Perspectives
opinion
Not always the bad guys: B cells as
regulators of autoimmune pathology
Simon Fillatreau, David Gray and Stephen M. Anderton
Abstract | When B cells react aggressively against self, the potential for pathology
is extreme. It is therefore not surprising that B‑cell depletion is seen as an attractive
therapy in autoimmune diseases. However, B cells can also be essential for
restraining unwanted autoaggressive T‑cell responses. Recent advances have
pointed to interleukin‑10 (IL‑10) production as a key component in B‑cell-mediated
immune regulation. In this Opinion article, we develop a hypothesis that triggering
of Toll-like receptors controls the propensity of B cells for IL‑10 production and
immune suppression. According to this model, B cells can translate exposure to
certain microbial infections into protection from chronic inflammatory diseases.
Evidence for a regulatory effect of B cells in
autoimmune diseases was first provided by
Wolf, Janeway and colleagues, who observed
that B10.PL mice lacking B cells suffered
an unusually severe and chronic form of
experimental autoimmune encephalomyelitis
(EAE)1. Dissection of the underlying
mechanism revealed that B cells regulate
this autoimmune disease through provision
of interleukin‑10 (IL‑10)2. A suppressive
function for IL‑10 produced by B cells
has also been demonstrated in a model of
inflammatory bowel disease (IBD) and in collagen-induced arthritis (CIA)3,4, suggesting a
general role for IL‑10-producing B cells in
immune homeostasis (BOX 1). More recently,
IL‑10-producing B cells have been identified
in humans5, and preliminary evidence show‑
ing that B cells from patients with multiple
sclerosis produce decreased amounts of IL‑10
suggest that these B cells have a regulatory
role6. Given the capacity of IL‑10-produc‑
ing B cells to assist in the termination of an
ongoing disease, and their broad involvement
in immune homeostasis, it is important to
understand the factors that control their sup‑
pressive function. It is conceivable that more
than one activation pathway can stimulate
a regulatory function in B cells and that
the receptors controlling antibody produc‑
tion by B cells — that is, B‑cell receptor
(BCR), CD40 (Ref. 7) and Toll-like receptors
(TLRs)8 — might also be involved in their
regulatory function (FIG. 1). Of course, other
antigen-presenting cells (APCs), such as
dendritic cells (DCs), can act in a suppressive
manner9–11 and may have a regulatory role
in some autoimmune situations12, but in the
variety of models described in this Opinion
article the DC contribution is insufficient
to bring about resolution of inflammation,
whereas B cells are crucial.
Signals for B-cell IL‑10 production
Signals from the B‑cell receptor. In EAE,
provoked by immunization with myelin
oligodendrocyte glycoprotein (MOG),
disease suppression required B‑cell trigger‑
ing through the BCR as B cells specific for
an irrelevant antigen (hen-egg lysozyme)
were unable to resolve EAE2. Furthermore,
mice deficient in CD19, a co-receptor that
augments BCR signalling, also display
exacerbated EAE, with their B cells produc‑
ing reduced amounts of IL‑10 on exposure
to MOG13. The suppressive B cells are most
likely specific for the autoantigen driving
disease, as shown by a correlation between
recovery from EAE and the accumulation
of MOG-reactive IL‑10-producing B cells2,
and the inhibition of CIA involved provision
of IL‑10 by collagen-specific B cells4. The
nature reviews | immunology
autoantigen activating these B cells could
either be derived from the immunization
cocktail, in which case regulation could start
early (possibly before disease initiation),
or it could be released from the damaged
target organ as antigenic debris, in which
case suppression could only occur after the
initiation of pathology. The importance
of the BCR is more difficult to appreciate
in the case of colitis because the antigens
involved in this spontaneous disorder are
unknown. Nevertheless, BCR-derived
signals might also be required because mice
lacking the p110δ subunit of the BCR sig‑
nalling enzyme phosphoinositide 3‑kinase
spontaneously develop IBD14,15.
Signals from CD40. In EAE and CIA,
production of IL‑10 by autoreactive B cells
required simultaneous stimulation through
the BCR and CD40 (Refs 2,4), and B‑cell
expression of CD40 was required for the
suppression of EAE and CIA. This predicts
that an interaction between B cells and
CD4+ T helper cells expressing CD40
ligand (CD40L) is necessary for B‑cellmediated suppression. As an alternative to
T helper cells, two evolutionary conserved
subsets of T-cell receptor (TCR)-invariant T cells
that are restricted through the CD1d and
MR1 (MHC class I related) non-polymorphic
MHC class Ib molecules can also express
CD40L and convey protection against
autoimmune diseases in mice16–18. In
particular, MR1-restricted T cells can
induce IL‑10 production by B cells and
protect against EAE18.
B cells themselves can express CD40L19,
allowing possible B‑cell intrinsic control of
IL‑10 production. This might have a signifi‑
cant role in systemic lupus erythematosus
(SLE), as during the development of this
disease, the production of IL‑10 is restricted
to CD40L+ B cells and correlates with their
CD40L expression levels20–22. It is notable
that IL‑10 can be a pathogenic cytokine in
SLE; polymorphisms in the IL10 promoter
that lead to high IL‑10 production are
associated with higher susceptibility to
SLE23, and blocking of IL‑10 with an
IL-10-specific antibody reduces disease
activity in patients with refractory SLE24,25.
Dysregulated production of IL‑10 by
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Perspectives
Box 1 | B cells as regulators of pathology in the central nervous system, joints and gut
In two models of experimental autoimmune encephalomyelitis (EAE; induced with
immunodominant peptides from myelin oligodendrocyte glycoprotein in C57BL/6 mice and
myelin basic protein in B10.PL mice), the presence of B cells was required for recovery from clinical
signs1,2. In collagen-induced arthritis (CIA), the transfer of B cells that had been activated through
CD40 ligation was found to have a protective effect4. A more complicated model shows the
development of spontaneous colitis (pathologically reminiscent of human ulcerative colitis) in
mice lacking T‑cell receptor (TCR) α‑chains. Although the disease is caused by TCRα–TCRβlowCD4+
T cells, an expansion in the B‑cell population is also evident in these mice and it is this B‑cell
population that has a key disease suppressive function3.
Beyond the organs that are the subject of autoimmune attack there are other differences in
these models. Autoantibodies can be present in EAE but pathology still occurs in their absence in
B10.PL and C57BL/6 mice. Because of the pathogenic activity of autoantibodies in CIA, it is not
possible to formally demonstrate that mice lacking B cells develop more severe disease, as is the
case in EAE and ulcerative colitis. That said, all three models have shown that the transfer of B cells
can have protective effects. Although the involvement of autoantibodies in the pathogenesis of
EAE and CIA differs, the pathogenic T‑cell response in these two models most likely involves the
pro-inflammatory T‑cell populations T helper 1 (TH1) cells and TH17 cells. The colitis model differs in
that the inflammation appears to be driven by TH2 cells. The overall conclusion that can be derived
from these models is that the B‑cell compartment has the capacity to control organ-specific
inflammation that may be driven by TH1‑, TH2- or TH17-cell responses with or without the
involvement of destructive autoantibodies.
B cells might therefore contribute to the
pathogenesis of SLE, rather than suppress‑
ing it. In support of this notion, injection of
IL‑10 into some lupus-prone strains of mice
can accelerate disease26, and transgenic
mice overexpressing CD40L in B cells
develop a lupus-like disease27. Nonetheless,
it is important to bear in mind that IL‑10
retains protective functions in other mouse
models of spontaneous SLE28.
although in this case the effect does not
appear to be mediated by IL‑10. TLR activa‑
tion may also be involved in B‑cell-mediated
regulation of IBD32, because mice deficient
for G‑protein α inhibitory subunit 2 (Gαi2),
which controls IL‑10 production by TLRactivated B cells, spontaneously develop a
fatal colitis33. Interestingly, the gene encoding
Signals from Toll-like receptors. Although
effector and/or memory autoreactive B cells
secrete IL‑10 following simultaneous stimu‑
lation through the BCR and CD40, these
two pathways are insufficient to elicit IL‑10
production from naive B cells, or from B cells
isolated from mice at the peak of EAE2.
TLR agonists, such as lipopolysaccharide
(LPS) from Gram-negative bacteria, peptido­
glycan from Gram-positive bacteria or
CpG-containing oligonucleotides that mimic
bacterial DNA, are potent inducers of IL‑10
production by naive B cells29,30. TLRs are
directly involved in the regulatory function
of B cells because mice with a B‑cell-specific
deletion of both Tlr2 and Tlr4, or of the
TLR adaptor Myd88 (myeloid differentia‑
tion primary-response gene 88), did not
recover from EAE29. MyD88-deficient B cells
could form germinal centres and mounted
an antigen-specific antibody response,
indicating that MyD88 signalling may have
a non-redundant role in driving regulatory
activity in B cells. This is in agreement with
the observation that adoptive transfer of
B cells activated with LPS in vitro protects
non-obese diabetic (NOD) mice from insulitis31,
TLR ligand
Gαi2 is a candidate gene for IBD pathogenesis
in humans32. A complete picture, however, is
lacking as other TLRs (including TLR9) may
also drive regulatory (IL‑10) responses in vivo
and in some circumstances TLR ligation
(often combinatorial) causes secretion of proinflammatory cytokines from B cells29,30,34,35.
The development of B‑cell regulation
almost certainly depends on context and
an integration of available signals.
As described above, B cells also require
activation through CD40 and the BCR to
induce recovery from EAE2. B cells activated
with LPS, and then re-stimulated via
CD40, maintain their IL‑10 production29,
suggesting that B‑cell-mediated regulation
is established in a two-step process. First,
TLR signalling initiates IL‑10 production
by B cells, but this probably stimulates too
little IL‑10 from each individual B cell for
effective regulation. In a second phase,
engagement of receptors classically involved
in B‑cell survival and expansion, such as
the BCR and CD40, amplifies the initial
population of IL‑10-producing B cells,
thereby securing IL-10 production for effec‑
tive suppression. This second phase may
preferentially expand autoantigen-reactive
B cells if autoreactive CD4+ T cells are the
main source of CD40L. This would establish
a feedback loop between pathogenic T cells
Antigen
IL-10
BCR
TLR
MHC
molecule
CD40L
B cell
T cell
DC
CD40
CD40
IL-10
CD40L
IL-10?
?
?
TCR
Invariant
T cell
Regulatory
T cell
Vα14–Jα18
or Vα19–Jα33
Figure 1 | B‑cell-derived interleukin‑10: stimuli and effects. B cells from immunized mice can be
stimulated to produce interleukin‑10 (IL‑10) by a combination of ligationNature
of theReviews
B-cell receptor
(BCR)
| Immunology
by antigen and of CD40 by CD40 ligand (CD40L). The source of CD40L may be the CD4+ T cells that
provide help during cognate interactions, T-cell receptor (TCR)-invariant T cells expressing TCR
Vα14–Jα18 or Vα19–Jα33, or the B cells themselves (not shown). Naive B cells can also produce IL‑10
in response to ligation of Toll-like receptors (TLRs). The ultimate effect of B‑cell production of IL‑10 is to
constrain pathology (irrespective of whether it is driven by T helper 1 (TH1)‑, TH2- or TH17-cell responses).
This may be mediated either by a direct effect on the CD4+ effector T cells themselves, by a reduction
in immune priming by innate cells (most likely dendritic cells (DCs)) or by enhanced activation of regu‑
latory T‑cell populations (which could be either forkhead box P3 (FOXP3)+, IL‑10-producing or CD8+).
392 | may 2008 | volume 8
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Perspectives
and B‑cell-mediated regulation. Such a
two-step process seems to be involved in
the regulation of colitis by IL‑10-producing
B cells3. In this model, B cells require MHC
class II expression and therefore interaction
with T cells to suppress colitis, but this
pathway is mainly needed to amplify the
pool of B cells producing IL‑10 as it can be
circumvented by increasing the number of
MHC-class‑II-deficient B cells available3.
Other signals. Other signals could contrib‑
ute to the production of IL‑10 by B cells.
Apoptotic cells can provide an endogenous
signal to trigger IL‑10 production, leading
to amelioration of CIA36, whereas plateletactivating factor and serotonin have been
implicated following skin exposure to ultra‑
violet irradiation37. These pathways may
induce some regulatory function by B cells
in the case of ‘sterile’ autoimmune reactions
that do not involve microbial infections.
Which B cells suppress autoimmunity?
All subsets of mature B cells (BOX 2) can
produce IL‑10 on TLR triggering in vitro29,30.
CD5+ peritoneal B‑1a cells produce par‑
ticularly large amounts of IL‑10 following
LPS stimulation38. Their splenic equivalent
has not been tested for IL‑10 secretion, but
given their expression of CD43 (a marker
that is used in cell sorting by negative
selection) it seems unlikely that it is the
B‑1 cells that transfer protection against
EAE, CIA and IBD2,4,39,40. Therefore, B‑2 cells
probably contain the subset regulating these
autoimmune diseases. The B cells regulating
ulcerative colitis express the marker CD1d,
which is found on transitional type 2 (T2)
and marginal zone (MZ) B cells3,41,42, and
adoptive transfer of spleen cells enriched
for T2 or MZ B cells ameliorates CIA and
colitis, respectively39,43. However, care is
needed when assigning a regulatory role
to MZ or T2 B cells. The B cells involved
in suppression of ulcerative colitis do not
have exactly the same phenotype as MZ
B cells3, and MZ B cells are less efficient than
mesenteric lymph node B cells at providing
protection from colitis39. Finally, T2 B cells
are ‘transitional’ by nature so that the
suppressive cell type in T2 B‑cell adoptive
transfer experiments could need to progress
through to a more advanced stage of B‑cell
development before attaining regulatory
function43. We cannot at present exclude the
possibility that suppression is mediated by
a subset of activated follicular-like B cells.
Overall, ambiguity remains over the B‑cell
subpopulation(s) involved in regulation of
EAE, CIA and IBD2,44.
Box 2 | B‑cell subpopulations
B cells are classically divided into two subpopulations: B‑1 cells that reside in pleural and
peritoneal cavities, and B‑2 cells that populate secondary lymphoid organs. B‑1 cells develop
mostly in fetal liver, whereas B‑2 cells are constantly generated in the adult bone marrow. As
immature B cells leave the bone marrow, they enter the spleen where they differentiate into
transitional type 1 and type 2 B cells that are then selected to become either marginal zone B cells,
which are mostly sessile, or follicular B cells, which recirculate between lymphoid organs and
populate lymph nodes. These B‑cell populations are characterized by the expression of distinct
cell-surface receptors.
How do IL‑10-producing B cells suppress?
B-cell-derived IL‑10 can suppress auto­
immune disorders with diverse aetiologies
(BOX 1). B‑cell-deficient mice44 and mice
with IL‑10-deficient B cells2 show height‑
ened lymph node T helper 1 (TH1)-cell
responses to immunization. B‑cell-regulation
of EAE therefore starts in the draining
lymph nodes within days of immunization.
B‑cell‑mediated regulation of EAE is also
associated with a suppression of TH17 cells,
suggesting that IL‑10 from B cells influ‑
ences disease progression by instructing
T‑cell differentiation29. In agreement with
this notion, targeting myelin autoantigen
to B cells inhibits EAE induction by diverting
the autoreactive response away from a
TH1-type response towards a TH2-type
response45,46. Similarly, suppression of CIA
is associated with an inhibition of TH1 cells4.
However, we found no correlation between
the levels of TH2-cell cytokines and IL‑10
production by B cells2,44. Furthermore,
IL‑10 produced by B cells also suppresses
ulcerative colitis, a disease that is primarily
driven by IL‑4-producing TH2 cells47 and,
in general, IL‑10 is a known suppressor
of TH2-type immune pathology, such as
mouse schistosomiasis48. Immune devia‑
tion towards a TH2-type response profile
therefore seems unable to provide a general
mechanism to account for suppression of
autoimmune pathology by IL‑10-producing
B cells.
IL‑10 has potent activity in limiting DC
function24, and therefore IL‑10-producing
B cells may exert their effects on T‑cell
responses indirectly by inhibiting the
innate immune system31,37,49. Indeed,
DCs from B‑cell-deficient mice produce
higher amounts of IL‑12 than DCs from
wild-type mice after immunization, and
this drives a stronger TH1-cell response44.
Furthermore, IL‑10 from B cells can
repress the production of IL‑6 and IL‑12
by DCs, and thereby inhibit the differen‑
tiation of TH17 and TH1 cells, respectively29.
Alteration in the balance of IL‑10 and
IL‑12 levels has important effects on
EAE50, IL‑10 inhibits EAE progression and
nature reviews | immunology
epitope spreading, resulting in a reduction
of IL-12 levels51. IL-10-producing B cells
similarly influence IL‑12 production by
DCs in the neonatal immune system, and
this contributes to the strong TH2-cell bias
observed in newborns52. Further evidence
that B cells can directly suppress inflam‑
matory reactions produced by the innate
immune system is provided by the capacity
of B‑cell transfer to inhibit spontaneous
IBD in lymphopaenic mice53.
Glossary
Anterior-chamber-associated immune deviation
(ACAID). Systemic antigen-specific tolerance that
develops after inoculation of antigen into the immuneprivileged site of the anterior chamber of the eye.
Collagen-induced arthritis
(CIA). An experimental model of rheumatoid arthritis.
Arthritis is induced by immunization of susceptible animals
with type II collagen.
Epitope spreading
A term originally applied to responses to autoantigens that
tend to become more diverse as the response persists.
Experimental autoimmune encephalomyelitis
(EAE). An animal model of multiple sclerosis. EAE can
be induced in several mammalian species by immunization
with myelin-derived antigens together with adjuvant.
The immunized animals develop a paralytic disease with
inflammation and demyelination in the brain and spinal
cord that has several pathological features in common
with multiple sclerosis in humans.
Inflammatory bowel disease
(IBD). A chronic condition of the intestine that is
characterized by severe inflammation and mucosal
destruction. The commonest forms in humans are ulcerative
colitis and Crohn’s disease. Animal models indicate that
they result from the dysregulation of the local immune
response to normally harmless commensal bacteria.
Non-obese diabetic (NOD) mice
A mouse strain that has a polygenic susceptibility to
spontaneous development of autoimmune, type 1
diabetes. The main component of susceptibility is the
unique MHC haplotype H2g7.
T-cell receptor (TCR)-invariant T cells
A term to describe conserved subsets of T cells that
express invariant TCR among which are the CD1drestricted natural killer T cells expressing Vα14–Jα18,
and the MR1-restricted mucosal associated invariant
T (MAIT) cells expressing Vα19–Jα33.
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Perspectives
Naturally occurring CD4+CD25+FOXP3
(forkhead box P3)+ regulatory T cells also
contribute to the recovery from EAE and
their effects are most likely required in the
inflamed central nervous system (CNS)
itself54,55. A transient reduction in Foxp3
mRNA levels in the CNS during the early
course of disease has been reported in B‑celldeficient mice and in mice in which B cells
cannot secrete IL‑10 (Ref. 56). The functional
consequence of such momentary effects
remains to be addressed. B cells are a main
source of B7H, and its receptor, inducible
T‑cell co-stimulator (ICOS), is selectively
present on activated and regulatory T cells57,58.
ICOS-deficient mice develop fulminant
EAE58, and blocking ICOS during the induc‑
tion phase of EAE exacerbates disease59. This
interaction may be crucial for the develop‑
ment of protective IL‑10‑producing T cells,
a
or for the optimal function of CD4+CD25+
regulatory T cells60. Whether B cells are the
crucial B7H-expressing cells in the described
regulatory mechanism still has to be tested.
MZ B cells have a key role in the complex
regulatory circuit underlying anterior-chamberassociated immune deviation (ACAID). Here,
their role is to capture ocular antigen from
migratory F4/80+ APCs and present it to
CD4+CD25+ and CD8+ regulatory T cells,
ultimately leading to tolerance61,62.
B cells can therefore orchestrate the regu‑
lation of autoimmune diseases from within
secondary lymphoid organs both directly
through inhibition of the pathogenic cells
(autoreactive T cells and innate immune
cells) and indirectly by inducing regulatory
activity in different T‑cell populations.
Our current model is that B cells constrain
the initial expansion of pathogenic T cells,
b
Mycobacterial
ligands
Mycobacterial
ligands
TLR2,
TLR4
TLR2, TLR4,
TLR9
IL-10
DC
B cell
IL-6
IL-12
IL-23
IL-6
IL-12
IL-23
Regulatory
T cell
Autoaggressive
T cell
Regulation suboptimal
Regulation optimal
Chronic disease
Disease resolution
Figure 2 | A model for how selective Toll-like receptor triggering of B cells to produce
interleukin‑10 constrains the autoaggressive response in experimental autoimmune
encephalo­myelitis. a | Following immunization with autoantigen in complete Freund’s adjuvant,
Nature Reviews | Immunology
activation of dendritic cells (DCs) through Toll-like receptor 2 (TLR2), TLR4 and TLR9 (by mycobacterial
ligands) drives the expansion of two autoantigen-reactive CD4+ T‑cell populations: an autoaggressive
(T helper 1 (TH1)-cell and/or TH17-cell) population and a forkhead box P3 (FOXP3)+ regulatory
T (TReg)‑cell population. In the absence of B cells (or B‑cell-derived interleukin-10 (IL‑10)), the early
expansion of the autoaggressive population dominates and the TReg-cell cohort is unable to control
this population subsequently (either in the lymph nodes or the central nervous system (CNS)).
b | Concomitant stimulation of B cells through TLR2 or TLR4 early in the response induces their produc‑
tion of IL‑10, which limits the initial expansion of the autoaggressive cohort. This smaller autoaggressive
population is sufficient to promote CNS inflammation, but the autoantigen-reactive TReg-cell cohort
is large enough to suppress the autoaggressive cells within the CNS, ultimately leading to resolution
of the disease. For simplicity, pathogenic B cells are not shown, their role in pathogenesis would be
twofold: first, to perpetuate presentation of autoantigen to T cells (initiated by the DCs) and second,
as plasma cells secreting autoantibodies (driven by autoreactive T cells).
394 | may 2008 | volume 8
allowing a balance with regulatory T cells
that ultimately leads to disease resolution.
Without functional B cells, there is over‑
expansion of autoaggressive T cells, the
balance with regulatory T cells is lost and the
pathology becomes chronic (FIG. 2).
B cells as effectors and regulators?
The involvement of the BCR, CD40 and TLRs
in the regulatory function of B cells raises
a conceptual difficulty because B cells are
activated in this way during most immune
responses. It is unlikely that activated B‑cell
populations always have a suppressive com‑
ponent. We do not favour the existence of a
natural ‘BReg-cell’ population; of which the
sole function is to regulate immune proc‑
esses. By analogy with thymically-derived
FOXP3+ TReg cells, this would require an edu‑
cation step allowing BReg cells to be selected
by self antigens, but there is no evidence for
promiscuous expression of tissue-specific
antigens in the bone marrow.
As an alternative, we propose a model in
which the suppressive activity of a B cell is
determined by its condition of activation,
and in particular by the TLR agonists
available. Only particular TLR agonists
trigger a regulatory function in B cells29.
TLR9 contributes to EAE severity63, but
has no influence on B‑cell-driven disease
resolution (mice bearing TLR9-deficient
B cells recover normally). By contrast, it
is TLR2 and/or TLR4 signalling in B cells
that drives recovery29. In EAE, components
from Mycobacterium tuberculosis present
in the complete Freund’s adjuvant used to
induce disease provide the TLR agonists that
trigger the regulatory function of B cells.
TLR2 and/or TLR4 are not required for
disease induction, indicating that distinct
components from a single microbial species
drive the induction and the resolution of this
autoimmune pathology29 (FIG. 2). This dual
role of microbial products resembles the
existence of protective and pathogenic bacte‑
rial species in IBD64. The balance between
these two types of signal appears to control
the initiation, progression and resolution of
T‑cell-mediated inflammation.
Why might the regulatory function of
B cells be coupled to specific microbial
products and TLRs? A possible explanation
is that B cells and cells of the innate immune
system, such as DCs or macrophages, use
TLRs differently to sense their environment.
Such cell-type-specific variation in TLR
function could be due to B‑cell-specific
differences in TLR signalling29,30. Indeed,
the function of MyD88 is highly cell-type
specific: although MyD88 signalling in B cells
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controls disease resolution, MyD88 signalling
in other cells is required for disease induc‑
tion63. Furthermore, in vitro stimulation of
B cells with TLR agonists produced a cytokine
milieu that could inhibit T‑cell activation
in an IL‑10‑dependent manner, whereas
activation of DCs in the same way produced
a milieu that contained very little IL‑10 and
that was able to enhance T‑cell proliferation29.
Comparing the signalling of distinct TLRs in
DCs and B cells will clarify this point. It is also
possible that B cells and DCs or macrophages
express different TLRs, or TLR co-receptors,
and thereby recognize different TLR agonists.
In this regard, it is intriguing that DCs and
B cells use the product of the same Tlr9 gene
to recognize distinct types of CpG-containing
DNA. Type A (also known as type D) CpGcontaining oligodeoxynucleotides strongly
stimulate DCs and macrophages, but fail to
stimulate B cells, whereas type B (also known
as type K) CpG-containing oligodeoxynucleo­
tides efficiently activate B cells65–67.
We predict that microorganisms rich in
the TLR agonists that trigger a regulatory
function in B cells will provide protection
from the development of autoimmune
diseases. The incidence of multiple sclerosis,
type 1 diabetes and IBD has increased dram­
atically during the past 50 years in western
countries, which inversely correlates with a
sharp decrease in some infectious diseases,
suggesting that certain microorganisms are
associated with protection from autoimmune
diseases68. Several microorganisms that can
induce IL‑10 production by B cells have
already been identified (BOX 3). Certain para‑
sitic infections are associated with reduced
multiple sclerosis progression69,70. Infection
with the helminth Schistosoma mansoni
induces IL‑10 production by B cells71, and
thereby protects mice from anaphylaxis72.
All these observations provide support for
the ‘hygiene hypothesis’ according to which
microbial or parasite exposure can limit
pathological immune hyper-reactivity. Our
model identifies a microbial product (the
TLR ligand) and an immune cell type (B cells)
that translate microbial exposure into protec‑
tion from chronic autoimmune disease.
An interesting extension of this model
is that a disease that is exacerbated by IL‑10
production from B cells should not fit
the paradigm that the hygiene hypothesis
provides. As noted earlier, SLE is one such
disease and appears to be relatively common
in developing world73 compared to other,
more ‘western’ autoimmune diseases such
as multiple sclerosis. Genetics may have an
important role in this, but in terms of our
model, it is nevertheless intriguing.
Box 3 | Multiple microorganisms can induce interleukin‑10 production by B cells
Several infectious agents use Toll-like receptor (TLR) signalling in B cells to limit the immune
response of the host by inducing the production of interleukin‑10 (IL‑10). This can sometimes be
beneficial to the host; for example, chronic infection with the tropical helminth Schistosoma
mansoni stimulates IL‑10 production by B cells, and thereby can provide protection from an
experimental model of anaphylaxis72 . This stimulation of IL‑10 production by B cells can be
recapitulated using a sugar molecule found in soluble egg antigens of S. mansoni: the
pentasaccharide lacto‑N-fucopentaose-III (LNFP-III) that terminates in Lewisx and that can interact
with TLR4 (Ref. 79). Similarly, B cells from mice injected with the trypanosome protozoan
Leishmania major or with a microfilarial extract from the roundworm Brugia malayi produce IL‑10
in response to stimulation with LNFP-III or microfilarial extract, respectively, whereas B cells from
naive mice do not80.
Viruses can also elicit IL‑10 production from B cells via TLR-dependent mechanisms81,82. Mouse
mammary tumour virus can subvert the immune response by stimulating B-cell IL‑10 production by
triggering TLR4 on accessory cells82. It is noteworthy that B-cell TLR4 expression was not required in
this model, indicating an additional indirect process for TLR triggering of IL‑10 production by B cells.
Similarly, the highly oncogenic polyoma virus can also elicit an IL‑10 response in B cells through
TLR4 signalling in susceptible strains of mice, which only mount weak and transient cytotoxic CD8+
T‑cell responses81. B cells from resistant strains of mice, which mount a sustained cytotoxic T‑cell
response, do not produce IL‑10 on exposure to polyoma virus. These data suggest that a broad
range of microorganisms can dampen host defence mechanisms through the induction of IL‑10
production by B cells, and may thereby suppress chronic inflammatory diseases.
Future directions
This model of immune regulation that
integrates B‑cell regulation of autoim‑
mune pathology within the framework
of the hygiene hypothesis will need to be
tested using different microorganisms and
autoimmune models. Although different
types of microorganism can induce IL‑10
production by B cells (BOX 3), the relationship
between these infections and autoimmune
diseases is not well known. Secretion of
IL‑10 from B cells can also be induced via
MyD88-independent pathways, for instance
following exposure to apoptotic cells or to
inflammatory mediators. Future experiments
will certainly need to address the role of
these pathways for the natural regulation
of autoimmune diseases.
A comparison of the signalling pathways
operating in TLR-activated DCs and B cells
should improve our molecular understanding
of both the suppressive function of B cells
and the stimulatory activity of DCs. Here,
we have focused on regulation mediated
by B cells through provision of IL‑10, but
TLR-activated B cells have at their disposal
a broader molecular arsenal to suppress
immune responses. They can produce the
regulatory cytokine transforming growth
factor‑β (TGFβ) or upregulate the death
receptor ligand CD95 ligand31, and TLRactivated B cells can also regulate immunity
independently of IL‑10 (Refs 31,53).
If B cells have a key regulatory role, why
would B‑cell-depletion strategies be beneficial
in human autoimmune disease74,75? Our
model predicts that reduced exposure to
relevant microorganisms will lead to a loss of
nature reviews | immunology
B‑cell-mediated regulation. We anticipate that
the level of TLR-triggered B‑cell‑mediated
regulation is poor in subjects suffering from
autoimmune diseases in the industrialized
world. Consequently, B‑cell depletion would
be mostly beneficial in these individuals,
because ecological changes have tilted the
balance towards pathogenic rather than
protective B‑cell function. If B cells do have
a regulatory effect in those diseases showing
remission phases (such as multiple sclerosis),
we suggest that the effects of B‑cell-depletion
therapy while the patient is in remission could
be complex. Once the balance has tipped
towards pathology, as well as carrying out the
role of pro-inflammatory APCs, B cells will
also make autoantibodies76. B‑cell depletion
therapy has a profound and surprisingly rapid
effect on the auto­antibody levels77. However,
it is possible that depletion therapy will only
be a long-term cure in autoimmune disease
if it is combined with an attempt, following
recovery, to reset the regulatory balance to
which B cells can clearly contribute78.
Simon Fillatreau is at the Immune regulation group,
Deutsches Rheuma-ForschungsZentrum,
Charitéplatz 1, 10117 Berlin, Germany.
David Gray and Stephen M. Anderton are at the
University of Edinburgh, Institute of Immunology and
Infection Research, School of Biological Sciences, Kings
Buildings, West Mains Road, Edinburgh EH9 3JT, UK.
Stephen M. Anderton is also at the University of
Edinburgh, Centre for Inflammation Research, Queen’s
Medical Research Institute, 47 Little France Crescent,
Edinburgh EH16 4TJ, UK.
Correspondence to S.M.A.
e‑mail: [email protected]
doi: 10/1038/nri2315
volume 8 | may 2008 | 395
© 2008 Nature Publishing Group
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nature reviews | immunology
Acknowledgements
Work in the authors’ laboratories is supported by the
Deutsche Forschungsgemeinschaft (SFB-650), the Association
pour la Recherche sur la Sclérose En Plaques (ARSEP), and
the Hertie Stiftung (S.F.); the Wellcome Trust (D.G.); and the
Medical Research Council, the Wellcome Trust and the UK
Multiple Sclerosis Society (S.M.A.). S.M.A. is an MRC Senior
Research Fellow and holds a Research Councils UK Fellowship
in Translational Medicine.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CD40 | CD40L | Gαi2 | IL‑10 | IL‑12 | Tlr2 | Tlr4
FURTHER INFORMATION
Stephen Anderton’s homepage: http://www.biology.ed.ac.
uk/research/institutes/immunology/homepage.
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