics are defined in the glossary on page nnn. in light of genetic defects discovered by studying primary
1
2 PIEPER, GRIMBACHER, AND EIBEL J ALLERGY CLIN IMMUNOL
nnn 2013
immunodeficiencies. By pointing out differences and common surface. These cells are termed immature B cells. Immature B
features with corresponding mouse models, we provide an over- cells leave the BM and migrate to the spleen, where they finalize
view on mechanisms regulating the maturation, survival, and se- early development by differentiating into naive, follicular, or
lection of B lymphocytes in protective and autoimmune responses. marginal zone (MZ) B cells.
Considering the enormous diversity of antibody specificities,
the first challenge of the immune system is to find a balance
EARLY B-CELL DEVELOPMENT IN THE BONE between variable specificities against pathogens while avoiding
MARROW autoreactivity. Therefore B cells are screened at several check-
In adult human subjects, as in all mammals, B lymphocytes points during development for their degree of autoreactivity. The
develop in the bone marrow (BM) from hematopoietic precursor first screen takes place after differentiation of pro-B into pre-B
cells. During embryonic life, the BM is seeded by hematopoietic cells.5 Expression of the productively rearranged m–H-chain, of
stem cells developing in the fetal liver. Their precursor cells the surrogate L-chains (in human subjects composed of l-like
originate from the aorta-gonad-mesonephros,1,2 which is formed and V-preB), and of the signal-transducing components Ig-a and
by descendants of the mesoderm. Early BM-dependent stages of Ig-b allows the formation of the so-called pre–B-cell antigen re-
B-cell development are structured along the functional rearrange- ceptor (BCR) complex. The pre-BCR has 2 tasks. The first task
ment process of the immunoglobulin gene segments.3 VH, DH, is to shut down the activities and expression of the enzyme machin-
and JH, rearrangements of the heavy chain (H-chain) together ery catalyzing the rearrangements of the H-chain gene segments, a
with the VL-JL rearrangements of the light chain (L-chain) process termed allelic exclusion.6 This prevents the expression of 2
gene segments generate a B-cell repertoire expressing antibodies H-chains with 2 different specificities by the same cell. The second
capable of recognizing more than 5 3 1013 different antigens. task is to initiate the rearrangement of the L-chain genes.
According to the rearrangement of the H-chain and L-chain Several genetic defects affecting components of the pre-BCR
gene segments, 3 developmental stages are defined. In the first or downstream signaling proteins have brought to light human
stage, pro–B cells rearrange the D and J segments of the H-chain, B-cell development and uncovered fundamental differences in
followed by a second rearrangement joining an upstream V region B-cell lymphopoiesis between mice and human subjects. In
to the rearranged DJ segment. human subjects, for example, mutations in genes encoding
The functional rearrangement of the m–H-chain gene segments components of the IL-7 signaling cascade, such as IL-2 receptor
opens the entry into the next phase, the pre–B-cell stage. In human common g,7 the IL-7 receptor a chain,8 or the associated kinase
subjects pre–B cells undergo 1 or 2 cell divisions and rearrange Janus kinase 3,9 do not affect the B-cell compartment, but they
the gene segments encoding the k and l chains.4 Combined with do interrupt T-cell development, leading to severe combined
the m chain, an IgM molecule is formed and expressed on the cell immunodeficiency (B1T2 severe combined immunodeficiency).
GLOSSARY
ACTIN: A protein found in microfilaments and active in muscular LIGHT CHAIN (L-CHAIN): An antibody molecule also contains 2
contraction, cellular movement, and maintenance of cell shape. identical L-chains that contain 1 variable domain and 1 constant
ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID): An enzyme that domain. The variable region of 1 H-chain is juxtaposed with the
catalyzes mutation of deoxycytidine to deoxyuracil in single-stranded variable region of 1 L-chain to form the antigen-binding site of the
DNA. AID is critical for somatic hypermutation. Mutations in AID result in antibody molecule.
autosomal recessive hyper-IgM syndrome. MARGINAL ZONE: A splenic zone located next to the marginal sinuses,
AFFINITY MATURATION: As a consequence of somatic hypermutation, the site of entry into the spleen for lymphocytes, macrophages, and
B cells increase their average affinity for antigen as the humoral immune dendritic cells in human subjects. The marginal sinus separates the
response progresses. Such cells are preferentially activated and there- white pulp from the red pulp.
fore have selective survival. Affinity maturation occurs in germinal MESODERM: The 3 primary germ layers of an embryo are the meso-
centers. derm, ectoderm, and endoderm. The mesoderm develops from the
5 3 1013: For comparison purposes, there are roughly 1014 cells in the ectoderm on the 15th day of life. The mesoderm is the source of bone,
human body, of which only 1013 are human. 5 3 1013 is roughly 40 billion muscle, connective tissue, and dermis.
more than the number of stars in the Milky Way Galaxy. There are NUCLEAR FACTOR kB (NF-kB): A family of transcription factors that
5 3 1012 known digits in p. One million years is approximately promote the expression of a variety of survival and differentiation
3.2 3 1013 seconds. factors, as well as inflammatory mediators. NF-kB is present in an
GERMINAL CENTER: A central proliferative area of a lymphoid follicle. It unstimulated state in the cytoplasm, where it is bound by IkB, an
forms during T cell–dependent humoral immune responses. inhibitory protein.
HEAVY CHAIN (H-CHAIN): Part of the core structure of an antibody PEYER PATCHES: Aggregates of lymphoid follicles that are a compo-
molecule. Antibodies contain 2 identical H-chains that consist of variable nent of gut-associated lymphoid tissue. Antigen-driven priming and
and constant regions. The constant regions of the H-chain mediate maturation of naive T and B lymphocytes occurs here. They are located
effector functions of the antibody. primarily in the ileum.
IL-7: A hematopoietic cytokine binding to cytokine receptors of the SOMATIC HYPERMUTATION: High-frequency point mutations that
common g chain family. In addition to being vital to the survival and occur in a mature B cell at the hypervariable sites of both the VH and
expansion of both precursor T lymphocytes, IL-7 stimulates the prolif- VL genes. The amino acid products of these sites, particularly at V, D,
eration and differentiation of cytotoxic T and natural killer cells and and J junctions, are the specific points of contact with antigen within
stimulates the antitumor properties of monocytes and macrophages. the binding groove.
The Editors wish to acknowledge Daniel A. Searing, MD, for preparing this glossary.
J ALLERGY CLIN IMMUNOL PIEPER, GRIMBACHER, AND EIBEL 3
VOLUME nnn, NUMBER nn
FIG 1. B-cell development and B-cell subsets. B cells develop in the BM from hematopoietic precursor cells
(HSC). Recombination-activating gene (RAG) 1/2–dependent rearrangement of the H-chain, D-gene, and
J-gene segments from germline (GL) starts at the pro–B-cell stage. V-gene segment rearrangement follows
in the early pre-B cell stage. In CD101 CD191 pre-B cells, functional H-chains (VDJ-Cm) pair with V-preB and
l-like, forming the pre-BCR, which is expressed within a cell and not detected on the surface. Pre-BCR–in-
duced signals shut down RAG expression, preventing the rearrangement of the second H-chain allele
and inducing proliferation. Next, RAG genes are re-expressed to initiate V-J rearrangement of L-chains. Suc-
cessfully rearranged k or l L-chains replace V-preB/l5 of the pre-BCR pair with the H-chain and form IgM.
IgM expressed by immature B cells changes the expression pattern of many genes and initiates egress
into the circulation. Immature B cells enter the spleen as transitional B cells, where they receive survival sig-
nals through BAFF-R and complete the first stage of development as MZ B cells or follicular B cells, depend-
ing on the specificity of their BCR. On contact with antigen and supported by NBH cells, MZ B cells develop
into short-lived plasma cells. Follicular B cells are activated by antigen binding and develop in GCs sup-
ported by TH cells into memory B cells (CSR1) or plasma cells (PC). Activation of B cells induces AID and
other components of the SHM/class-switch machinery, thus changing the affinity of the BCR and the isotype
(IgM to IgG, IgA, or IgE).
Bruton tyrosine kinase (BTK), a central signaling component numbers and proliferation.18 In contrast, mice lacking Btk have
downstream of the pre-BCR and the BCR, links the activation of a milder reduction in peripheral B-cell numbers and close to nor-
the pre-BCR and the BCR to Ca21 influx,10 the activation of the mal IgG1, IgG2a, IgG2b, and IgA antibody titers; only a significant
mitogen-activated protein kinase cascade, and changes in the reduction in IgM and IgG3 levels in serum was demonstrated.19,20
activity of transcription factors, including nuclear factor kB Thus mice on a Btk-deficient background are still able to mount
(NF-kB).11 In contrast to mice,12 the development of human B humoral immune responses.
cells in the BM is strongly dependent on BTK activity.13,14 Up Similar to BTK, defects in B-cell linker protein (BLNK;
to 90% of patients who receive diagnoses of early-onset hypo- SLP65) have different outcomes in human subjects and mice.
gammaglobulinemia carry mutations in the BTK gene located Deletion of Blnk in mice inhibits B-lymphocyte development at
on the X chromosome (X-linked agammaglobulinemia).15-17 In the stage of small pre-B cells,21 but because the block is permis-
infants and adults the lack of peripheral blood B cells leads to sive, Blnk-deficient B cells populate peripheral lymphoid tissues
severely reduced antibody titers of all isotypes. Analysis of BM in adult mice and mount T cell–dependent immune responses.22
samples from patients with X-linked agammaglobulinemia In human subjects BLNK-deficient B cells stop development at
revealed normal levels of the earliest B-cell progenitors, whereas the stage of pro-B cells, resulting in a phenotype very similar to
cytoplasmic Ig-m1 pre-B cells showed abnormalities in cell BTK deficiency.23 Circulating B cells are almost absent, and
nnn 2013
serum concentrations of IgM and IgA are less than detection B-cell precursors do not depend on IL-7 as a pre–B-cell growth
levels. Moreover, the lack of BLNK/SLP65 function in mice24 factor, whereas mutations in genes encoding components down-
but not in human subjects21,25 promotes the proliferation of pro- stream of pre-BCR signaling completely block development in
B/pre-BI cells and the spontaneous development of pre–B-cell the BM. Mutations in BCR coreceptor genes impair humoral im-
acute lymphoblastic leukemia. Because BLNK/SLP65 and BTK mune responses and increase susceptibility to bacterial infections.
are both critical elements of pre-BCR function, signals induced Inhibitors of BCR signaling are promising new therapeutics to
by the pre-BCR in human subjects induce pre–B-cell develop- treat B-cell malignancies and B cell–dependent autoimmune
ment and inhibit rearrangement of the second H-chain allele at diseases.
the same time. In mice the pre-BCR–derived signals also inhibit
IL-7–driven pre-B-cell proliferation.
BCR signaling has most recently received the utmost clinical BM EGRESS AND GUIDANCE TO THE SECONDARY
attention not only because most of the monogenetic defects in LYMPHOID ORGANS
patients with agammaglobulinemia and different hypogamma- Circulating through the body through the bloodstream and the
globulinemias have been identified in this pathway but also lymph, B cells regularly visit secondary lymphoid organs, such as
because the specific inhibitor of BCR signaling ibrutinib (PCI- the spleen, lymph nodes, tonsils, Peyer patches, and mucosal tis-
32765), a BTK inhibitor, is about to revolutionize not only the sues. Homing to B-cell follicles, formation of germinal centers
treatment of B-cell lymphomas26,27 but also might turn out to be (GCs), and egress from tissues back to the circulation are regu-
beneficial in B cell–driven autoimmune conditions.28,29 In gen- lated by adhesion molecules and by the interplay between differ-
eral terms, the causes of all antibody deficiencies arising from ent G protein–coupled receptors. Although chemokine receptors
conditions with B-cell dyscrasia will teach us about B-cell respond to a gradient of chemokines produced by tissue stromal
biology, which in turn might become premier targets for hematol- cells, sphingosine-1-phosphate (S1P) receptors react against
ogists treating B-cell malignancies. S1P. S1P is a multipotent lipid mediator synthesized by plate-
However, mutations affecting proteins of the BCR complex, lets,46 erythrocytes,47 and vascular endothelial cells.48 High
such as the m-chain, Ig-a, and Ig-b, lead to similar phenotypes in S1P concentrations in blood and lymph attract B cells and induce
mice and human subjects. Patients with a m-chain deletion present the egress from the lymphoid tissues, where S1P concentrations
as having severe hypogammaglobulinemia caused by a block in are low.49
early B-cell development.30,31 Although pro-B cells are present at Mouse models with deleted S1P receptor genes have shown
normal levels, patients lack pre-B cells in the BM and, conse- that the egress of immature B cells from the BM is in part
quently, all mature B-cell subsets in the periphery, which is sim- regulated by S1P receptor 1.50 S1P receptor 1 knockout mice have
ilar to what is observed in mice with a deletion of the m-chain.32,33 less circulating transitional B cells, whereas the number of imma-
Similarly, B-cell development is arrested at the pro–B-cell ture B cells in the BM is increased, where they stay longer.51
stage in patients with null mutations in genes encoding Ig-a Cannabinoid receptor 2 (CNR2) was shown to play a role in the
(CD79a)34,35 and Ig-b (CD79b).36 A missense mutation in the sinusoidal retention of immature B cells in the BM.52 CNR2
CD79B gene results in an amino acid substitution near a cysteine antagonists displaced immature B cells from the sinusoids, and
residue, thus preventing the formation of the disulfide bond moreover, CNR2 deficiency in mice resulted in a reduction in
between Ig-b and Ig-a and the assembly of a functional l1 B-cell numbers in the periphery, mainly because immature
pre-BCR.37 Phenotypically, the defect results in severe B-cell B cells in the BM had less time for secondary rearrangements
lymphopenia with less than 0.1% peripheral B cells. of their L-chain genes.52
Recently, a homozygous deletion of the downstream BCR After leaving the BM, B lymphocytes home to the spleen. Here
signaling component caspase recruitment domain–containing B cells populate niches to form the MZ and the follicular B-cell
protein 11 (CARD11) was shown to result in an antibody compartment. The positioning of cells into the MZ of mice was
deficiency by blocking B-cell differentiation.38,39 CARD11 inter- shown to be guided by the expression of CNR2. Mice deficient for
acts with B-cell lymphoma 10 (BCL10) and mucosa-associated CNR2 have fewer numbers of MZ B cells.53,54 Antagonists of en-
lymphoid tissue lymphoma translocation protein 1 (MALT1) docannabinoids were able to deplete the B cells from the MZ, and
and functions in the signaling pathway by activating canonical vice versa, overexpression of CNR2 guided B cells to the MZ.55
NF-kB after BCR engagement.40 Interestingly, work conducted Synopsis: In mice G protein–coupled receptors, such as S1P re-
in mice has demonstrated that CARD11 acts also as a modulator ceptors and CNR2, regulate the egress of B cells from the BM, as
of B-cell tolerance41 because point mutations in Card11 equiv- well as positioning in the B-cell follicles and the splenic MZ.
alent to those found in B-cell lymphomas induce the proliferation
of self-reactive B cells instead of apoptosis.
Although mutations affecting major components of the BCR MZ B CELLS, TOLL-LIKE RECEPTORS, AND
signaling machinery, such as the m-chain, Ig-a, Ig-b, and BTK, CYTOSKELETAL REMODELING
lead to a developmental block of early B cells in the BM, T cell–independent humoral responses are mounted by B cells
mutations in genes encoding components of the B-cell coreceptor of the MZ and the mucosa. In the spleen MZ B cells are the first
complex have been shown to be less severe. Human subjects line of defense against blood-borne pathogens.56 During the first 3
lacking CD19,42,43 CD21,44 or CD8145 showed normal numbers days of an infection, they rapidly develop into extrafollicular
of B cells in the periphery. However, affinity maturation and an- plasma cells secreting IgM,57 which forms immune complexes
tibody responses were impaired, thus leading to hypogammaglob- with the pathogen.
ulinemia and increased susceptibility to infections. Human MZ B cells express IgM carrying somatic hypermuta-
Synopsis: Striking differences exist between murine and human tions (SHMs) within the variable regions and recirculate, whereas
B-cell development. In contrast to murine pre-B cells, human their murine counterparts have unmutated variable regions and
remain in the spleen.58,59 Several findings indicate that the SHM have autoimmunity as well.76 Because MZ B cells shuttle in
in IgM variable regions of human MZ B cells originate indepen- response to S1P and chemokine signals between follicles and
dently from antigen-driven clonal expansion in GCs. First, young the MZ,50 WAS mutations inhibit the development and mainte-
children show a higher clonal diversity in the MZ subset than in nance of MZ B cells.77
switched B cells.59 Second, the MZ compartment found in chil- Synopsis: MZ B cells form a first line of defense against blood-
dren less than 2 years of age shows expression of low levels of borne pathogens and elicit a T-independent immune response. In
activation-induced cytidine deaminase (AID), a critical enzyme human subjects mutations in TLR signaling components impair
for SHM,60 whereas AID expression was not detected in MZ MZ B-cell responses.
B cells from adult spleens.61,62 Third, although their numbers
are reduced, MZ B cells are found in patients with genetic defects
in the CD40LG or CD40 genes encoding 2 molecules essential for SURVIVING IN THE PERIPHERY: THE B-CELL
TH cell–dependent GC reactions.63,64 Therefore it was proposed ACTIVATOR OF THE TNF-a FAMILY AND A
that MZ B cells develop and mutate during the first years of age PROLIFERATION-INDUCING LIGAND SYSTEM
independently from immune responses. The survival of B cells in the periphery depends on the
Recently, it was shown that human MZ B cells strongly depend expression of a functional BCR and on signals generated by
on myeloid differentiation primary response gene–88 (MyD88), B-cell activator of the TNF-a family (BAFF) binding to BAFF
IL-1 receptor–associated kinase 4 (IRAK4), and Toll–IL-1 recep- receptor (BAFF-R).78 During B-cell maturation, BAFF-R is
tor domain–containing adaptor protein (TIRAP), which are expressed first by immature B cells in the BM.79 In addition to
downstream signaling components of many Toll-like receptors BAFF-R, BAFF binds to 2 receptors termed transmembrane acti-
(TLRs).65 However, abnormalities in MZ B-cell numbers were vator, calcium modulator, and cyclophilin ligand interactor
not found in patients with mutations in Toll-like IL-1 receptor (TACI) and B-cell maturation factor (BCMA).80 These 3 recep-
domain–containing adapter inducing IFN-b (TRIF) and tors form a ligand-receptor system that includes the homologous
uncoordinated-93B (UNC93B). Both factors are essential for sig- ligand a proliferation-inducing ligand (APRIL). APRIL, in con-
naling through TLRs located in endosomes, such as TLR3, TLR7, trast to BAFF, binds only TACI and BCMA but does not interact
TLR8, and TLR9. Thus the authors postulated that the develop- with BAFF-R (Fig 2).
ment, homeostasis, or both of human MZ B cells might depend BAFF-R expression increases when transitional B cells differ-
on TIRAP-transmitted signals induced by TLRs expressed on entiate into MZ and follicular B cells. However, BAFF-R is not
the cell surface, such as TLR10. found on long-lived plasma cells in the BM, which express
Two studies of patients with severe immunodeficiencies have BCMA,81 whereas TACI is expressed by B cells of the MZ and
uncovered dedicator of cytokinesis 8 (DOCK8) as an important switched memory B cells.82
factor for the generation of humoral immune responses.66,67 The role of BAFF-R in B-cell survival was first demonstrated in
DOCK8 is a guanine exchange factor interacting directly with mice.78,83 The main function of BAFF-R is to provide survival
the Rho GTPase cell division control protein 42 (cdc42),68 a crit- signals for immature and mature B cells.84,85 Mice with a deletion
ical component of signaling pathways regulating cell morphol- in the Baff-r or Baff genes showed a marked reduction in B-cell
ogy69 and division.70 The clinical manifestations linked to numbers and a developmental block at the transitional T2 stage.
DOCK8 deficiency are characterized by a highly increased sus- Specific antibody production was low in BAFF-R–deficient
ceptibility to bacterial infections and to increased IgE levels, mice but increased after immunization with T cell–independent
resulting in an hyper-IgE syndrome.66 DOCK8-deficient patients and T cell–dependent antigens.83 The phenotype of BAFF-R–de-
lack MZ B cells, do not produce protective antibodies after vacci- ficient mice is less severe than in Taci2/2 mice because they show
nation, and have extremely low numbers of switched memory a robust T cell–independent antibody response that can be main-
B cells.66,67,71 In addition to the role of DOCK8 as a guanine tained by TACI. Reflecting the main role of BAFF-R in survival,
nucleotide exchange factor regulating cytoskeletal remodeling the overexpression of transgenic Bcl2 in Baff-r2/2 mice allowed
and immunologic synapse formation, it was recently shown that mature B cells to develop.83
DOCK8 associates with MyD88 and serves as an adaptor in the In human subjects BAFF-R deficiency was discovered by
TLR9 signaling pathway in B cells.72 Because B-cell prolifera- screening patients with common variable immunodeficiency
tion was affected in DOCK8-deficient B cells after TLR9 but (CVID) with low numbers of B cells.86 In addition to a strong
not after CD40 costimulation, DOCK8 might be more important B-cell lymphopenia, B-cell phenotyping revealed a relative in-
for T-independent than for T-dependent B-cell responses. crease in numbers of transitional B cells. The strong reduction
Apart from DOCK8, another regulator of the cytoskeletal in MZ and switched memory B-cell numbers was accompanied
reorganization, termed L-plastin, was shown to be essential for by reduced serum IgM and IgG levels and impaired T cell–inde-
the development of murine MZ B cells.73 In addition to a greater pendent immune responses against pneumococcal polysacchar-
than 80% reduction in MZ B-cell numbers, Lpl2/2 mice have only ides. Unlike in other patients with CVID, IgA serum levels
60% of follicular B cells. As an actin-binding protein, L-plastin were normal, and IgA1 plasma cells were found in the gut.86
plays a role in BCR signaling, as well as in S1P-directed position- Likewise, Baff2/2 mice have normal IgA levels.87 In contrast to
ing of B cells into the MZ zone. BAFF-R deficiency, deletion of Taci88 or April89 in mice and
Another defect disturbing cytoskeletal organization and B-cell mutations in the TACI-encoding TNFRSF13B gene in human sub-
responses is caused by mutations in the WAS gene, resulting in jects have significantly reduced IgA levels.90,91 Therefore it
Wiskott-Aldrich syndrome (WAS).74 Because it encodes a critical seems that serum IgA concentrations depend on functional
regulator of actin polymerization, mutations in WAS result in TACI-APRIL interactions.
defective B-cell migration and breaking of B-cell tolerance.75 TACI deficiency is also associated with humoral immunodefi-
Therefore in addition to immunodeficiency, patients with WAS ciency, as documented by severely decreased T cell–independent
nnn 2013
FIG 2. BCR and BAFF-R signaling cascades in B cells. Antigen binding to surface IgM induces conformational
changes in the BCR, including the signaling components Ig-a (CD79A) and Ig-b (CD79B). The conformational
changes allow binding of the tyrosine kinases, such as spleen tyrosine kinase (SYK), and initiates several key
signaling cascades composed of protein phosphorylation and processing reactions. Spleen tyrosine kinase
phosphorylates Ig-a/Ig-b and the adapter protein SLP65 (BLNK), serving as scaffold for other substrates,
including BTK. Phosphorylation of downstream substrates, including the phosphatidylinositol-4.5 bisphos-
phate 3-kinase (PI3K) and phospholipase C (PLCg2), activates downstream transcription factors, such as
NF-kB1, nuclear factor of activated T cells (NFAT), and serum response factor (SRF). AKT (PKB) induces pro-
tein synthesis and cellular fitness, prolonging cell survival. BCR signals activate sphingosine-kinase
1 (SPHK1). The enzyme phosphorylates sphingosine (Sph), a metabolite of the membrane lipid sphingomyelin,
to generate S1P, which is required by TNF receptor–associated factor 2 (TRAF2) as a cofactor. BAFF binds to
BAFF-R and with lower affinity to TACI and BCMA, whereas APRIL only binds to TACI and BCMA. BAFF-R is
expressed by all B cells, TACI by MZ and memory B cells, and BCMA by activated B and plasma cells. The
alternative NF-kB pathway is activated by BAFF binding to BAFF-R. Conformational changes of BAFF-R promote
TRAF binding and allow release of the NF-kB–inducing kinase (NIK). NIK activates inhibitor of NF-kB kinase a
(IKKa), which phosphorylates NF-kB2 p100. Phosphorylated p100 is processed on ubiquitination into the active
form p52, which assembles with relB into a transcriptional activator upregulating prosurvival genes. BAFF-R
signaling also induces AKT and protein synthesis, thus increasing cellular fitness. DAG, Diacylglycerol; IP3,
inositol-1,4,5-trisphosphate; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein;
MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PKC, protein kinase C.
immune responses to polysaccharide antigens. Correspondingly, in some TACI-deficient patients also supports the role of TACI
TACI is expressed on MZ B-cell subsets, strong responders to in immune responses to blood-borne pathogens. It has also been
T cell–independent type II antigens. Because TACI-deficient mice suggested that decreased numbers of BAFF-binding receptors
have high numbers of B cells, it was proposed that TACI acts as a caused by the absence of TACI give rise to more circulating
negative regulator of B-cell survival. Consistent with this, TACI- BAFF binding to BAFF-R, thus supporting B-cell survival.94 In
deficient mice tend to have lymphoproliferative disorders and human subjects it was recently shown that the numbers of BAFF
autoimmune diseases with high titers of autoantibodies.92,93 binding sites can regulate steady-state BAFF concentrations.95
Patients with CVID share immunologic features of Taci2/2 High levels of BAFF, as demonstrated by BAFF transgenic
mice, including immunodeficiency, lymphoproliferation, and mice, increase numbers of mature B cells and lead to a progressive
autoimmunity. In fact, 5% to 10% of patients with CVID carry autoimmune disease similar to systemic lupus erythematosus.96
at least 1 germline mutation in TACI.90,91 B cells from TACI- In the human spleen the areas surrounding the MZ are
deficient patients do not initiate class-switch recombination colonized by a special subtype of neutrophils termed B-cell
(CSR) when cocultured with either APRIL or BAFF.91 Low IgA helper neutrophils (NBH cells), which are distinct from their circu-
and IgG antibody titers in TACI-deficient patients underline the lating counterparts, NC cells.97 The MZ colonization with NBH
role of this receptor in CSR in human subjects. The absence of cells occurs through a noninflammatory pathway in the absence
pneumococcal cell wall polysaccharide-specific IgG antibodies of an infection. NBH cells provide an MZ B cell–interacting
structure facilitating antibody production and SHM by activating components and receptor-ligand pairs are required for successful
MZ B cells with APRIL and BAFF. In contrast to TH cells, which B/T-cell interactions, such as CD40,106 CD40 ligand,107 or induc-
support follicular B cells in the GC reaction, NBH cells induce a ible costimulator,108 which is expressed by follicular TH cells.
potent extrafollicular B-cell response against T cell–independent Similar to these defined genetic defects, patients with CVID
antigens. Correspondingly, patients with congenital neutropenia with impaired plasma cell development have almost no switched
had fewer MZ B cells with less SHMs. memory B cells. This suggests that the development of switched
The role of BCMA as a survival factor for plasma cells is still memory cells is intimately connected to plasma cell development.
unclear. Originally, it was described that mice deficient for However, it is still unknown where exactly switched memory
BCMA had a normal B-cell compartment. However, the survival B cells branch off from the path to plasma cell development.
of long-lived plasma cells was impaired.98 On a Fas/CD95- The human memory B-cell compartment is far less uniform
deficient background, Bcma2/2 mice have a fatal lymphoprolifer- than originally thought. A recent publication has defined the
ative syndrome caused by an enormous increase in both short- and existence of several memory B-cell subsets differentiating from 3
long-lived plasma cells.99 The pathologic features include high different origins.64 The origin of CD272IgG1 memory B cells is
titers of autoantibodies against nuclear antigen, rheumatoid fac- the spleen, whereas CD271IgM1IgD2 and class-switched
tor, and deposition of immune complexes. Similar to Bcma2/2 CD271IgG/IgA1 memory B cells develop in the GCs. Sharing
mice, Fas2/2Bcma2/2 mice had lower numbers of BM plasma common features with IgA1 B cells in the lamina propria,
cells. Therefore BCMA might have dual function. Because CD272IgA1 B cells can come from the gut, where they are gen-
BCMA is rapidly upregulated together with Fas on activated erated outside of the GCs, even in CD40 ligand–deficient patients.
B cells, both receptors seem to control synergistically B-cell pro- This memory B-cell subset is characterized by a limited replica-
liferation and selection in the GC reaction. However, in the BM tion history and dominant IgA2 H-chain and Igl L-chain use.
BMCA might act as a survival factor for long-lived plasma cells. Switched memory B cells also differ from their precursors by
Synopsis: B-lymphocyte survival depends on BAFF-R signal- their requirements for survival signals. Treatment of patients with
ing because BAFF-R deficiency blocks B-cell development at systemic lupus erythematosus with the BAFF-neutralizing mAb
the stage of transitional B cells. Mutations in the related receptor belimumab revealed that persistence of memory B cells does not
TACI impair the development of IgA- and IgG-secreting plasma require BAFF/BAFF-R interactions, as is the case for transitional,
cells and promote lymphoproliferation. NBH cells surrounding the follicular, and MZ B cells.109
splenic MZ are critical for the production of BAFF and APRIL, 2 Treatment of patients with autoimmune diseases with the B
TNF-like ligands binding to BAFF-R and TACI, respectively. cell–depleting anti-CD20 mAb rituximab revealed that plasma
cells in human subjects can be both short and long lived.110,111
Long-lived plasma cells survive in specialized niches of the
DEVELOPMENT AND MAINTENANCE OF MEMORY BM112,113 or through the continuous, antigen-driven differentia-
B CELLS AND PLASMA CELLS tion of memory B cells.114 Analyses of serum immunoglobulin
Studies with survivors of the 1918 influenza pandemic have titers against viral antigens or vaccines in rituximab-treated
shown that antigen-specific memory B cells can persist for patients, whose B cells were entirely eliminated, showed that
decades in the absence of antigen.100 Antigen-induced T cell–de- CD202 long-lived plasma cells can persist for years. Part of the
pendent B-cell activation takes place in GCs in the spleen and long-lived plasma cell repertoire of the BM is replaced by newly
lymph nodes and leads to development of plasma and switched incoming plasma cells generated during acute immune
memory B cells.101,102 B-cell activation in GCs upregulates responses.115 It has been widely accepted that long-lived plasma
AID. The enzyme deaminates cytidine residues in the DNA, cells originate from B cells activated in concert with T-follicular
thus generating uracil residues, which are marked by the uracil- helper cells in the GC reaction. However, recent findings revealed
N-glycosylase (UNG) to be recognized by repair enzymes. This T cell–independent methods of long-lived plasma cell formation.
process is part of the enzymatic machinery generating SHMs in For example, long-lived plasma cells can be generated in T cell–
the variable region of the expressed immunoglobulin gene.103 deficient mice that have been treated with haptenated LPS.116
Hypermutations in the variable regions increase or decrease the Although IgM antibodies were thought to be secreted by short-
affinity of antibodies to antigen. Therefore they represent, in lived plasma cells, it has now been reported that chronic infec-
addition to the immunoglobulin gene rearrangement in the BM, tions with Ehrlichia muris induce CD138highIgMhigh BM plasma
a second diversification step. This has evolved to transform anti- cells, contributing to a long-lasting IgM titer.117
bodies with intermediate or low affinities into highly specific tools Development of both short-lived and long-lived plasma cells
against pathogenic antigens. In parallel, immunoglobulins change depends on the expression of the transcription factor B lympho-
their effector functions by replacing the IgM constant region cyte–induced maturation protein 1 (Blimp-1),118 a master gene of
against those of IgG, IgA, or IgE. This process, termed immuno- plasma cell development. Blimp-1 induces X-box binding protein
globulin CSR, is catalyzed by components of the SHM machin- 1 (XBP1),119 a key transcription factor, to initiate the unfolded
ery, including AID and enzymes of the nonhomologous protein response. Blimp-1 activity is also required to downregu-
end-joining complex. Ultimately, GC B cells become long-lived late the transcription factor paired-box protein 5 (PAX5),120 the
memory B cells or plasma cells. They can reside either in second- master gene for B-cell development induced in common lympho-
ary lymphoid organs or migrate to the BM. Also shown by cyte progenitor cells to initiate B-lineage commitment.
humoral immunodeficiencies, the development of long-lived The guidance of plasma cells to their niches is achieved by
memory and plasma cells is interrupted by mutations in genes changing the responsiveness to tissue-specific chemokines.
encoding components of the SHM/CSR machinery, such as Downregulation of GC-related chemokine receptors, such as
AID,60 UNG,104 and postmeiotic segregation increased 2 CXCR5, as well as upregulation of CXCR4, promotes plasma cell
(PMS2).105 As shown by humoral immunodeficiencies, other homing to sites with high expression of the CXCR4 ligand
nnn 2013
CXCL12, which is produced, for example, by BM stromal anergy and deletion, secondary rearrangements of L-chain genes
cells.121-123 expressed by autoreactive, IgM1 immature B cells in the BM
Long-lived plasma cells are terminally differentiated and seem were found to be one of the key regulatory mechanisms. This pre-
not to divide. Therefore they need survival signals to ensure long- vents the exit of highly autoreactive B cells from the BM into the
term existence. Potent in vitro plasma cell survival factors are circulation.136,137 Which of these mechanisms plays a role in the
IL-6 and ligands for CD44, such as hyaluronic acid.124 selection of human B cells and in shaping the B-cell repertoire in
Recently, it has been shown that human and murine plasma human subjects? The comparison of antibody specificities be-
cells express CD28 together with its ligands, B7.1 and B7.2. tween newly formed immature B cells in the BM, circulating tran-
CD28 is expressed on T cells, providing costimulatory signals on sitional B cells, and mature B cells has clearly shown that the
binding to B7 molecules on antigen-presenting cells. Mice repertoire of immature B cells contains a large proportion of spec-
deficient for CD28 have been used to uncover a role of this ificities recognizing self-antigens, such as insulin or DNA.138 In
receptor in both short-lived and long-lived plasma cells. This is contrast, these specificities represent only a small part within
because plasma cells secrete higher levels of antibodies in the the repertoire of mature B cells. Repertoire analysis with B cells
absence of CD28. Because the deficiency in the B7 molecules from patients with defects in the BCR,139 TLRs,140 and accessory
causes the same phenotype,125 CD28-B7 interactions seem to receptor signaling141,142 revealed that in human subjects BCR and
negatively regulate the rate of antibody secretion by plasma TLR signals are critical in guiding the selection of B cells.143
cells.126 However, in malignant plasma cells CD28 signaling These analyses show that the human immune system is equipped
was shown to induce cell survival, thus protecting them against with an effective counterselection system precluding the exit of
apoptosis induced by cytostatics.127 autoreactive B cells into the pool of mature, circulating B cells.
Despite these extensive studies on the role of ligands, receptors, However, autoimmune diseases and the many specificities of au-
signaling components, and transcription factors, the mechanisms toantibodies clearly prove that this selection process leaves many
for how long long-lived plasma cells persist in the BM are not yet holes, allowing autoreactive B cells to sneak through. Where are
completely understood. these holes, and which mechanisms might allow autoreactive
Synopsis: In T-dependent immune responses, class-switched B cells to develop into short- or even long-lived plasma cells?
memory B cells and plasma cells develop in GCs. Mutations The anti-HEL IgM/D X HEL transgenic mouse model clearly
affecting components of the class-switch and SHM machinery showed that B cells expressing surface IgM/IgD with high affinity
prevent the formation of memory B and plasma cells expressing to soluble HEL as autoantigen are ‘‘silenced’’ because their BCR
IgA, IgG, and IgE. The human memory B-cell compartment is does not respond to antigen triggering. The unresponsiveness is
more complex than originally thought, including extrafollicular mainly due to the different rates of receptor internalization
memory B lymphocytes and cells originating from the gut and between surface IgM and surface IgD because surface IgD is
spleen. Nondividing, long-lived plasma cells reside in the BM. more stable144 and less rapidly downregulated than IgM on bind-
These cells are not eliminated by rituximab treatment. Fig 3 sum- ing to HEL as a self-antigen.145
marizes genetic defects interrupting B-cell development and Regulation of B-cell responsiveness by different recycling
activation. rates of autoantigen-binding surface IgM and surface IgD has
very recently been shown by Zikherman et al146 in a transgenic
mouse model. It is based on the observation that transcription
B-CELL TOLERANCE of nuclear receptor 77 (nur77), a steroid-thyroid hormone retinoid
It was already recognized by Paul Ehrlich, after he postulated receptor family member, is rapidly induced after antigen binding
the ‘‘side-chain-theory’’ in 1897 to describe the function of the yet to the BCR. Expressing a green fluorescent protein (GFP) trans-
to be discovered antibodies, that reactivity against self-antigens gene under the transcriptional control of nur77 regulatory ele-
represents a thread to the organism.128 Bearing this in mind, he ments, B cells of these mice emit green fluorescence when the
coined the term ‘‘horror autotoxicus.’’ Decades later, Frank BCR binds antigen. There the system is an ideal reporter to mon-
Mcfarlane Burnet developed the concept of clonal deletion or se- itor BCR engagement in vivo. Surprisingly, and in contrast to
lection of autoreactive or nonautoreactive B cells, respectively. current concepts, all mature B cells expressed nur77-driven
This concept explains how reactivity against foreign antigens GFP, although at different intensities, suggesting that all B cells
and pathogens can be achieved without generating a large spec- are autoreactive. Autoantigen binding was detected first in transi-
trum of potentially harmful autoreactivities.129 With the onset tional B cells on entering the spleen, whereas immature and pre-B
of transgenic and knockout/knock-in mouse technology, it was cells in the BM did not activate nur77-GFP expression. This might
then possible to prove these concepts directly for defined antibody be explained by assuming that the signals sensed by autoantigen-
specificities in vivo. Chris C. Goodnow developed a very elegant binding immature B cells in the BM might not be strong enough to
mouse model to demonstrate clonal B-cell anergy and clonal de- upregulate nur77 transcription. However, in the spleen nur77-
letion as mechanisms evolved to silence autoreactive B cells. The GFP fluorescence intensity correlated directly with the pattern
model is based on transgenic mice expressing hen’s egg lysozyme of IgM and IgD surface expression. The highest GFP levels
(HEL)–specific IgM/IgD immunoglobulins from m-d/k trans- were found in IgDhiIgMlo follicular B cells. Because IgDhiIgMlo
genes that were combined with another mouse strain expressing B cells had a stronger response by Ca21 flux to anti-IgD than to
transgenic HEL either in a soluble or membrane-bound IgM cross-linking, these follicular B cells have all the attributes
form.130-132 It has been widely used to investigate the selection of silenced anergic B cells, as described in the HEL model. In hu-
mechanisms acting on B cells and the molecules involved in man subjects most of the follicular B cells have an IgDhiIgMlo
this process. Clonal deletion of autoreactive B cells at the stage phenotype. Therefore a major part of our B-cell repertoire seems
of immature B cells was also shown by several other groups using to be formed by self-reactive B cells that are kept alive by BAFF/
different transgenic mouse models.133-135 In addition to clonal BAFF-R signaling waiting to be activated by TH cells on antigen
FIG 3. Genetic defects interrupting B-cell development. Genetic defects interrupting B-cell development at
different stages are boxed in red.
binding. Thus everyone has a large repertoire of autoreactive antigens and self-antigens found only outside the GC, the latter
B cells forming a reservoir of clones that have the potential to dif- might serve as targets for high-affinity autoantibodies.
ferentiate in the GC reaction into plasma cells secreting highly
autoreactive pathogenic autoantibodies.147,148
In another anti-HEL/HEL transgenic mouse model, it was SUMMARY
shown that the development of such clones is regulated by their Many different lines of genetically engineered mice carrying
affinity for the self-antigen and by the distance of the autoantigen germline mutations in immunologically important genes were
from the GC, in which autoreactive B cells are activated by cross- and still are indispensable to study the molecular mechanisms
reactive foreign antigens.149 Sufficiently high levels of self- regulating B-cell development, selection, and response. However,
antigens within the GC effectively prevent the differentiation of the comparison of mouse mutants with corresponding genetic
autoreactive GC B cells into plasma cells, even if their BCRs defects in human subjects revealed significant differences
are highly cross-reactive to foreign antigens. However, if self- between human and murine B cells with respect to early phases
antigens are expressed in other tissues and organs outside of the of development, subset composition, and responses to antigens.
GC, self-reactive B cells escape deletion and can be positively Human B-cell development, for instance, does not depend on
selected to initiate a high-affinity autoimmune response.149 This IL-7, whereas mutations in genes like BTK and BLNK block
mechanism might account, for instance, for the presence of maturation of human but not murine pre-B cells. Human subjects,
cross-reactive autoantibodies in antiviral immune responses150 but not mice, have circulating MZ B cells carrying somatic
and in hepatitis C–related autoimmune thrombocytopenia. There- mutations right after birth, and human subjects have a large
fore the balance between the relative affinity of BCRs to self- compartment of circulating class-switched memory B cells that is
antigens and foreign antigens and the distance of self-antigens much smaller in adult mice. Because primates and rodents
from activated B-cell clones in the GC are key parameters in diverged from a common ancestor at least 65 million years ago,
determining the fate of self-reactive GC B cells and in discrimi- such differences reflect the adaptation of the respective immune
nating between protective immune responses and autoimmunity. systems to the different physiologies, the different life spans, the
Fig 4 summarizes checkpoints for autoreactive B cells. environment, pathogens, commensal agents, and so on.
Synopsis: In the BM autoreactive B cells are rescued by second- Despite the increase in knowledge about human B-cell
ary rearrangement of their L-chains, resulting in new antibody biology, many basic questions still remain. For example, how
specificities. In the spleen most if not all B cells seem to bind do GC B cells decide whether they prefer to develop into
self-antigens to some extent. Cells with higher affinity are switched memory B cells or plasma cells. Do different switched
rendered unresponsive to IgM-dependent signaling. They can memory B-cell subsets have different functions in immune
be rescued by antigen binding to their BCR in cooperation with responses? Do they develop into short- or long-lived plasma
T-cell help. Self-antigens expressed in GCs block the formation cells? Which survival signals keep memory B cells and plasma
of memory and plasma cells expressing high-affinity autoanti- cells alive over decades, or how can we exploit the character-
bodies. Because B cells do not discriminate between foreign istics of human B cells to improve vaccination? With the current
nnn 2013
FIG 4. B-cell tolerance models. If immature B cells bind to self-antigens, they can undergo secondary
rearrangement of L-chain loci to generate new specificities with lower affinity to self-antigens. Strongly
binding cells will die in the BM; all other cells emigrate to the spleen, where BCRs bind to self-antigens with
various affinities. Strong binding can lead to exclusion from B-cell follicles, and intermediate binding can
lead to enhanced IgM internalization and functional anergy. Binding of (foreign) antigens to IgD combined
with T-cell help rescues anergic B cells and allows activation and entry into the GC reaction. Cells exposed to
self-antigens in the GCs are not selected into the pool of long-lived switched memory B cells and plasma
cells. B cells expressing BCRs reactive against self-antigens located outside of the GCs are selected into the
memory B lymphocyte and plasma cell pool. This mechanism might account for the generation of
autoreactive B cells in patients with autoimmune diseases.
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Mechanisms of allergic diseases

B-cell biology and development

B cells develop from hematopoietic precursor cells in an ordered

From athe Centre of Chronic Immunodeficiency, University Medical Centre Freiburg,

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