Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity

Abstract

B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated co-stimulatory receptor expression or intracellular signalling thresholds can lead to diseases. For example, autoimmune diseases can result from altered regulation of B cell responses leading to the emergence of high-affinity autoreactive B cells, autoantibody production and tissue damage. The exact cause(s) of defective B cell responses in autoimmune diseases remains unknown. However, there is evidence that defects or mutations in genes that encode individual intracellular signalling proteins lead to autoimmune diseases, thus confirming that defects in intracellular pathways mediate autoimmune diseases. This review provides a synopsis of current knowledge of signalling proteins and pathways that regulate B lymphocyte responses and how defects in these could promote autoimmune diseases. Most of the evidence comes from studies of mouse models of disease and from genetically engineered mice. Some, however, also come from studying B lymphocytes from patients and from genome-wide association studies. Defining proteins and signalling pathways that underpin atypical B cell response in diseases will help in understanding disease mechanisms and provide new therapeutic avenues for precision therapy.

Full text

Intracellular B Lymphocyte Signalling and the Regulation
of Humoral Immunity and Autoimmunity
Taher E. Taher
1
&Jonas Bystrom
1
&Voon H. Ong
2
&David A. Isenberg
3
&
Yves Renaudineau
4
&David J. Abraham
2
&Rizgar A. Mageed
1
Published online: 29 April 2017
#The Author(s) 2017. This article is an open access publication
Abstract B lymphocytes are critical for effective immunity;
they produce antibodies and cytokines, present antigens to T
lymphocytes and regulate immune responses. However, be-
cause of the inherent randomness in the process of generating
their vast repertoire of antigen-specific receptors, B cells can
also cause diseases through recognizing and reacting to self.
Therefore, B lymphocyte selection and responses require tight
regulation at multiple levels and at all stages of their develop-
ment and activation to avoid diseases. Indeed, newly generat-
ed B lymphocytes undergo rigorous tolerance mechanisms in
the bone marrow and, subsequently, in the periphery after their
migration. Furthermore, activation of mature B cells is regu-
lated through controlled expression of co-stimulatory recep-
tors and intracellular signalling thresholds. All these regulato-
ry events determine whether and how B lymphocytes respond
to antigens, by undergoing apoptosis or proliferation.
However, defects that alter regulated co-stimulatory receptor
expression or intracellular signalling thresholds can lead to
diseases. For example, autoimmune diseases can result from
altered regulation of B cell responsesleading to the emergence
of high-affinity autoreactive B cells, autoantibody production
and tissue damage. The exact cause(s) of defective B cell
responses in autoimmune diseases remains unknown.
However, there is evidence that defects or mutations in genes
that encode individual intracellular signalling proteins lead to
autoimmune diseases, thus confirming that defects in intracel-
lular pathways mediate autoimmune diseases. This review
provides a synopsis of current knowledge of signalling pro-
teins and pathways that regulate B lymphocyte responses and
how defects in these could promote autoimmune diseases.
Most of the evidence comes from studies of mouse models
of disease and from genetically engineered mice. Some, how-
ever, also come from studying B lymphocytes from patients
and from genome-wide association studies. Defining proteins
and signalling pathways that underpin atypical B cell response
in diseases will help in understanding disease mechanisms and
provide new therapeutic avenues for precision therapy.
Keywords Blymphocytes .Intracellular signalling .
Autoimmune diseases
Introduction
Autoimmune diseases are pathological conditions in which
defects in immunological tolerance to self lead to the initiation
of effector immunity to self, chronic inflammation and tissue
and organ damage. These diseases affect about 5–10% of
human populations worldwide and cause significant degrees
of morbidity and early death [1]. The cause of most autoim-
mune diseases remains largely unknown. However, suscepti-
bility to develop these diseases is associated with a combina-
tion of genetic, environmental and hormonal factors [2]. These
factors combine to cause defects in the survival and selection
of self-reactive T and B lymphocytes. Evidence from the last
50 years of research indicates that T lymphocytes initiate au-
toimmune responses in conjunction with, or following
*Rizgar A. Mageed
r.a.mageed@qmul.ac.uk
1
Centre for Experimental Medicine and Rheumatology, William
Harvey Research Institute, Queen Mary University of London,
Charterhouse Square, London EC1M 6BQ, UK
2
Centre for Rheumatology and Connective Tissue Diseases, Royal
Free Hospital, University College London, London, UK
3
Centre for Rheumatology, University College London, London, UK
4
Immunology Laboratory, University of Brest Medical School,
Brest, France
Clinic Rev Allerg Immunol (2017) 53:237–264
DOI 10.1007/s12016-017-8609-4
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incitement by, B lymphocytes. In addition to autoantibody
production, there is compelling evidence that B lymphocytes
also contribute to the development of the autoimmune dis-
eases through mechanisms such as autoantigen presentation
to activate autoreactive T cells and/or promote their polariza-
tion to produce disease-promoting/perpetuating cytokines. In
this respect, it is perhaps revealing that a significant proportion
of genetic susceptibility risk factors to develop autoimmune
diseases corresponds with defects in the regulation of B cell
responses, intracellular signalling and tolerance induction.
These observations highlight changing perceptions about the
role played by B cells in autoimmune diseases (Fig. 1;
Tab les 1and 2). The importance of these roles is supported
by the therapeutic benefit gained from depleting B cells in
patients with a range of autoimmune diseases. For example,
patients with diseases such rheumatoid arthritis (RA) [71],
type 1 diabetes (T1D) [72], anti-neutrophil cytoplasmic
antibody (ANCA) vasculitis [73], multiple sclerosis (MS)
[74], systemic sclerosis (SSc) [75,76], primary Sjögren’ssyn-
drome [77–80] and systemic lupus erythematosus (SLE)
[81–83] benefit from therapeutic depletion of B cells. Of note
in this respect is that B cell-depleting therapy has a clinical
benefit without significantly affecting autoantibody levels,
suggesting that, perhaps, other B cell functions, including an-
tigen presentation and cytokine production could be critical
aspects of B cell involvement in the pathogenesis of the auto-
immune diseases.
The need for, and the ability to generate, a vast B cell
repertoire to combat a universe of pathogens requires
tolerance checkpoints and exquisite fine-tuning of B cell
receptor (BCR) signalling to limit the emergence of path-
ogenic autoreactive B cells. Highly coordinated and inte-
grated intracellular signalling transduced through the
BCR and other co-stimulatory receptors, including innate
Fig. 1 Signalling molecules and pathways in regulating B cell selection
and responses. The diagram illustrates major signalling proteins/
pathways involved in B cell physiology and whose regulation has been
reported to be altered/defective in B cells in autoimmune disease. Proteins
indicated in yellow are kinases, red for phosphatases, pink for proteins
involved in ubiquitination, black for transcription factors and brown for
adaptor proteins. Arrows indicate proteins that promote positive
signalling, while blunt-ended lines indicate the protein negatively
regulate signalling. Minus signs (encircled) indicate proteins/signalling
pathways are reduced in mice and/or patients with autoimmune diseases
or that reduction by genetic engineering promotes B lymphocyte
hyperactivity and autoimmune disease. Positive signs (encircled)
indicate enhanced activity of the proteins/signalling pathways in B
lymphocytes from patients with autoimmune disease, mouse models or
that their genetic manipulation promotes autoimmunity
238 Clinic Rev Allerg Immunol (2017) 53:237–264
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Tab le 1 Reported defects in signalling molecules and pathways and their impact on B cell responses and association with diseases
Signalling
molecule
Encoding
gene
Effect on B cell response and disease in animal models Association with human diseases
Lyn LYN B cell hyperactivity causing lupus-like disease in gene-deficient mice [3] Reduced cellular expression leading to IgG autoantibody and cytokine production [4]
SHP-1 PTPN6 Selective deficiency in B cells promotes systemic autoimmune disease [5] Reduced cellular expression and SNP association with SLE [6,7]
LYP PTPN22 Expression of the R619W variant in B cells causes systemic autoimmunity [8] The R619W is a risk allele in several systemic autoimmune diseases [9,10]
CD45 CD45 Mutation in the inhibitory wedge causes autoantibody production leading to
severe glomerulonephritis [11]
Decreased expression, increased translocation signalling domains and altered isoform
expression associated with SLE [12]
BTK BTK Over expression increases plasma cell numbers, spontaneous germinal centre
formation, autoantibody production and lupus-like disease [13,14]
Gene defect causes X-linked agammaglobulinemia, reduced B cell numbers and deficiency in
all immunoglobulin isotypes [15]. Increased phosphorylation in SLE B cells [16]
CD22 CD22 Deficiency causes autoantibody production and lupus-like disease [17,18] Splicing defect causes expression of a truncated CD22 expression and increased leukemic B
cell precursors [19]
CD19 CD19 Altered expression correlates with autoimmune diseases [20,21] Increased expression in patients with systemic sclerosis; polymorphism is associated with
susceptibility to SLE [22,23]
FCγRIIB FCγRIIB Deficiency causes SLE-like autoimmune disease and renders non-permissive
H2B mouse strain susceptible to collagen-induced arthritis (CIA) [24,25]
Decreased expression in SLE [26]
SHIP-1 INPP5D B cell-specific deficiency causes lupus-like disease [27] Hypophosphorylated in SLE patients [28]
PTEN PTEN B cell-specific deficiency causes hyperresponsiveness and anti-ssDNA autoanti-
body production [29,30]
Decreased expression in SLE patients [31]
PTP1B PTPN1 B cell-specific deficiency causes systemic autoimmunity in aged mice [32] Reduced expression in RA patients [32]
Act1 TRAF3IP2 Deficient mice develop Sjögren’s syndrome-like disease [33] Susceptibility gene in psoriatic arthritis and SLE and SNP associated with RA [34–36]
A20 TNFAIP3 B cell-specific deficiency causes systemic autoimmunity [37–39] SNPs associated with SLE and RA [40,41]
Cbl CBL B cell-specific deficiency of c-Cbl and Cbl-b causes systemic autoimmunity [42] SNP associated with SLE and type 1 diabetes [43,44]
WASP WA S B cell-specific deficiency causes systemic autoimmune disease [45] About 40% of Wiskott-Aldrich syndrome patients develop autoimmunity [46]
The table summarizes data on reported clinical and immunological phenotypes in engineered mice gene deficient/mutated for signalling proteins. The table also provides some of the reported data on defects
in the expression or function of the corresponding protein in patients
Clinic Rev Allerg Immunol (2017) 53:237–264 239
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pattern recognition receptors such as Toll-like receptors
(TLRs), costimulatory/inhibitory molecules and cytokine
receptors, are essential for regulating the outcome of
BCR engagement by antigens. The available evidence
indicates that minimal alterations in established thresh-
olds of activating or inhibiting intracellular signalling
can lead to a breakdown of immunological tolerance.
This review provides a synopsis of current knowledge
of signalling molecules and pathways involved in medi-
ating and regulating B cell responses and how changes
could lead to aggressive self-reactivity and autoimmune
diseases.
Tabl e 2 Polymorphisms and mutations in genes encoding co-receptors, signalling proteins, transcription factors and cytokines/chemokines that are
associated with human diseases
Gene Chromosome Disease association Protein Function in B cells Reference
PTPN22 1p13.2 RA, SLE, GT, T1D LYP Lymphocyte-specific tyrosine phosphatase
a
[47]
NCF2 1q25 SLE p67phox Subcomponent of NADPH oxidase, ROS generation
a
[48]
IL10 1q31-q32 SLE, UC, T1D IL-10 Anti-inflammatory cytokine
a
[49]
PTPRC 1q31.3-q32.1 SLE, RA, MS, T1D CD45 Membrane protein tyrosine kinases [50]
FCGR2A 1q23.2 SLE, RA IGFR2 Low-affinity IgG FC receptor
a
[51,52]
RASGRP3 2p25.1-p24.1 SLE GRP3 Signalling downstream of the BCR
a
[53]
BANK1 4q24 SLE, SSc, RA BANK1 Scaffold protein involved in BCR signalling [54]
IL21 4q27 SLE, PSO, CEL IL-21 Cytokine, class switch recombination, plasma cell
differentiation
a
[55]
BACH2 6q15 SLE, AS, ATD, CEL,
CD, MS, T1D, IBD, PSC
BACH2 Negative regulator of transcription
a
[50]
PRDM1-ATG5 6q21 SLE, RA, CD Blimp1 Differentiation and development of plasma cells
a
[49]
IKZF1 7p12.2 SLE, CD Ikaros TF, differentiation, development, self-tolerance
a
[53]
BLK 8p23-p22 SLE, SS, RA, SSc, pAPS BLK Tyrosine kinase, BCR signalling, development [56]
LYN 8q12 SLE Lyn Tyrosine protein kinase, BCR signalling [4,57]
CCL21 9q13.3 RA CCL21 Chemokine, germinal centre formation [58]
ETS1 11q23.3 SLE Ets1 TF, negative regulator of differentiation
a
[59]
CXCR5 11q23.3 SS CXCR5 Chemokine receptor, migration to B cell follicles
a
[60]
SLC15A4 12q24.32 SLE PTR4 Proton-coupled amino-acid transporter located in
endolysosomes, autoantibody production
a
[53,61]
ELF1 13q13 SLE Elf1 TF, binding the IgH enhancer
a
[62]
CSK 15q24.1 SLE Csk Increases BCR-mediated activation of mature B cells
a
[63]
ITGAM 16p11.2 SLE CD11B Regulation of BCR signalling
a
[64]
IRF8 16q24.1 SLE IRF8 TF, cell development
a
[65]
IKZF3 17q21 SLE Aiolos TF, downregulation of the pre-BCR
a
[65]
CD40 20q13.12 RA CD40 Co-stimulatory molecule, promotes antibody production [58]
IKBKE 1q32.1 SLE IKKI Phosphorylates IκBα
a
[50]
TNIP1 5q33.1 SLE, SS, PS NAF1 TNFAIP3 interacting protein
a
[49,60]
TNFAIP3 6q23 SLE, SS, RA, T1D
UC, CEL, PSO
A20 Ubiquitination and negative signalling regulator ubiquitin
editing enzyme
a
[58,60]
PRKCB 16p11.2 SLE PRKCB1 Member of the PKC family, BCR-dependent NF-κB
activation
a
[66]
UBE2L3 22q11.21 SLE, CD, RA, CEL UBE2L3 Ubiquinase, NFkB activation, plasmablast and plasma cell
development
a
[67]
IRAK1/MECP2 Xq28 SLE, RA Irak1 TACI-dependent Ig class switching via MyD88
a
[68,69]
REL 2p16.1 RA Rel Survival and proliferation
a
[70]
TRAF1 9q33.1 RA Traf1 CD40 and TLR signalling
a
[58]
The table lists polymorphic risk loci associated with the development of autoimmune diseases. The data are generated in GWAS and genes cited include
those that encode proteins with known functions in B lymphocytes
RA rheumatoid arthritis, SLE systemic lupus erythematosus, GT Graves thyroiditis, T1D type 1 diabetes, CEL coeliac disease, MS multiple sclerosis, CD
Crohn’s disease, PSO psoriasis, UC ulcerative colitis, AS ankylosing spondylitis, ATD autoimmune thyroid disease, JIA juvenile idiopathic arthritis, AA
alopecia areata, IBD inflammatory bowel disease, PSC primary sclerosing cholangitis, SS Sjögren’s syndrome, SSc systemic sclerosis, TF transcription
factor, BCR B cell receptor
a
Not specific for B cells
240 Clinic Rev Allerg Immunol (2017) 53:237–264
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Signals Controlling B Cell Development
and Functions
The BCR repertoire for antigens is vast, generated through
random recombination of germline V(D)J mini genes, to pro-
vide broad immunity against pathogens. However, an intrinsic
feature of generating this vast repertoire is the randomness
with which germline V(D)J mini genes are recombined. This
leads, in up to 80% of newly generated B cells, to the
generation of BCRs that recognize self (Fig. 2). There is,
therefore, a necessity for emerging B cells to undergo toler-
ance in the bone marrow and also subsequently in the periph-
ery for B cells that escape bone marrow tolerance or those that
emerge as a result of mutations in secondary lymphoid organs.
Newly generated B cells first encounter self-antigens in the
bone marrow, and their elimination or survival depends to a
great extent on the strength with which their BCRs bind self-
antigens and strength of the resulting intracellular signalling.
Fig. 2 Pathways of B cell development and differentiation. B cells are
generated from haematopoietic progenitor cells in the bone marrow. This
process involves the expression of B lineage cell-specific proteins and the
rearrangement of mini antibody V(D)J genes to generate the BCR
repertoire. During the pro-B cell stage, antibody heavy chains are first
generated by randomly rearranging and combining V, D and J mini genes.
Pre-B cells express the pre-B cell antigen receptor (BCR) on the cell
surface with the fully arranged heavy chain associated with the
surrogate light chain (red). At later stages, light chain V and J mini
genes are rearranged and a complete BCR is expressed in association
with the Ig-αand Ig-β(green) subunits of the BCR complex. Immature
B cells then undergo tolerance mechanisms with B cells recognizing
self-protein undergoing light chain editing, apoptosis or functional
inactivation (anergy). Surviving immature B cells then exit the bone
marrow and migrate to secondary lymphoid organs where they develop
into transitional (T) B cells. Transitional B cells can be subdivided into a
number of developmentalsubsets. These include T1 B cells that express a
high level of IgM and T2 B cells that express both IgM and IgD. These B
cells undergo a range of tolerance checkpoint and cells that recognize
self-antigens with high affinity are deleted. Cells with intermediate/low
affinity to self-antigens and those that do not recognize self survive and
circulate for about 3 weeks to survey the body for their target antigens.
Transitional B cells develop into either marginal zone (MZ) B cells or
follicular B cells. MZ B cells sample antigens and those that recognize
antigens expand independently of T cell help. For their expansion, MZ B
cells require TLR signalling to into short-lived plasma cells that produce
antibodies with limited avidity for their target antigens. Follicular B cells
are activated when they encounter their target antigens in the presence T
cell help. Activated follicular B cells then migrate to B cell follicles and
initiate somatic maturation in germinal centres. During this process, the
cells proliferate, acquire somatic mutations, produce antibodies with
higher avidity and class switch to IgG. Antigen-specific mature B cells
then leave germinal centres and differentiate into either plasma cells or
memory B cells. Plasma cells can either remain secondary lymphoid
organs or travel to bone marrow to produce antibodies. B1 cells comprise
a distinct subset of B cells that develop in the bone marrow and migrate to
the periphery (peritoneal and pleural cavities in mice). B1 cells produce
polyreactive IgM antibodies and partake in providing a first line of
immunity against pathogens
Clinic Rev Allerg Immunol (2017) 53:237–264 241
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Thus, recognition of self with high affinity initiates strong in-
tracellular signalling, and as a result, B cells undergo receptor
editing to replace nascent light chains that endow self-reactivity
or, if this fails, apoptosis or anergy [84–87]. To facilitate B cell
tolerance yet provide effective B cell immunity, intracellular
signalling is regulated by highly refined thresholds. These
thresholds regulate the magnitude and duration of intracellular
B cell signalling and the outcome of BCR engagement by
antigens. Subsequent to undergoing tolerance in the bone mar-
row, immature B cells migrate to the periphery where they will
need tonic signalling for their transition to full maturity in read-
iness to respond to antigens. Signalling thresholds are also set
for co-stimulatory receptors that modulate B cell responses
following antigen recognition. These co-stimulatory receptors
include CD40, TLR, BAFF and receptors for a range of other
cytokines. Most of these signals involve the activation of phos-
phatidylinositol 3 kinase (PI3K) and the canonical pathway of
NF-κB activation [88,89].
BCR-Mediated Signalling
Proximal BCR Signalling Initiates B Cell Development
and Responses
The BCR associates with a heterodimer of signalling proteins,
Ig-αand Ig-β(also known as CD79a and CD79b), to form the
BCR complex. The cytoplasmic domains of both Ig-αand
Ig-βhave immunoreceptor tyrosine-based activation motifs
(ITAMs). ITAMs initiate signalling when their tyrosine resi-
dues are phosphorylated following BCR engagement and
translocation to lipid raft signalling domains that contain the
Src family tyrosine kinase Lyn. Downstream, activation of
ITAMs generates a docking site for spleen tyrosine kinase
(Syk) recruitment and phosphorylation [89,90]. The activa-
tion of Syk is fundamental for initiating signalling cascades
leading to lymphocyte activation [90–92]. Substrates of acti-
vated tyrosine kinases are adaptor molecules that, in turn,
recruit other kinases to the BCR complex. B cell linker protein
(BLNK) is a Syk substrate with nine tyrosine residues that are
rapidly phosphorylated following engagement of the BCR
[92,93]. Phosphorylated BLNK is recruited to the plasma
membrane and this requires its association with CIN85. The
BLNK-CIN85 complex then coordinates the recruitment of
growth factor receptor-bound protein 2 (Grb2) and
phosphoinositide phospholipase C gamma (PLCγ)[94], a
process essential for B cell development and responses.
Defective Regulation of BCR-Mediated Signalling Leads
to Aberrant B Cell Responses and Autoimmune Diseases
Src Family Tyrosine Kinase Lyn Lyn is a key dual activity
kinase. It initiates BCR-mediated signalling by phosphorylat-
ing Ig-α/Ig-βITAMs but then regulates this signalling by
phosphorylating immunoreceptor tyrosine-based inhibition
motifs (ITIMs) in CD5, CD22 and FcγRIIB [95]. Thus,
Lyn-deficient mice develop spontaneous lupus-like autoim-
mune disease, splenomegaly and glomerulonephritis and pro-
duce anti-dsDNA autoantibodies [96,97]. In addition, BCR-
mediated calcium (Ca
2+
) influx is enhanced in B lymphocytes
in Lyn
−/−
, mice and there is accelerated class switching of anti-
dsDNA and anti-RNA autoantibodies [97]. Interestingly,
however, deletion of myeloid differentiation primary response
gene 88 (MyD88) in Lyn
−/−
mice, both globally or selectively
in B lymphocytes, suppresses B cell activation and class
switching of autoantibodies and ameliorates lupus disease
[98]. This finding suggests that aberrant B cell responses in
Lyn
−/−
mice are likely to be influenced not only by BCR-
mediated signalling bust also by signalling through TLRs.
In humans, there is evidence for reduced Lyn expression in
B lymphocytes from patients with SLE and that this reduction
impacts B cell responses. For example, B cells from Lyn-
insufficient SLE patients produce IgG autoantibodies to
dsDNA and disease-promoting cytokines in vitro [4]. The
association between Lyn insufficiency and SLE is supported
by genetic studies. Thus, single nucleotide polymorphism
(SNP) analyses and genome-wide association studies have
revealed that polymorphisms in LYN, as well as other Src
family tyrosine kinases including BLK, are risk factors for
susceptibility to SLE [56,99].
CD45 Tyrosine Phosphatase CD45 is a membrane protein
tyrosine phosphatase that positively regulates Lyn activation
by dephosphorylating a tyrosine residue at position 507
(Y-507). This causes a conformational change that exposes
the catalytic domain of Lyn and promotes autophosphoryla-
tion of the positive regulatory tyrosine at position 396 (Y-396)
[100]. In addition to Lyn, CD45 regulates the activation of
other kinases, such as Janus kinases (JAKs) and, thus, influ-
ences cytokine signalling [101], Src kinases involved in cell
adhesion [102], TLR signalling [103] and apoptosis [104].
Dysregulation of CD45, therefore, can affect multiple B lym-
phocyte functions leading to autoimmune-like diseases, but
the precise impact of changes of each of the multiple pathways
that CD45 regulates in promoting autoimmune disease re-
mains unclear. In genetically engineered mice, a single nucle-
otide replacement in the dimerization wedge of the CD45
molecule was shown to lead to autoantibody production and
the development of lupus-like disease [11]. However, it is
established that CD45 also influences apoptosis and defects
in its expression have been shown to promote lupus disease in
Fas ligand-mutant (Fasl
gld/gld
) mice. In this setting, reduced
CD45 expression enhanced B lymphocyte hyperactivity and
auto-Ab production [105]. Furthermore, defects in CD45 reg-
ulation has been shown to affect B lymphocyte tolerance. For
example, CD45
−/−
mice and CD45
−/−
B cell lines show re-
duced CD22 activation, SHP-1 recruitment, increased Syk
242 Clinic Rev Allerg Immunol (2017) 53:237–264
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activation [106]andCa
2+
influx [107]. Of note, however, is
that loss of function mutations in sialic acid acetyl esterase
(SIAE), which is required for the inhibitory function of
CD22, has been shown to also create a significant risk for
developing RA, T1D and SLE [108]. In hen egg lysozyme
(HEL) transgenic mice, HEL induced tolerance in mature
CD45
+/+
B lymphocytes but led to the activation and accumu-
lation of long-lived CD45
−/−
HEL-reactive B lymphocytes
[109].
Studies of B lymphocytes in patients with SLE in our lab-
oratory revealed that Lyn insufficiency was associated with
increased CD45 translocation to lipid raft signalling domains
and, ultimately, to reduced cellular expression of this phospha-
tase [12]. The noted increase in the translocation of CD45 to
lipid raft signalling domains is likely to be relevant to reduced
Lyn expression since CD45 promotes Lyn activation, ulti-
mately its degradation in the proteasome [4].
Downstream Kinases Defects in the regulation of BCR-
associated signalling molecules downstream of Lyn have also
been reported and shown to promote aberrant B cell responses
and autoimmune diseases. For example, defective regulation
of the adaptor protein B cell adaptor protein with ankyrin
repeats 1 (BANK1) which initiates BCR-mediated Ca
2+
sig-
nalling after Lyn-mediated phosphorylation of inositol 1,4,5-
trisphosphate receptor (IP3R) causes autoimmune-like disease
in mice. Thus, while BCR-mediated Ca
2+
influx was shown to
be normal in Bank1
−/−
primary B cells, this deficiency led to
enhanced CD40-mediated proliferation, survival, increased
Akt activation, and enhanced T-dependent antibody produc-
tion and formation of germinal centres [110]. In humans, ge-
netic studies have revealed that two variants of BANK1,
R61H and A383T, are strongly associated with susceptibility
to SLE [54]. The molecular basis for this association, howev-
er, remains to be determined. Nevertheless, the increase in
CD40-mediated Akt activation in Bank1
−/−
B cells suggests
that the allelic variants may promote autoimmunity through
affecting cognate B-T cell interactions.
More recent studies of B cells from patients with SLE car-
ried out in our laboratory revealed that the extent of defects in
intercellular signalling is more complex and extensive than
previously thought with each of the many identified defects
likely to impact different B cell responses and clinical symp-
toms differently [28]. For example, these studies identified
defective regulation of PI3K, MAPK, cyclin-dependent ki-
nase1 (CDK1) and PKC to varying degrees in B cells from
patients with SLE compared with matched healthy controls.
These studies also revealed that the activity of Rho, a serine/
threonine kinase involved in cell motility, was reduced in B
cells from patients with SLE. Although as stated above, the
relevance of many of these defects remains to be determined,
it is likely that reduced activity of Rho can lead to defective
migration of B lymphocytes. In addition to the above defects,
reduced activity of the cell cycle kinase ATR was noted in the
SLE patients. ATR is involved in activating the DNA damage
response pathway, which leads either to cell cycle arrest or
apoptosis and is, therefore, a key checkpoint in regulating cell
responses to DNA damage.
Protein Tyrosine Phosphatases In addition to kinases that
positively regulate BCR-mediated signalling, defects in phos-
phatases that control the activation of kinases downstream of
Lyn have also been reported to be involved in promoting
aberrant B cell responses in autoimmune diseases. For exam-
ple, defects in LYP tyrosine phosphatase, which is encoded by
the protein tyrosine phosphatase non-receptor 22 (PTPN22),
were shown to be sufficient to promote systemic autoimmu-
nity. GWAS studies also revealed that a SNP in PTPN22,
1858C/T that resulted in R620W amino acid substitution is
associated with increased risk of SLE, TID and RA
[111–113]. Interestingly, expression of the R619W LYP vari-
ant in B cells alone was shown to be sufficient to develop
splenomegaly, spontaneous germinal centre formation, glo-
merulonephritis and anti-dsDNA autoantibody production [8].
Calcium and Diacylglycerol Signalling
In Transcriptional Activation and B Cell Survival
The recruitment of PLCγto the BCR signalling complex fol-
lowing engagement by antigens initiates phosphatidylinositol
4,5 biphosphate (PIP2) hydrolysis leading to the generation of
inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG)
[94,114]. DAG binds to the cysteine-rich domain of Ras/
Rap guanyl-releasing protein and this activates rat sarcoma
(Ras) and ras-related protein (Rap) GTPases, the serine/
threonine protein kinase C (PKC) and protein kinase D
(PKD). IP3, in contrast, binds to IP3 receptors on the endo-
plasmic reticulum (ER) to release Ca
2+
from its stores and,
thus, increase cytosolic Ca
2+
concentration [114]. The deple-
tion of Ca
2+
stores in the ER is sensed by stromal interaction
molecules 1 and 2 (STIM1 and STIM2). As a result, these
proteins relocate to the ER-plasma membrane junction where
they bind to the Ca
2+
-release activated channel (CRAC) pro-
tein Orail and/or canonical transient receptor potential 1
(TRPC1) channels allowing extracellular Ca
2+
entry to in-
crease its intracellular level. As a consequence, the sustained
increase in intracellular Ca
2+
triggers the activation of the
Ca
2+
/calmodulin-dependent protein kinase kinases
(CaMKKs), serine threonine kinases involved in the regula-
tion of important cellular processes such as survival and cyto-
skeletal reorganization [115]. The BCR-induced increase in
intracellular Ca
2+
levels also activates calcineurin (also known
as protein phosphatase 2B, PP2B), a protein phosphatase that
controls intracellular localization of nuclear factor of activated
T cells (NFAT) family of transcription factors [116,117]. In
Clinic Rev Allerg Immunol (2017) 53:237–264 243
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

resting B cells, NFATs are constitutively phosphorylated by
casein kinase 1 and glycogen synthase kinase-3 (GSK3) and
are sequestered in the cytosol as a result of binding to 14-3-3
proteins. The BCR-induced activation of calcineurin leads to
dephosphorylation of NFATs, thus permitting their transloca-
tion to the nucleus. In the nucleus, NFATs form complexes
with other transcription factors to regulate the transcription of
target genes including IL-2, IL-4, IL-10, tumour-necrosis fac-
tor alpha (TNFα) and interferon gamma (IFNγ)[117,118].
Defective Regulation of Ca
2+
Signalling Promotes Defective
B Cell Tolerance
Numerous studies have examined molecular mechanisms
leading to aberrant Ca
2+
signalling in B lymphocytes with
special emphasis on how BCR and co-receptors CD19 and
CD21 mediate PLCγ2-IP3-Ca
2+
signalling. CD21-mediated
Ca
2+
signalling plays an important role in breaching B lym-
phocyte tolerance leading to autoantibody production [119].
Furthermore, changes in the regulation of Ca
2+
signalling are
recognized as a major signalling event that contributes to the
loss of B lymphocyte tolerance. Noteworthy, and perhaps par-
adoxically, is that an elevation in the baseline level of Ca
2+
and reduced BCR-mediated elevation have been noted in
tolerized/anergic B cells [84,120]. Elevated baseline level of
Ca
2+
is likely to be due to persistent but low level engagement
of the BCR by self-antigens and a recognized characteristic of
anergic B cells in experimental models [84,121]. In response
to antigen engagement, naïve B cells show a rapid increase in
intracellular Ca
2+
followed by a drop to reach a plateau within
minutes. This plateau is similar to the basal level seen in
anergic B cells and continues as long as the BCR is engaged
by the antigen. Thus, anergic B cells represent the physiolog-
ical equivalent of chronically antigen-stimulated naïve B cells.
Modulating BCR-mediated mechanisms of Ca
2+
signalling
could, therefore, provide a potential therapeutic approach for
treating autoimmune diseases. Indeed, treatment of B cells
with 1,4-benzodiazepine Bz-423 which increases sensitivity
to BCR engagement by causing sustained high level of Ca
2+
promotes apoptosis [122]. Since hyperactivation and altered
Ca
2+
signalling are distinguishing features of autoreactive B
cells, treatment with Bz-423 has been suggested to be a useful
approach for eliminating autoreactive B cells in autoimmune
diseases.
Phosphatidylinositol 3 Kinase Signalling
PI3K Signalling in B Cell Development, Survival
and Activation
PI3K signalling is important for B cell development, survival
and activation. PI3Ks represent a family of lipid and protein
kinases that function mainly through phosphorylation of
phosphoinositide [123,124]. Based on molecular structure
and functions, PI3Ks are divided into four classes: I, II, III
and IV. Members of class I PI3Ks are the ones whose altered
activation is implicated in autoimmunity and inflammation.
This class of PI3Ks is subdivided into two distinct subgroups,
IA and IB. In mammals, the IA subgroup includes three mem-
bers: PI3Kα,PI3Kβand PI3Kδ[125]. All three kinase mem-
bers of the IA subgroup are heterodimers consisting of p110
catalytic subunits (p110α,p110βand p110δ)andaregulatory
subunit, usually referred to as p85 [125]. Subgroup IB, in
contrast, consists of one catalytic subunit, p110γ,associated
with either a p101 or p84 regulatory subunit [123]. These
different PI3Ks function in different signalling pathways in
lymphocytes with p110δexpression been restricted to
haematopoietic cells. Upon receptor activation, PI3Ks phos-
phorylate PIP2 leading to the production of PIP3 [126]. The
production of PIP3 requires recruitment of PI3Ks to the plas-
ma membrane either through binding of the SH2 domain of
their regulatory units to the phosphorylated tyrosine residues
in receptor signalling complex domains and adaptors, or
through direct recruitment by Ras. Signalling through PI3K
is negatively regulated by the lipid phosphatase, SH2 domain-
containing inositol phosphatase (SHIP) and phosphatase and
tensin homologue deleted on chromosome ten (PTEN) [127].
Upon engagement of the BCR, CD19 recruits PI3K to the
plasma membrane through binding of p85 to its tyrosine-
phosphorylated cytoplasmic domain. In B lymphocytes, the
B cell activating factor (BAFF) and low basal signalling by
un-engaged BCR maintains low PIP3 levels [87]. The level of
PIP3 increases dramatically following BCR engagement by
antigens and co-stimulation through CD19, IL-4 receptor
and/or TLRs. The recruitment and binding of the key down-
stream target of PI3K, Akt [also known as protein kinase B
(PKB)], to the PIP3 through its pleckstrin homology (PH)
domain causes conformational changes to Akt and, as a result,
permits PIP3-dependent kinase 1 (PDK1)-mediated phos-
phorylation of Akt at threonine 304 within its catalytic do-
main. PDK1 has a PH domain that binds PIP3 and promotes
its translocation to the plasma membrane to co-localize with
Akt [128]. Once activated, Akt phosphorylates important
downstream targets including Rheb GAP TSC2, FOX1/3
and Fox4A. Akt-induced phosphorylation of Ras homologue
enriched in brain (Rheb) GAP TSC2 that leads to the accumu-
lation of Rheb-GTP complex results in the activation of mam-
malian target of rapamycin complex 1 (mTORc1) [129]. The
Faxo family of transcription factors is active and located in the
nucleus in resting cells; however, when phosphorylated by
Akt, they translocate to the cytosol where their transcriptional
activities are terminated. Akt is, therefore, important for me-
tabolism and cell survival in peripheral B lymphocytes [87].
Additionally, Akt/Foxo pathway plays a critical role in regu-
lating the expression of recombinase activating genes (RAGs)
that are responsible for antigen-receptor rearrangement in B
244 Clinic Rev Allerg Immunol (2017) 53:237–264
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

cells [130]. When Akt is inactive in quiescent B lymphocytes,
Foxo1, Foxo3 and Foxo4A drive transcription of genes
encoding IL-7, an essential homeostatic cytokine for lympho-
cytes, as well as for Kruppel-like factor 2 (KLF2) transcription
factor [131]. KLF2 directly regulates the expression of adhe-
sion molecules and chemokine receptors responsible for con-
trolling B lymphocyte entry into and exit from secondary
lymphoid organs.
Dysregulated PI3K Signalling Alters Normal B Cell
Development and Differentiation to Plasma Cells
in Autoimmune Diseases
The involvement of aberrant PI3K signalling in the pathogen-
esis of autoimmune diseases is intriguing as all leukocytes
express all members of class I PI3Ks. However, evidence for
the involvement of defective regulation of PI3K signalling has
mainly emerged from studying pathways involving PI3Kγ
and PI3Kδas these two class I PI3Ks are exclusively
expressed in immune cells. In contrast to PI3Kαand PI3Kβ
where ablation of their genes leads to embryonic lethality
[132], PI3Kγ- and PI3Kδ-deficient mice are viable but are
immunodeficient [133–137]. Furthermore, enhanced activity
of either PI3Kγor PI3Kδhas been implicated in promoting
autoimmunity [138–140]. In murine models of lupus and in
SLE patients, the activity of PI3K is increased [141]. The
exact cause(s) and impact of enhanced PI3K activity on SLE
and autoimmune diseases in general remains to be determined.
However, PI3K promotes B cell survival and the generation of
short-lived plasma cells and suppresses class switch recombi-
nation through activating Akt, which, in turn, represses Foxo
transcription factors [142,143]. Of note, is that PI3Kδis the
main PI3K family member that is involved in regulating B
lymphocyte responses. Thus, mice lacking PI3Kδshow re-
duced development of pro-B to pre-B cells in the bone marrow
and impaired responses of mature B cells [136,144].
Additionally, PI3Kδis involved in regulating marginal zone
(MZ) and B-1 B cell responses including antibody production
[145]. Interestingly, B cell development in PI3Kγ
−/−
δ
−/−
mice
is similar to PI3Kδ
−/−
mice, whereas no defects are seen in B
cell development in PI3Kγ
−/−
mice [146]. These observations
indicate that PI3Kγdoes not play a notable role in B cell
development. Indeed, genetically engineered mice expressing
a catalytically inactive PI3Kδmanifest impaired BCR signal-
ling and reduced IgM and IgG antibody production [144].
Similarly, heterozygous deletion of PI3Kδdiminishes autoan-
tibody production, ameliorates nephritis and improves surviv-
al in Lyn-deficient mice that develop lupus-like disease. In
contrast, mice expressing constitutively active PI3Kδshow a
reduced ability to eliminate autoreactive B lymphocytes [140].
In addition to its involvement in regulating BCR-mediated
signalling, PI3Kδis involved in mediating inflammation trig-
gered by the engagement of TLRs [147]. These observations
suggest that targeting of PI3Kδcould be an attractive thera-
peutic option for treating patients with autoimmune diseases
and chronic inflammation [148–150]. Of note in this respect is
that studies using mouse models of lupus have shown that
inhibiting PI3K blocked glomerulonephritisand extended sur-
vival [139].
In addition to direct evidence for the role of dysregulated
PI3K signalling in promoting autoimmune diseases in mice,
there is indirect evidence for its involvement in promoting
disease in patients. For example, there is evidence for de-
creased expression of PTEN, a lipid phosphatase that nega-
tively regulates PI3K signalling in B cell subsets, except in
memory B cells, in patients with SLE [31]. Furthermore, the
level of PTEN in B cells from patients with SLE is inversely
related to disease activity. Decreased levels of PTEN also
concur with the upregulation of microRNA (miR-7) that
downregulates PTEN expression. These findings suggest that
defective miR-7 regulation of PTEN could contribute to B cell
hyperresponsiveness in SLE [31]. Functional screening of a
microRNA library also revealed that another miR, miR-148a,
is a potent regulator of B cell tolerance [151]. Furthermore,
increased expression levels of miR-148a were reported in pa-
tients with lupus and also in lupus-prone mice [151]. Elevated
miR-148a levels impair B cell tolerance through enhancing
the survival of immature B cells following BCR engagement
by self-antigens [151]. Molecular studies revealed that miR-
148a functions by suppressing the expression of Gadd45α,
PTEN and the pro-apoptotic protein Bim. Furthermore, in-
creased expression of miR-148a leads to lethal autoimmune
disease in a mouse model of lupus [151]. Using adoptive
transfer of anergic B cells, a recent study revealed that contin-
uous signalling through the inhibitory molecules SHP-1 and
SHIP-1 was required to maintain B cell anergy. Furthermore,
reducing signalling through either of these two signalling
pathways leads to rapid B cell activation, proliferation and
the generation of short-lived plasma cells [152].
Ubiquitination-Regulated Signalling
Ubiquitination Regulation of BCR-Mediated Signalling
and Antigen Processing
Ubiquitination is an important posttranslational modification
process that regulates signal transduction through covalent
attachment of ubiquitin (Ub) moieties, a 76-amino acid pep-
tide, to targeted proteins. The process involves at least three
enzymes, Ub-activating enzyme (E1) that activates Ub, Ub-
conjugating enzyme (E2) and Ub ligase (E3). E3 enzymes,
such as Cbl, catalyse ligation of the C-terminal residue of
Ub to a lysine residue on the target protein [153]. Lysine
residues K6, K11, K27, K29, K33, K48 and K63 of Ub can
potentially form seven different types of linkages in branched
poly Ub chains, whereas a linear form of the Ub chain can be
Clinic Rev Allerg Immunol (2017) 53:237–264 245
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

formed when only one lysine in each Ub in involved in link-
age formation [153,154]. Mono ubiquitination promotes
endocytic trafficking and DNA repair and the K48-linked
Ub moieties tag proteins for degradation via the proteasomal
system. In contrast, K63-linked and linearly linked Ub chains
provide docking sites for downstream effectors and promote
protein-protein interactions and signalling [155].
Ubiquitination can also be regulated through deubiquitinating
enzymes, proteases that remove mono-ubiquitins and poly-
ubiquitins from proteins. In this regard, A20 acts as a
deubiquitinating as well as an ubiquitin-editing enzyme.
A20 inhibits the activation of NF-κB. It also restricts apopto-
sis induced by TNFα[156]. The following section will review
data on two key effector enzymes involved in the
ubiquitination cycle, Cbl and A20, since there is an abundance
of evidence for their involvement in autoimmunity.
In mammals, the Casitas B lineage lymphoma (Cbl) family
of proteins has three members: c-Cbl, Cbl-b, and Cbl-3. c-Cbl
and Cbl-b are expressed in B cells [157] and function as prom-
inent substrates for tyrosine phosphorylation and regulators of
the threshold of signalling [157–160]. c-Cbl effectively in-
hibits B cell responses through downregulating Syk kinase
[161]. c-Cbl and Cbl-b interact with several BCR-associated
signalling molecules such as PLCγ2, BLNK, PI3 kinase, Lyn,
Va v a n d S y k [ 42,162,163]. Subsequent to binding to ITAMs,
Syk is phosphorylated on tyrosine 323 and this creates a bind-
ing site for c-Cbl [164]. c-Cbl recruits components of the
ubiquitin conjugation pathway and acts as an ubiquitin ligase
[165]. Binding of c-Cbl results in Syk ubiquitination and
downregulation of BCR signalling [164]. Apart from regulat-
ing BCR signalling, c-Cbl mediates BCR ubiquitination, a
process crucial for facilitating antigen processing and presen-
tation by B cells through the internalization of antigen-BCR
complexes and guiding them to multi-vesicular body-like
MIIC. In these multi-vesicular body-like MIICs, antigen-
BCR complexes are processed into peptides and loaded onto
MHC class II for presentation to T cells [166–169]. The re-
cruitment of Cbl-b to clustered BCRs is also required for the
entry of endocytosed BCRs into late endosomes. Recruitment
of Cbl-b is also required for the entry of TLR9 into endosomes
as has been noted after in vitro activation of TLR9 by BCR-
captured antigens [170].
In contrast to Cbl, A20 is a widely expressed cytoplasmic
protein that inhibits NF-κB activation and signalling down-
stream of interleukin-1 receptor (IL-1R), TNF receptor 1
(TNFR1), CD40 as well as signalling through innate-type re-
ceptors such as TLRs and NOD-like receptors (NLRs)
[171–174]. In addition, A20 promotes cell survival through
which it can regulate immune responses [174]. By
destabilizing E2 enzymes, A20 can disrupt the interaction be-
tween E2 and E3 and, therefore, restrict ubiquitination of tar-
get proteins [175]. To achieve its critical biochemical func-
tions, A20 interacts with key effectors including the receptor
interacting kinase-1 (RIPK1), a key player in inflammation
and cell death, E2, E3, ABIN-1 (ubiquitin sensors) and
NEMO/IKKγ,akeyplayerinNF-κBsignalling[
176–181].
Additionally, A20 binds directly to ubiquitin chains [177,179]
and modifies ubiquitinated protein substrates in multiple
ways. For example, A20 cleaves poly-ubiquitin chains, there-
by, exhibiting a deubiquitinating activity. In addition, A20
works with E1 and E2 proteins to build ubiquitin chains, thus
displaying E3-like activity [171,182]. Through its Ub-editing
functions, A20 also removes K63-linked poly-ubiquitin
chains from substrates and builds K48-linked ubiquitin chains
[182].
Altered Ubiquitination in Defective in B Cell Tolerance
Inappropriate ubiquitination has been associated with the de-
velopment of autoimmune diseases. A large body of evidence
implicates defects in the level and regulation of Cbl and A20
in the pathogenesis of autoimmune diseases. Thus, Cbl-b-
deficient mice develop autoimmune diseases and highlight a
connection between Cbl-b-mediated protein degradation and
the regulation of BCR signalling thresholds [158]. These mice
produce high levels of autoantibodies to double-stranded
DNA and develop signs of spontaneous lupus-like disease
[158]. Another study revealed that Cbl-b-deficient mice had
an enhanced susceptibility to develop experimental autoim-
mune encephalitis (EAE) [183]. B cells from Cbl-b-deficient
mice showed an enhanced ability to proliferate in response to
BCR and CD40 engagements [158]. The lowering of BCR
thresholds caused by the loss of Cbl-b correlated with in-
creased susceptibility to develop autoimmune disease.
Many signalling proteins associate with Cbl-b, including
PLCγ, PI3K, Syk and the adaptor proteins Slp-76 and Vav.
However, Cbl-b-deficient cells have a selective enhancement
of Vav phosphorylation, indicating that Cbl-b is a negative
regulator of Vav phosphorylation. Vav is a key guanine nucle-
otide exchange factor for the Rho family of GTP-binding pro-
teins [184], and mice with B cell-specific ablation of c-Cbl
and Cbl-b manifest lupus-like disease and have a significant
increase in MZ and B1 B cell numbers [184]. Interestingly,
however, c-Cbl/Cbl-b-deficient B cells were not hyperrespon-
sive to BCR engagement, did not proliferate extensively nor
produced antibodies but tolerance induction was impaired
[42]. Apart from attenuated BLNK phosphorylation, these
mutant B cells showed enhanced phosphorylation of BCR-
proximal signalling proteins including Syk, PLCγ-2 and Vav
and increased Ca
2+
mobilization. These results, therefore, in-
dicate that Cbl proteins regulate B cell tolerance possibly
through fine-tuning of BCR-mediated signalling thresholds
[42].
In contrast to Cbl proteins, as cited earlier, A20 is expressed
in all cell types and regulates the canonical pathway of NF-κB
activation and promote cell survival. The regulation of these
246 Clinic Rev Allerg Immunol (2017) 53:237–264
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

signals by A20 is important for preventing autoimmune dis-
eases and defects could lead to autoimmune inflammatory
diseases. For example, A20-deficient mice were shown to
develop multi-organ inflammation and perinatal lethality
which prevented detailed studies of A20 functions in adult
mice [173]. However, mice lacking A20 expression specifi-
cally in B cells provided better insights into how A20 regu-
lates B cell development and functions. These mice spontane-
ously developed a lupus-like disease characterized by in-
creased plasma cell and germinal centre B cell numbers, ele-
vated levels of IgM and IgG autoantibodies and immunoglob-
ulin deposits in the kidney [37–39]. The increase in germinal
centre B cell numbers could be due to resistance to FAS-
mediated apoptosis [39] and/or enhanced expression of
NF-κB-dependent anti-apoptotic proteins including Bcl-X.
Of note, however, is that these mice did not develop renal
failure but severe nephritis when lupus-prone mice were used.
Furthermore, heterozygous mice which expressed reduced
levels of A20 specifically in B cells manifested increased
numbers of germinal centre B cells and produced autoanti-
bodies [38]. In addition to enhanced BCR-mediated signal-
ling, A20-deficient mice were hyperresponsive to TLR and
CD40 engagement. Furthermore, when stimulated, A20-
deficient B cells produced higher levels of IL-6 compared
with wild-type B cells [39]. Enhanced IL-6 production in
A20-deficient B cells may account for the moderate increase
in T cell numbers in mice lacking A20 expression in B cells
[39].
In humans, GWAS and SNP analyses of TNFAIP3, the
gene encoding A20, revealed a potential role for A20 in sus-
ceptibility to autoimmune diseases in humans (Table 2)[185].
Subsequent studies confirmed an association with a number of
autoimmune diseases including SLE [186], RA [187], psoria-
sis [188], T1D [189,190] and SSc [191,192]. Since mice
expressing low levels of A20 develop spontaneous inflamma-
tion and autoimmune diseases [37–39], TNFAIP3 SNPs might
affect its function or expression. Indeed, reduced A20 func-
tions in patients with SLE were associated with a SNP in the
coding region of TNFAIP3 that caused a substitution in residue
127 from phenylalanine to cysteine. In contrast, reduced A20
level was associated with a SNP at the 3′enhancer region of
TNFAIP3 [193]. Additionally, it was suggested that SNPs lo-
cated outside of the coding regions of TNFAIP3 may confer
susceptibility to diseases by reducing A20 expression [194,
195]. Polymorphisms could also have prognostic and thera-
peutic values. Thus, TNFAIP3 polymorphisms and altered
A20 expression levels were associated with therapeutic re-
sponses to RA patient treated with anti-TNFαagents [196].
The association of TNFAIP3 polymorphisms with lymphoma
in patients with Sjögren’s also highlights the potential role of
A20 in regulating B cell hyperactivity and malignant transfor-
mation leading to lymphomagenesis [197]. Moreover, the
presence of certain TNFAIP3 SNPs was associated with the
risk of severe renal or haematological complications in pa-
tients with SLE [193].
The NF-κB-associated signalling cascade is regulated by
an E2 enzyme, UBE2L3 (also called UBCH7). UBE2L3 par-
ticipates in the ubiquitination of p53, c-Fos and the NF-κB
precursor p105, and defects are associated with increased sus-
ceptibility to many autoimmune diseases including RA and
SLE [198,199]. A single haplotype spanning UBE2L3,
rs140490, was associated with increased UBE2L3 expression
in B cells and aligned across multiple autoimmune diseases.
Additionally, the UBE2L3 risk allele correlated with increased
numbers of plasmablasts and plasma cells in patients with
SLE suggesting a role for UBE2L3 in plasmablast and
plasmacyte development [67,200].
Innate Immune Receptor-Mediated Signalling
Innate Immune Receptor-Mediated Signalling and B Cell
Tole ra n ce
Innate immune receptors, such as TLRs, are pattern recogni-
tion molecules that bind conserved pathogen-associated mo-
lecular patterns (PAMPs) on pathogens. Ten TLRs are
expressed in human cells, whereas in murine cells, there are
13 such receptors. Naïve human B cells express TLR1, 2, 3, 4,
6, 7 and 9, while plasma cells only express TLR3 and 4 [201].
TLR7 and TLR9 are known to be able to directly influence B
cell tolerance. Engagement of TLR2 and TLR4, in contrast,
has been implicated in promoting autoimmune diseases in
mice although there is no direct evidence to support how, or
indeed if, these two receptors modulate B cell. TLR7 and
TLR9 are intracellular receptors that bind their ligands in
endosomes. TLR7 binds ssRNA while TLR9 binds CpG
DNA in viruses and bacteria. Interestingly, these receptors
can be stimulated in self-reactive B cells by RNA and/or
DNA-containing immune complexes. The two receptors di-
merize upon ligand binding and recruit the adaptor protein
myeloid differentiation primary response gene 88 (MyD88).
The IL-1 receptor-associated kinase 4 (IRAK4) binds to
MyD88 and activates IRAK1 and IRAK2. The resulting sig-
nalling complexes initiate the activation of NF-κB, MAPK
and IFN-regulatory factor 1 (IRF1) and IRF5 signalling path-
ways and regulate the production of pro-inflammatory cyto-
kine [202–205].
Dysregulated Innate Immune Receptor-Mediated Signalling
Promotes B Cell Autoreactivity
A key feature of immunological abnormality in patients with
autoimmune diseases is the production of autoantibodies, such
as autoantibodies with specificity for nuclear antigens includ-
ing DNA and proteins. There is evidence that crosstalk be-
tween signalling mediated by the BCR and TLRs could play
Clinic Rev Allerg Immunol (2017) 53:237–264 247
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

an important role in the loss of B cell tolerance to these anti-
gens [206,207]. For example, BCR engagement by nucleic
acid associated with self-antigens facilitates trafficking to
endosomal compartments where TLRs reside leading to their
engagement and B cell activation [208,209]. In this respect,
both TLR7 and TLR9 which initiate MYD88-dependent sig-
nalling pathways have been implicated in the pathogenesis of
animal models of lupus and the production of anti-nuclear
autoantibodies. Indeed, deletion of the TLR7 gene in lupus
mice suppresses the production of autoantibodies to RNA-
associated proteins and ameliorate systemic autoimmunity.
Paradoxically, however, deletion of the TLR9 gene abolishes
anti-dsDNA and anti-chromatin autoantibody production but
exacerbates clinical symptoms [210,211]. Since both TLR7
and TLR9 are expressed in B cells and myeloid cells, it is
unclear whether the phenotype seen in these mice could be
attributed to the effect of the two receptors on myeloid and/or
B cells. However, deletion of TLR7 in Wiskott-Aldrich syn-
drome protein (WASp) in mice inhibited systemic autoimmu-
nity, whereas deletion of TLR9 promoted systemic autoimmu-
nity which recapitulates the phenotype seen in TLR7/9-defi-
cient lupus mice [212–214]. WASp is expressed in
haematopoietic cells and is implicated in BCR- and TLR-
mediated signalling. Mutations in the WASp gene in humans
cause Wiskott-Aldrich syndrome, an X-linked recessive dis-
ease characterized by primary immunodeficiency and high
levels of autoantibodies [215]. In contrast to attenuating T cell
receptor (TCR)-mediated signalling, WASp-deficient B cells
are hyperresponsive to both BCR and TLR engagement lead-
ing to enhanced signalling adequate to mediate autoimmune
disease even in the autoimmune-resistant B6 mouse [216]. In
addition, WASp-deficient B cells are capable of activating
wild-type CD4
+
T cells and inducing spontaneous germinal
centre formation, glomerulonephritis and the production of
class-switched autoantibodies in mixed bone marrow chi-
meras in mice [216]. These effects were all MyD88-
dependent since deletion of MyD88 in B cells abrogated T
cell activation and spontaneous germinal centre formation
[98,217–219]. The pivotal role of TLR7 signalling in the
pathogenesis of lupus was confirmed in several mouse models
with the Y-chromosome-linked genomic-modifier Yaa in
which there is duplication of the Tlr7 gene [220]. In Yaa
mouse models, duplication of the Tlr7 gene was reported to
be the sole requirement for accelerated autoimmunity and that
reduction of Tlr7 gene dosage abolished the autoimmune phe-
notype.Furthermore,inTLR7 transgenic mice, B cells prefer-
entially homed to spontaneous germinal centres in competi-
tive chimeras suggesting a key role for TLR7-expressing B
cells in driving the formation of autoreactive germinal centres
[221]. Of note, overexpression of soluble RNAase ameliorat-
ed autoimmunity in TLR7-transgenic mice suggesting an im-
portant role for RNA in the pathogenesis of disease in these
mice [222]. In genetic studies in humans, SNPs within Tlr7
and polymorphisms in genes encoding proteins and transcrip-
tion factors downstream of TLR signalling, including
TNFAIP3, TNIP1 and IRF5, associate with susceptibility to
SLE [53,223–226]. In addition, variants of SLC15A4, a his-
tidine transporter involved in lysosomal TLR signalling, also
associate with susceptibility to SLE. Furthermore, deletion of
SLC15A4inBcellslimitsautoimmunityinmurinemodelsof
the disease [61]. Noteworthy in this respect is that humans
deficient in either IRAK4 or MYD88, downstream effectors
of TLR signalling, show increased autoreactivity within the
naïve B cell compartment suggesting a pivotal role for TLR
signalling in regulating tolerance in B cells [227,228].
Co-stimulatory Receptor-Mediated Signalling
Co-stimulatory Receptor Signalling and B Lymphocyte
Responses
The outcome of BCR engagement is influenced by signalling
generated through a number of co-stimulatory receptors in-
cluding CD5, CD19, CD21, CD22, CD40, CD45, CD72 and
FcγRIIB. Signalling through these molecules upregulate and/
or downregulate BCR-mediated signalling to fine-tune B cell
responses. Any imbalance, or dysregulation, in signalling me-
diated through these co-receptors can either mediate autoim-
mune responses, or limit the ability of the immune system to
mount an effective humoral response.
One of the key co-receptors involved in modulating BCR-
mediated signalling is CD19. The cytoplasmic domain of
CD19 has nine tyrosine residues which, when phosphorylat-
ed, act as docking sites for SH2-containing adaptors and ki-
nases including PI3Ks, Vav-family guanosine exchange fac-
tors (GEFs) and growth factor receptor-bound protein 2
(Grb2). The engagement of CD40 by its ligand, CD40L, in
contrast, initiates signalling through TNFR-associated factors
(TRAFs) leading to the activation of downstream signalling
pathways including MAPKs and NF-κB.
The activation of BCR-mediated signalling is also regulat-
ed by protein tyrosine phosphatases (PTPs), some of which,
such as CD45, play dual positive and negative roles as cited
earlier. Cytoplasmic phosphatases are recruited to the BCR
complex through ITIM-containing co-receptors, such as
CD5, CD22 and the low-affinity Fcγreceptors, specifically
FcγRIIB [229]. Altered expression and/or activation either of
kinases or phosphatases can lead to defective BCR-mediated
signalling which, in turn, alters B-lymphocyte responses
[230–232].
Co-ligation of the BCR and the FcγRIIB by antigen-
antibody complexes leads to tyrosine phosphorylation of
ITIMs [233], which, in turn, recruit SHIP, a lipid phosphatase
with specificity for 5′-phosphate of PIP3 [234]throughSH2-
domain-mediated binding. SHIP dephosphorylates PIP3 to
produce PI(3,4)P2 and, thus, diminish BCR-mediated
248 Clinic Rev Allerg Immunol (2017) 53:237–264
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elevation of PIP3. B lymphocytes also express the siglec fam-
ily member CD22, an ITIM-containing receptor which inter-
acts with ligands carrying a 2–6-linked sialic acids [235].
CD22 modulates BCR signalling threshold and inhibits sig-
nalling by recruiting SHP-1, a tyrosine phosphatase.
CD72 is constitutively expressed on B cells at all stages of
their development except on plasma cells. CD72 negatively
regulates BCR-induced signalling by recruiting SHP-1
through its cytoplasmic ITIM motif [236]. CD72 plays an
essential regulatory role in modulating BCR-mediated signal-
ling in autoreactive B cells [237]. In anergic B cells, CD72
downregulates BCR-mediated signalling by limiting antigen-
induced Ca
2+
influx and the activation of NFATc1, NF-κB,
MAPK and Akt. Noteworthy, CD72 associates with SHP-1
and Cbl-b, suggesting a role for SHP-1 and Cbl-b in CD72-
mediated inhibitory effects on BCR-mediated signalling in
anergic B cells. CD100, a ligand for CD72, can turn off the
negative effect of CD72 by inhibiting the phosphorylation of
CD72 and, consequently, disrupting the interaction between
SHP-1 and CD72 [238,239].
Dysregulated Co-stimulatory Receptor-Mediated Signalling
Promotes Autoreactive B Cell Expansion and Autoantibody
Production
Cognate interactions between B and T cells involving co-
stimulatory receptors such as CD40 and CD40L are critical
for thymus-dependent humoral immunity. Ligation of CD40
induces B cell proliferation, class switching and somatic mu-
tations. In lupus disease, loss or blockade of cognate B-T cell
interactions involving CD40-CD40L ameliorates disease and
prolongs survival in the NZB/NZW F1 and MRL-lpr sponta-
neous models of lupus [240–242]. In addition, the use of ag-
onist anti-CD40 antibodies inhibits apoptosis of rheumatoid
factor (RF) precursor B cells in arthritic mice, while blockade
of CD40-CD40L abolishes RF production in transgenic mice
[243,244]. Furthermore, cd40l gene-deficient mice or treat-
ment of neonatal NOD mice with anti-CD40L antibodies sup-
presses autoimmune diabetes [245–248]. Moreover, treatment
of EAE mice with anti-CD40L antibody improved disease
[249,250]. Preclinical assessment of anti-CD40 antibody in
a model of multiple sclerosis (MS) in monkeys provided ad-
ditional support for the importance of CD40-CD40L interac-
tion in autoimmune diseases [251–253]. However, clinical
trials of anti-CD40L in patients with lupus had mixed out-
comes, and in addition, some patients developed thromboem-
bolism [254–256].
As cited above, in addition to CD40, defective regulation
of engagement or signalling through other co-stimulatory re-
ceptors such as CD5, CD22 and FcγRIIB can also promote
autoimmune diseases. CD5 and CD22 negatively regulate
BCR-mediated signalling through ITIMs in their intracellular
domains and PTPs. The PTPs can have dual inhibitory and
activating effects. In autoimmune diseases, there is substan-
tive evidence that defects in the regulation of co-stimulatory
receptors and associated PTPs promote lupus disease, both in
animal models and in patients. For example, there is evidence
for altered expression of CD22 and SHP-1 in patients with
SLE [4,6,257]. In genetically engineered mice, deletion of
cd22,FcγRIIB or PTPN6, which encodes SHP-1, leads to B
lymphocyte hyperactivity, auto-Ab production and lupus-like
disease [5,96,258]. However, it remains unclear whether
defects in the regulation of these co-stimulatory receptors
and associated PTPs in patients are inherent or result from
the disease process or, indeed, if they have a causal relation-
ship with the disease.
In addition to the role of dysregulated kinases and phos-
phatases that regulate proximal BCR signalling, defects in co-
stimulatory receptors that regulate downstream signalling
have been associated with the development of autoimmune
diseases. For example, dysregulation of CD72 has been
shown to promote autoimmune diseases. In anergic B cells,
CD72 constitutively regulates BCR-mediated signalling and
limits proliferation and survival through suppressing cyclin
D2 expression and Rb phosphorylation, key regulators of the
cell cycle. Indeed, CD72-deficient mice spontaneously pro-
duce autoantibodies and develop lupus-like disease.
Furthermore, CD72-deficient B cells proliferate and survive
when their BCRs are engaged by self-antigens. The prolifera-
tive response of anergic B cells to BCR engagement by self-
antigens results in the loss of immunological self-tolerance,
upregulation of cyclin D2 and Bcl-xL, proliferation and sur-
vival of autoreactive B cells [259]. In contrast to anergic B
cells where calcineurin/NFAT and NF-κBsignallingpathways
are defective [260,261], self-antigen binding to anergic
CD72
−/−
B cells leads to the activation of both calcineurin/
NFAT and NF-κB[259]. Both calcineurin/NFAT and NF-κB
are required for the induction of cyclin D2 [262,263] and
activation of MAPK and Akt, key regulators of cell cycle
and survival.
Cytokine-Mediated Signalling
Cytokine Signalling in B Cell Differentiation
Dynamic regulation of cytokine production and cytokine re-
ceptor expression is required for B cell development, differ-
entiation and efficient immune responses. Cytokines are in-
volved in cellular communications and signalling and initiate
a wide range of effects including cell differentiation, prolifer-
ation and regulation. Cytokines involved in B cell differenti-
ation and responses include interferons (IFNs), interleukins
(ILs) and members of the TNF family of ligands and recep-
tors. Almost 40 cytokine receptors are known to initiate intra-
cellular signalling mostly through JAKs and signal transduc-
ers and activators of transcription (STATs) [264,265]. In
Clinic Rev Allerg Immunol (2017) 53:237–264 249
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

addition to activating JAKs and STATs, cytokines can also
initiate other signalling pathways such as activating Ras and
PI3Ks [266,267]. The binding of cytokines to their receptors
induces dimerization or polymerization of the receptors and
this activates associated JAKs. Activated JAKs induce phos-
phorylation and homo- and hetero-dimerization of STATs.
Dimerized STATs translocate to the nucleus where they induce
transcription of their target genes.There are four JAKs (JAK1,
JAK2, JAK3 and TYK2) and seven known STATs (STAT1,
STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6).
Receptors for type 1 IFN signal via JAK1 and Tyk2, whereas
receptors for IL-12 and IL-23 signal through JAK2 and Tyk2.
Receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-23 signal
through JAK1 and JAK3, whereas IFNγreceptor signals via
JAK1 and JAK2 [268].
BAFF, which is a member of the TNF family of ligands and
receptors, is crucial for B cell survival and development [269,
270]. The cytokine can bind to three different receptors:
BAFF-R, B cell maturation antigen (BCMA) and transmem-
brane activator and Ca
2+
modulator and cyclophilin ligand
interactor (TACI) [271,272]. Binding of BAFF to BAFF-R
plays a predominant role in B cell maturation and survival,
and mice deficient in either BAFF or BAFF-R exhibit a B cell
developmental block at the T2 stage of transitional B cell
maturation. In contrast, B cells in BCMA- or TACI-deficient
mice develop normally into mature cells [273]. BAFF-R is
linked to TRAFs and signals through both the canonical and
alternative NF-κB pathways as well as through MAPK and
PI3K pathways [274,275]. Activation of the NF-κBpathway
by engagement of the BAFF-R rescues transitional B cells
receiving BCR signals from apoptosis in response to engage-
ment by self-antigens, possibly through increased transcrip-
tion of anti-apoptotic proteins and posttranscriptional modifi-
cations of pro-apoptotic proteins [276–278]. Interestingly, re-
cent studies have revealed that there is crosstalk between
BAFF-R and BCR signals that can induce survival signals
independent of NF-κB activation [279,280]. Thus, BAFF
promotes rapid phosphorylation of proximal BCR signalling
involving Ig-αand Syk. Deletion of Syk impairs survival and
renders B cells non-responsive to BAFF. Survival in this set-
ting can partially be restored by ectopic activation of MAPK
or PI3K suggesting that BAFF-R signalling is likely to facil-
itate BCR-induced survival through activation of MAPK and
PI3K.Inthisrespect,BCRandCD19havebeenimplicatedin
regulating BAFF-R levels [86,273].
Altered Cytokine Prof iles Impacts Intracellular B Cell
Signalling and Responses
Studies over the last few years have suggested that B cells can
be subdivided into effector subsets based on the profile of
cytokines they produce. Thus, B cells have been subdivided,
in a manner akin to the subdivision of Th1 and Th2 cells, into
B effector 1 cells that produce IFNγand IL-12 and B effector
2 cells that produce IL-2, IL-4 and IL-6. More recent studies
identified another effector B cell subset, B-regulatory cells
(Bregs), characterized by their ability to produce IL-10,
TGFβand IL-35 and with immunosuppressive functions
[281]. However, the available evidence indicates that, in con-
trast to effector T cell subsets, effector B cell subsets do not
fulfil requirements of classic immune lineages such as defin-
ing transcription factors and may also exhibit plasticity de-
pending on their microenvironmental settings. Nevertheless,
the evidence provides support for a differential profile of cy-
tokine production in B cells in different pathophysiological
conditions. For example, altered profiles of cytokine produc-
tion have been implicated in aberrant B cell responses in au-
toimmune diseases. Furthermore, in addition to the role of
cognate T-B cell interactions in diverging cytokine production
in B cells, TLR co-engagement with CD40 has been shown to
synergize in promoting IL-10 and IL-35 production
[282–284]. Both cytokines have important regulatory func-
tions including limiting the generation of autoreactive germi-
nal centres [284]. Interestingly, IL-10 can have dual effects on
autoimmune diseases: acting as a B cell stimulator and also
suppressor of T cell activations [285]. In this respect, IL-10
impacts autoimmune disease pathology differently depending
on which cell and/or mechanism drives a disease. For exam-
ple, while the transfer of IL-10-producing Bregs drives Treg
cell expansion and modulates arthritis in mice, treatment of
SLE patients with IL-10-specific monoclonal antibodies ame-
liorates disease [286,287]. This outcome is consistent with
evidence showing that high levels of IL-10 correlate with lu-
pus disease activity in patients [288]. Interestingly, however,
there is also evidence for defective signalling that regulate IL-
10 production by B cells in patients with SLE [281,282].
Similar to IL-10, IL-35 production by B cells has been shown
to have immune regulatory functions and essential for recov-
ery from EAE in mice [283].
In addition to the differentiation of B cells to distinct effec-
tor subsets with different cytokine profiles that impact auto-
immune diseases differently, altered regulation of cytokine
signalling in B cells can promote or enhance autoimmune
disease pathology. For example, lupus is associated with high
levels of IFNαand INFγproduction with both altering B
lymphocyte responses and autoantibody isotype production
[289–291]. IFNαlowers BCR activation thresholds and pro-
motes B cell differentiation through activating IRF5 transcrip-
tion factor [292]. Indeed, polymorphism in the IRF5 gene has
been associated with susceptibility to SLE [7]. Interestingly,
excess production of IFNαcan be induced by immune com-
plexes suggesting a positive feedback circuit between IFNα
and autoreactive B cells in lupus [290]. High levels of IFNγ,
in contrast, enhance the production of complement-fixing IgG
subclass of autoantibodies in lupus mice and promote lupus
disease in patients with RA when treated with the cytokine
250 Clinic Rev Allerg Immunol (2017) 53:237–264
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Tab l e 3 Studies, clinical trials and approved therapeutic targeting of cytokines and signalling pathways in B cells for treating autoimmune diseases
Targeted signalling
molecule/pathway
Agent used Structure of agent Biological effects on B lymphocytes Disease/status Reference
JAK1/JAK2/JAK3
and to a lesser
extent TYK2
Tofacitinib Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
Approved for treating RA in many countries but
not yet in the EU
[302]
JAK1/JAK2 Baricitinib Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase III clinical trials [302]
JAK3 Decernotinib
(VX-509)
Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase II clinical trials [302]
Pan-JAK Peficitinib (ASP015
K)
Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase II clinical trials [302]
JAK1 Filgotinib
(GLPG-0634)
Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase II clinical trials [302]
JAK1 ABT-494 Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase II clinical trials [302]
JAK1/JAK2 INCB039110 Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
RA in phase II clinical trials [302]
JAK/SYK R333 Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
Discoid lupus in phase II clinical trials [303]
JAK1 GSK2586184 Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
SLE in phase II clinical trials [303]
JAK1 GLG0778 Chemical inhibitor Inhibits the JAK/STAT pathway and blocks cytokine
signalling
SLE in phase II clinical trials [303]
SYK Fostamatinib Chemical inhibitor Inhibits SYK and blocks BCR and FcγR signalling Clinical trials concluded that it is effective in
treating RA; however, its clinical application
is precluded due to unexpected side effects
[304]
BLyS (BAFF) Atacicept Recombinant fusion
protein (TACI-Ig)
Blocks BLyS/APRIL binding and reduces survival and
the number of some B cell subsets
Reduced B cell and plasma cell numbers and
SLE disease activity but phase II/III trial
stopped due to low blood Ab levels and
pneumonia
[305]
Belimumab Fully human monoclonal
Ab (mAb)
Inhibits BLyS binding to membrane receptors;
promotes apoptosis of B lymphocytes
Approved for treating SLE. However, patients
with active lupus nephritis are excluded.
Use for active lupus nephritis at phase III clinical
trials. Sjögren’s syndrome phase III clinical
trials
[305]
Briobacept (BR3-Fc) Recombinant fusion
protein
Inhibits BLyS binding to its receptor and promotes
apoptosis
SLE clinical trials did not show sufficient
efficacy
[305]
Blisibimod
(AMG-623)
Peptide-Fc fusion protein
with 4 BLyS binding
domains
Inhibits BLyS binding to its receptors and promotes
apoptosis
SLE clinical trial is in phase III [305]
IL-6 Sirukumab Fully human mAb Reduces B lymphocyte proliferation and differentiation Clinical trials concluded its effectiveness in
inhibiting progression of joint damage and
improved signs and symptoms of disease in
RA
[306]
IL-6R Tocilizumab Humanized mAb Blocks B lymphocyte differentiation and reduces Ab
production
Clinical trials concluded its effectiveness as a
therapy for treating early RA
[307]
IFNαRontalizumab Humanized mAb Inhibits B lymphocyte activation and Ab production Clinical trials concluded its effectiveness in
treating SLE
[307]
Clinic Rev Allerg Immunol (2017) 53:237–264 251
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

[293]. Further evidence for the harmful role of excess IFNγ
production in promoting B cell abnormalities and lupus dis-
eases comes from studies in which deletion of IFNγreceptor
in B cells abrogates spontaneous germinal centre formation,
class switching of autoantibodies and nephritis in lupus-prone
mice [294].
Studies in humans and mice have also revealed an impor-
tant role for excess IL-21 production in promoting B cells to
differentiate to plasma cells [295]. Thus, IL-21
−/−
mice have a
diminished ability to produce IgG1 in response to immuniza-
tion, whereas transgenic mice with enhanced expression of IL-
21 develop hypergammaglobulinemia [295]. In contrast, IL-
21 blockade successfully ameliorates lupus symptoms in
lupus-prone MRL mice. Furthermore, knocking out il-21r
gene suppresses lupus manifestations in the BXSB Yaa mouse
model [295].
Overproduction of other cytokines, such as BAFF, a cyto-
kine crucial for peripheral B cell development, has also been
implicated in promoting autoimmune diseases [269,270]. As
cited earlier, BAFF binds to BAFF-R, BCMA and TACI.
BAFF-R plays a key role in B cell maturation and survival
and excess BAFF production is noted in many autoimmune
diseases including SLE, RA and MS [296]. Indeed, transgenic
mice expressing a high level of BAFF (BAFF-Tg) display B
cell hyperplasia and develop lupus-like disease [297]. Of note
in this respect is that high levels of BAFF rescue low-affinity
self-reactive transitional B cells from negative selection at
tolerance checkpoints and allows them to become mature B
cells [298,299]. These observations suggest that signalling
through BAFF-R synergizes with BCR-mediated signalling
in autoreactive B cells to override tolerance in these cells
and permit the generation of pathogenic autoreactive B cells.
Interestingly, MyD88, essential for TLR signalling, is crucial
for autoantibody production in BAFF-Tg mice, suggesting
that there is an interplay between BAFF-R and TLR signalling
in promoting autoimmune diseases [297].
In addition to overt changes in cytokine production and
signalling abnormalities in B cells, subtle changes in the reg-
ulation of signalling pathways activated by cytokine binding
can also promote humoral autoimmunity. For example, het-
erozygous mutations in the stat3 gene leading to replacements
of key amino acids, such as K392R, M394T and K658N, and
enhanced STAT3 binding, or dimerization are associated with
multi-organ autoimmunity, lymphoproliferation and
hypogammaglobulinemia with terminal B cell maturational
arrest [300]. Similarly, SNPs in stat3 and stat4 genes have
been associated with autoimmune thyroid diseases [301].
However, the mechanism involved in promoting altered B cell
responses inindividuals with these polymorphisms and how B
cells promote disease are yet to be determined.
It is noteworthy that several JAK inhibitors have been re-
cently developed as new therapies for treating patients with
inflammatory autoimmune diseases such as RA. Thus,
Tab l e 3 (continued)
Targeted signalling
molecule/pathway
Agent used Structure of agent Biological effects on B lymphocytes Disease/status Reference
Sifalimumab Fully human mAb Inhibits B lymphocyte activation and Ab production Clinical trials concluded its effectiveness in
treating SLE
[308]
TLR4 NI-0101 Humanized mAb Inhibits signalling through TLR4 In phase I clinical trial for treating RA [309]
TLR7/8/9 Chloroquine Chemical TLR7/8/9
antagonist
Reduces endosomal acidification and inhibits signalling
through TLR
A mainstay therapy for SLE [308]
TLR7/8/9 IMO-8400 Chemical TLR7/8/9
antagonist
Inhibits signalling through TLR7/8/9 In phase I clinical trials for SLE [308]
TLR7-RLR9 IMO-3100 Chemical TLR7/9 antag-
onist
Inhibits signalling through TLR7/9 SLE clinical trial is in phase I [308]
The table summarizes available information on the use of therapeutic agents to target signalling pathways in B lymphocytes in clinical trials and in practice
252 Clinic Rev Allerg Immunol (2017) 53:237–264
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

tofacitinib that inhibits JAK1, JAK2, JAK3 and, to a lesser
extent, TYK2 is used in the clinic for treating RA patients in
many countries (Table 3). JAKs are a family of non-receptor
tyrosine kinases that are critical for signalling through cyto-
kine receptors. At present, a number of other JAK inhibitors
are in clinical trials for treating patients with diseases includ-
ing RA and SLE (Table 3).
Conclusions
It is now established that B cells play a key role in initi-
ating and driving pathogenesis in many autoimmune dis-
eases including SLE, RA, MS and SSc beyond their role
in producing autoantibodies. Pathogenic roles played by B
cells depend on tolerance status of the cells, which co-
receptors are co-engaged with the BCR, the cytokine mi-
lieu and, ultimately, the nature and extent of intracellular
signalling generated within B cells. The outcome of BCR
engagement by antigens, self or exogenous, is determined
by optimal levels or engagement and activation of kinases
and phosphatases that regulate the strength and duration
of intracellular signalling. Therefore, abnormal or incon-
gruous engagement/regulation of signalling proteins, co-
receptors or cytokines/TLRs can override B cell tolerance
and lead to autoimmune disease development. Indeed, the
available evidence indicates that regulated and coordinat-
ed engagement of co-receptors and signalling pathways
ensures immune response specificity and efficiency and
prevents the development of autoimmune diseases. This
article has provided an overview of some of the key B cell
signalling pathways and how defects in these could im-
pact pathophysiology (Fig. 1). The available functional
evidence on how changes in the level or function of sig-
nalling proteins and pathways impact B cell responses
provides molecular mechanisms for how GWAS and
SNP association with diseases such as SLE, RA, MS
and TID could predispose to these diseases (Table 2).
Noteworthy is that even in healthy individuals,
autoreactive B cells, perhaps with low affinity for self-
antigens, persist in the naïve B cell repertoire, yet these
fail to become high-affinity pathogenic B cells. Thus, de-
fining the molecular mechanisms that constrain the acti-
vation and/or regulation of self-reactive B cells will help
understanding disease mechanisms and could also pave
the way for new therapeutic strategies in precision medi-
cine. Although B cell depletion therapy has proved to be
highly effective in treating a number of autoimmune dis-
eases including RA, MS and SSc, total ablation of B cells
carries its own risks including life-threatening infections.
In this respect, some recent studies have revealed that
treatment of lupus mice with inhibitors of Bruton’styro-
sine kinase (BTK) can ameliorate disease [310,311].
Thus, targeting dysregulated signalling effectors associat-
ed with proximal or downstream of BCR, CD40, TLR or
cytokine receptors could prove an effective therapeutic
strategy. However, despite substantial progress in the past
few years in defining the role of altered B cell signalling
in autoimmune diseases many questions and challenges
remain.
Take-Home Points
–B lymphocytes are essential for effective immunity to
pathogens, but they can also cause diseases through pro-
ducing autoantibodies, disease-promoting cytokines and
presenting antigens to autoreactive T lymphocytes.
–The potential of B lymphocyte to cause diseases is
prevented by tolerance and by a tight control of intracel-
lular signalling pathways.
–Defects in intracellular signalling, however, can occur
and these lead to autoimmune, lymphoproliferative or
immunodeficient diseases.
–Defects in proximal BCR signalling due to reduced Lyn
and/or CD45 levels promote autoreactive B cell activa-
tion, class switching to IgG autoantibodies and disease.
–Defects in downstream BCR signalling, e.g. Ca
+2
or di-
acylglycerol pathways, lead to increased activation of
NFAT transcription factor, tolerance defects, B lympho-
cyte hyperactivity and autoimmune diseases. Defects in
PI3K lead to apoptosis defects and the generation of
short-lived autoreactive plasma cells.
–Defects in ubiquitination, which regulates signalling in B
lymphocytes through controlling protein levels and tran-
scription factors, enhance activation leading to enhanced
B lymphocyte proliferation to BCR and CD40 engage-
ments and autoantigen presentation to T lymphocytes and
lead to autoimmune diseases.
–Defects in innate immune receptor signalling, such as
TLRs, exaggerate defects in BCR signalling and enhance
autoreactive B cell expansion and responses.
–Dysregulated expression of co-stimulatory receptors,
stimulatory or inhibitory, including CD5, CD19, CD21,
CD22, CD40, CD45, CD72 and FcγRIIB, leads to B
lymphocyte hyperactivity, auto-Ab production and auto-
immune diseases.
–Altered cytokine production, cytokine receptor expres-
sion and/or cytokine signalling help rescue low-affinity
self-reactive B lymphocytes, their differentiation and IgG
isotype autoantibody production.
–Defects in the level and activation of JAKs and STATs
enhance B lymphocyte differentiation leading to multi-
organ autoimmunity, lymphoproliferation or
hypogammaglobulinemia.
Clinic Rev Allerg Immunol (2017) 53:237–264 253
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Acknowledgments Grant UC5 from the Raynaud’s and Scleroderma
Association (new name: Scleroderma research-UK) awarded to Rizgar
Mageed and David Abraham.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Funding Dr. Taher E Taher was funded by grant UC5 from
Scleroderma and Raynaud’s-UK (SR-UK) awarded to Professors Rizgar
Mageed and David Abraham.
Ethical Approval This articledoes not contain any studies with human
participants or animals performed by any of the authors.
Informed Consent Informed consent was obtained from all individual
participants included in the study.
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