PERSPECTIVES
by IgG and self-antigen activates the C1
OPINION
A protective role for innate immunity
in systemic lupus erythematosus
Michael C. Carroll
Abstract | Clinical and genetic studies in
humans and animal models indicate a
crucial protective role for the complement
system in systemic lupus erythematosus
(SLE). This presents a paradox because the
complement system is considered to be an
important mediator of the inflammation that
is observed in patients with SLE. One
current view is that complement provides
protection by facilitating the rapid removal
of apoptotic debris to circumvent an
autoimmune response. In this Opinion
article, I discuss an alternative model in
which complement — together with other
components of the innate immune system
— participates in the ‘presentation’ of SLE-
inducing self-antigens to developing B cells.
In this way, the complement system and
innate immunity protect against responses
to SLE (self) antigens by enhancing the
elimination of self-reactive lymphocytes.
Systemic lupus erythematosus (SLE) is an
incurable autoimmune disease of unknown
aetiology that affects more than one million
individuals each year1. It is characterized by
circulating IgG autoantibodies that are specific
for self-antigens, such as DNA, nuclear pro-
teins and certain cytoplasmic components.
Immune complexes comprising autoantibody
and self-antigen mediate a systemic inflamma-
tory response. IgG-containing immune com-
plexes are particularly pathogenic because they
both activate the complement system (BOX 1
and FIG. 1) and crosslink Fc receptors expressed
by leukocytes2. Activation of complement
leads to the release of the pro-inflammatory
NATURE REVIEWS | IMMUNOLOGY
peptides complement component 3a (C3a)
and C5a, which function in a synergistic
manner with Fc-receptor crosslinking to
activate mast cells and stimulate inflamma-
tory cells, thereby leading to tissue injury.
SLE is considered to be a B-cell disorder
because of the pathogenic nature of the
autoantibodies and because disease fails to
develop in the absence of B cells3, although
self-reactive T cells that promote class-
switch recombination (CSR) and somatic
hypermutation (SHM) are also required.
Recent studies using mouse models of SLE
also indicate a role for B-cell expression of
Toll-like receptors (TLRs), stimulation
through which CSR and possibly SHM can
be potentiated, similar to the engagement
of TLRs expressed by T cells3,4. The source
of antigen is probably apoptotic blebs that
include nuclear proteins and chromatin,
the main targets for most autoantibodies in
SLE5. Interestingly, SLE antigens have the
common characteristic of being highly
conserved and are probably cleared by sim-
ilar innate mechanisms as microbial anti-
gens, which could provide an important
clue to the mechanism of this clearance
(discussed later).
The complement system, which is an
important mediator of inflammation, is a
family of more than 20 serum and cell-surface
proteins that function as a cascade — in a
manner similar to the blood-coagulation
pathway — resulting in the induction of
inflammation (BOX 1) and the enhancement
of the adaptive immune system6,7 (BOX 2).
Chronic release of immune complexes formed
©2004 Nature Publishing Group
complex, leading to the formation of C3
convertase and the enzymatic cleavage of
the central complement component C3.
Activation of C3 — the most abundant of
the serum complement proteins — results
in covalent attachment of the C3b fragment
to pathogens and/or host cells. This is an
important step for amplification through
the alternative complement pathway and
for continued activation of the terminal
complex (C5 to C9) (BOX 1). Moreover, cou-
pling of activated C3 to host cells provides
a ligand for various receptors that are
expressed by macrophages, granulocytes
and mast cells, which become activated and
enhance inflammation after ligation of these
receptors.
Intriguingly, as discussed later, despite
being an important mediator of inflamma-
tion, the classical complement pathway can
be protective in patients with SLE, leading
to the paradox that, on the one hand, com-
plement is pathogenic but, on the other, it
is protective. Early attempts to explain a
protective role for the complement system
in SLE focused on its intrinsic role in clear-
ance of immune complexes 8,9. Because a
hallmark of SLE is the development of IgG-
containing immune complexes, it was pro-
posed that complement provides protection
by the rapid clearance of complexes, which
limits their pathogenicity10. Although this
effector function is probably important, it
would not explain the initial formation of
autoantibodies in complement-deficient
individuals, so more recently, the clearance
hypothesis was formulated to explain how
defects in the uptake of apoptotic cells can
lead to the formation of SLE autoantibodies.
In this Opinion article, I review the evi-
dence supporting this model and discuss its
strengths and weaknesses. In addition, I
present an alternative model that proposes
a novel role for the innate immune system in
the regulation of self-reactive B cells. These
two models are not necessarily mutually
exclusive.
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PERSPECTIVES

The SLE paradox who are deficient in C1 or C4, which are specific for C1q can also lead to SLE14,15.
Susceptibility to SLE is heritable, and studies major susceptibility factors. For several Moreover, partial deficiency in C4 — of
in humans and mice indicate that multiple decades, it has been clear that individuals which there are two human isotypes, C4A
genetic loci are involved11–13. An exception to who are deficient in the C1 and C4 early and C4B — is relatively common and is an
polygenic predisposition to disease seems to complement proteins almost always develop important factor for susceptibility to SLE in
be single-gene deficiency in either C1 (C1q, SLE. Although genetic deficiencies in the the Scandinavian population16,17. Taken
C1r or C1s) or C4. Notably, individuals who individual loci are rare, acquired deficien- together, these observations indicate that the
are deficient in C3 have a low level of suscep- cies that result from drugs that inactivate early complement proteins are important in
tibility to SLE compared with individuals C4 or from the development of antibodies protecting humans against the development
of SLE. Mice that are deficient in C1q18 or C4
(REFS 19,20) are also predisposed to SLE-like
Box 1 | Complement pathways disease, but the frequency and severity of
disease is strain dependent. For example,
Classical Lectin Alternative mice that are deficient in C1q or C4 on a
complement complement complement
pathway pathway pathway mixed background of 129 and C57BL/6
develop SLE autoantibodies and evidence of
Immune complex (IgM or IgG) Mannan-binding lectin complex C3b-coated pathogen renal disease, whereas the same deficiency on
a C57BL/6 background has little effect. As
noted earlier, these observations present a
paradox because the complement system is
C1 MASP1 and MASP2 Factor B also an important effector of the innate
immunity and inflammation that mediate
the pathogenesis of SLE6.
C4 and C2 Factor D
C3 convertase Innate immunity and SLE
(C4b–C2b or C3b–Bb)
C5 convertase With the advent of gene targeting and the
(C4b–C2b–C3b availability of genetically modified strains of
or C3b–Bb–C3b)
mice, it has become evident that single-gene
deficiencies in other components of the
C3a and C5a
innate immune system also predispose indi-
viduals to SLE-like disease. Intriguingly, mice
C3b and C4b C5 that are deficient in serum amyloid protein
Peptide mediators of
inflammation through (iC3b and C3d)
(SAP)21,22, DNase I (REF. 23), natural IgM24,25
C3a receptor- and C5a or the receptor for C3b and C4b (comple-
receptor-mediated C5b, C6, C7, C8 and C9
activation of leukocytes Opsonize pathogens ment receptor 1, CR1; also known as CD35)
and antigens (REFS 26–28) develop SLE-like disease in a
Bind immune complexes strain-dependent manner. What do these
and associate with Membrane-attack complex
proteins have in common with early comple-
erythrocytes, which take
the immune complexes Bind complement receptors ment components? SAP and DNase I func-
to the liver and spleen and mediate uptake by tion together to bind and degrade chromatin
for clearance phagocytes Lysis of pathogens and cells
that is released by dying or apoptotic cells,
thereby clearing the potential SLE autoanti-
More than a century ago, Bordet and Gengou identified a heat-sensitive substance in the blood gens from the body. Natural IgM, which
that was required for the lysis of antibody-coated bacteria and erythrocytes55. They named the accounts for most of the IgM in the circula-
substance ‘complement’. It is now clear that the complement system is a large family of 20 or tion and is produced mainly by B1 cells (a
more serum proteins and cell-surface receptors that are crucial for both innate and adaptive particular subset of B cells), is an important
immunity6. The complement system is activated by three different pathways: the classical, lectin recognition protein that binds many of the
and alternative complement pathways (see figure). The classical pathway is initiated by activation known SLE antigens and activates the C1q-
of the complement component 1 (C1) complex by IgM- or IgG-containing immune complexes. dependent classical complement pathway29,30.
Activated C1 cleaves C4 and C2 to generate C4b–C2b (also known as the classical C3 convertase),
Although many of these IgM proteins are
which converts C3 to C3a and C3b. The complement proteins C4 and C3 both have an internal
self-reactive, they seem to be protective rather
thioester bond that becomes exposed after activation and forms spontaneous covalent ester or
than harmful. C1q can also bind double-
amide links with antigens56–59. Activated C3 (C3b) combines with C4b–C2b to form
C4b–C2b–C3b (also known as the classical C5 convertase), which converts C5 to C5a and C5b.
stranded DNA, directly leading to the activa-
Alternatively, C3b can interact with factor B to form C3b–Bb (also known as the alternative tion of C4 through the classical complement
C3 convertase) and C3b–Bb–C3b (also known as the alternative C5 convertase). The alternative pathway31. Mannan-binding lectin (MBL)
complement pathway can also be activated spontaneously when C3 binds covalently to acceptor also binds apoptotic debris, and through acti-
sites and interacts with factor B to form an active C3 convertase. The lectin complement pathway vation of MBL serine protease 2 (MASP2), it
is activated when collectins, such as mannan-binding lectin (MBL) or ficolins, bind their ligands induces cleavage of C4 to C4b (using the
(mannan or N-acetylglucosamine, respectively), which are expressed by microbial pathogens. lectin complement pathway)32,33. After activa-
Both ficolins and MBL — which is structurally similar to C1q — are associated with MBL serine tion through the classical or lectin comple-
proteases (MASPs), which cleave C4 and C2 to form a C3 convertase52,60. iC3b, inactivated C3b. ment pathways, C4b binds antigen, and these

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©2004 Nature Publishing Group

complexes can be rapidly cleared from the
system without activating inflammation,
through their uptake by phagocytic cells
that express CR1 or C1q receptors34,35. In
humans, CR1 provides an important mech-
anism for the clearance of C3b- and C4b-
bound antigens without activation of an
inflammatory response, and it is widely
expressed by B cells, erythrocytes and other
haematopoietic cells, as well as certain stro-
mal cells36. In mice, expression of CR1 is
more limited, but it is known to participate
in the uptake of C3b- and C4b-bound anti-
gens by B cells and stromal cells in the lym-
phoid compartment37. Recently, a novel
CR1-like receptor transcript (CR1L) was
identified in human haematopoietic cells
and fetal liver38. The novel receptor is a
truncated form of CR1 that includes the
binding site for the inactivated form of C4b
(iC4b) but not for the equivalent form of
C3b (iC3b). So, it is the first reported recep-
tor that binds C4b but not C3b, indicating a
function for C4 that is independent of that
of C3. Together, these results allow one to
envisage a common pathway in which the
innate immune system participates in the
specific binding, degradation and clearance
of apoptotic debris in a non-inflammatory
manner. This indicates that innate immu-
nity, including complement, is protective
against the development of SLE, possibly
through the scavenging of apoptotic debris.
The clearance hypothesis
Given the importance of the complement
system and related serum proteins in the
uptake and clearance of apoptotic blebs,
Walport and colleagues have proposed that
defects in this pathway could result in overt
presentation of self-antigens and develop-
ment of high-affinity IgG autoantibodies18.
This hypothesis is known as the clearance
hypothesis. Accordingly, this hypothesis
states that innate immunity protects by
sequestering apoptotic debris, thereby pre-
venting exposure of the adaptive immune
system to SLE antigens (FIG. 2a). The model
is supported by results that show a correla-
tion between deficiency in C1q or C4 and
impaired clearance of apoptotic debris15,18,35.
This indicates that, in the absence of the
relevant innate pathway, apoptotic debris is
not effectively cleared, and it accumulates
in tissues that are rich in dying cells. So, the
attraction of the clearance hypothesis is
that it explains a known function of comple-
ment (and the associated innate pathways)
in the clearance of putative SLE antigens,
and deficiencies in this pathway might
be predicted to result in accumulation of
NATURE REVIEWS | IMMUNOLOGY
PERSPECTIVES
Lymphoid compartment
IgM
Apoptotic
cell
TCR
B cell T cell
b
MHC
class II
a T-cell–B-cell co-operation
IgG
c
Immune complex
C1
C4b
Kidney
C2b
C3b
C3
C3a
Neutrophils Macrophage
Figure 1 | Autoantibody-mediated pathogenesis of SLE. Systemic lupus erythematosus (SLE) is
an autoimmune disease that is characterized by autoantibodies specific for highly conserved nuclear
antigens, such as double-stranded DNA, histones and ribonuclear proteins. The requirements for the
activation and response of self-reactive B cells — the source of autoantibodies — seem to be similar
to those of normal, mature B cells. Encounter with cognate self-antigen in the presence of T-cell help
induces activation (a). Activated B cells then form germinal centres, where they undergo class-switch
recombination, somatic hypermutation and clonal selection — forming both effector and memory
B cells. Effector B cells release IgG autoantibodies into the circulation (b), where they form immune
complexes in the presence of ligands (SLE antigens). Despite the normal mechanisms (such as the
complement system) for the uptake and clearance of immune complexes, excess immune complexes
accumulate in the small vessels of organs, such as the kidney, where they become pathogenic.
Accumulated immune complexes induce inflammation through local activation of the complement
system and/or the binding of Fc receptors, which leads to the degranulation of mast cells and the
infiltration of neutrophils and macrophages (c). C, complement component; TCR, T-cell receptor.
self-antigens in sites such as the lymphoid cells. This seems especially unlikely in the
compartment, where they could become lymphoid compartment, where there is a
immunogenic. high frequency of dying cells and mature
There are several concerns inherent in this lymphocytes that could respond to cognate
hypothesis. First, as noted earlier, in humans antigen are present. Third, another limita-
and mice, deficiency in C3 is only a minor tion of this model is that it implies that self-
susceptibility factor for SLE compared with reactive mature lymphocytes are present in
deficiency in C1q or C4 (REF. 39). Given the the circulation and respond when exposed to
importance of C3 for the elimination of SLE self-antigens. However, given the rigor-
immune complexes, it would seem that if the ous negative selection of B cells (BOX 3) and
clearance of apoptotic debris is the main role T cells, it seems unlikely that apoptotic debris
of complement in protection, then C3 defi- directly activates circulating lymphocytes40.
ciency might be expected to have a consider- However, it is known that inappropriate pre-
able effect on susceptibility to SLE. Second, it sentation of self-antigens — such as occurs
seems unlikely that innate immunity is effec- after intravenous injection of apoptotic
tive in concealing or sequestering all of the cells — can induce a loss of tolerance and
apoptotic debris that is released from dying production of autoantibodies41.
VOLUME 4 | OCTOBER 2004 | 8 2 7
©2004 Nature Publishing Group
PERSPECTIVES

The tolerance hypothesis
In an attempt to explain how defects in innate
immunity could account for a loss of B-cell
tolerance and the production of self-reactive
antibodies, I propose an alternative hypo-
thesis, which is referred to as the tolerance
hypothesis. This hypothesis states that the
innate immune system ‘delivers’ self-antigens
Box 2 | Complement enhances the adaptive immune response
to developing B cells (and possibly T cells)
to enhance their negative selection (FIG. 2b).
Therefore, defects in innate immunity
would result in loss of efficient B-cell toler-
ance and escape of self-reactive cells into the
circulation. During development, B cells,
similar to T cells, undergo rigorous negative
selection to eliminate potentially self-reactive
lymphocytes (BOX 3). When developing self-
reactive B cells encounter self-antigen, they
undergo receptor editing, clonal deletion or
anergy42. Therefore, the tolerance hypothe-
sis presumes that B-cell tolerance is efficient
and that self-reactive cells are eliminated
during normal development. The rationale
for the hypothesis is that the classical com-
plement pathway has a known role in the
regulation of both B- and T-cell activation43
(BOX 2). For example, mice deficient in C1q44,

Fearon and Locksley were the first to secreted IgM45, C4 (REF. 46), C3 (REF. 47), CR1
a C3a or CR2 (also known as CD21) (REFS 48,49)
propose that the complement system +
Antigen C3d have defective B-cell responses to T-cell-
instructs the B-cell response through C3b
complement receptors, thereby bridging dependent and T-cell-independent antigens.
the innate and adaptive immune Given the importance of innate immunity in
C4b directing or instructing the humoral response
pathways61. Recognition and binding of IgM
foreign antigens by molecules of the innate C1 to non-self-antigens, it seems logical that the
C2b
immune system — such as C-reactive pathway is also involved in directing the
protein, natural IgM, collectins (mannan- encounter of self-reactive B cells with self-
binding lectin or ficolin) — or by specific antigens. Deficiency in this pathway would
antibody produced by cognate B cells leads result in reduced exposure to self-antigens
to activation of the complement system and would allow self-reactive cells to escape
C3
(BOX 1) and covalent attachment of to the periphery (FIG. 2b). So, in normal
complement component 3b (C3b) to mice, uptake of C1q- and/or C4-bound self-
the protein or carbohydrate antigen b FDC antigen complexes present on stromal cells
(see figure, part a). Attachment of C3b would provide an efficient mechanism for
to an antigen marks the antigen as foreign presentation of self-antigens to immature
and provides a ligand for complement CR1
C3d self-reactive B cells, thereby resulting in
receptors. Rapid inactivation of C3b
their elimination.
to iC3b and subsequently to C3d by
Experimental support for a role for com-
complement-control proteins and factor I
provides ligands for different receptors.
plement in B-cell tolerance derives from
Complement receptor 1 (CR1) and CR2, CD19 BCR
studies in which complement-deficient mice
CD81 are crossed with mice that carry a transgene
which are expressed by B cells and
follicular dendritic cells (FDCs), recognize B cell encoding a hen-egg lysozyme (HEL)-specific
C4b, C3b, iC3b and C3d. Phagocytic immunoglobulin or transgenes for both this
Enhanced B-cell signalling
receptors, such as CR3 (also known as HEL-specific immunoglobulin and a soluble
CD11b–CD18) and CR4 (also known as form of HEL (sHEL). In this well-characterized
CD11c–CD18), recognize iC3b but not c Stromal cell
model, the HEL-specific B cells seem to develop
C3b or C3d. On B cells, CR2 (and CR1 normally in the absence of self-antigen, but
in mice) can form a co-receptor when when mice expressing the HEL-specific
CR1
complexed with CD19 and CD81. immunoglobulin transgene are crossed with
Co-ligation of the B-cell receptor (BCR) C4a mice that express sHEL, the transgenic B cells
and the co-receptor by C3d-coated antigen + are anergic, fail to fully mature in the periph-
C4b
enhances B-cell signalling62 (see figure, eral lymph nodes and have a reduced lifespan.
part b). The importance of B-cell Development of anergy depends on the
expression of the CR2–CD19–CD81 strength of the signal through the B-cell recep-
co-receptor has been confirmed in vivo C1 tor (BCR), because low serum levels of sHEL
by studies using mice with a disrupted or mutations that reduce the strength of the
C4
Cr2 locus (which are deficient in both CR1
signal through the BCR result in a loss of non-
and CR2)48,49,63 and by immunization of
responsiveness and an extended lifespan50.
wild-type mice with fusion proteins consisting of hen-egg lysozyme and multiple copies of
Moreover, the form in which self-antigen is
C3d64. The retention of antigen by FDCs through CR1 and CR2 is also important in humoral
immune responses65,66. Similar to C3, activated C4 (that is, C4b) covalently binds antigen
encountered — that is, soluble, membrane-
and could enhance B-cell signalling through the co-receptor or enhance uptake by FDCs bound or aggregate — affects the signal
(see figure, part c; FIG. 2). In mice, CR1 forms a functional co-receptor with CD19 and CD81 through the BCR and the extent of negative
on B cells37. So, the binding of C4b-coated self-antigens by immature self-reactive B cells selection. To test whether early complement
through the CR2–CD19–CD81 co-receptor and the cognate BCR would deliver an enhanced proteins or their receptors, CR1 and CR2, are
negative signal and promote elimination of the B cell. Alternatively, FDC uptake of C4b- important in the development of B-cell toler-
coated antigen through CR2 (or a novel C4 receptor, such as human CR1L) would provide ance in the HEL model, mice deficient in C3,
a mechanism for enhancing antigen encounter by self-reactive B cells that are at the C4 or CR1 and CR2 were crossed with the
immature stage. double-transgenic mice. Deficiency in either

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 PERSPECTIVES

C4 or CR1 and CR2, but not C3, led to a par- a

tial loss in B-cell anergy 26. One possible expla- Apoptotic IgM
nation for these results is that, in the absence blebs
of C4 or its receptor (CR1), the encounter
with self-antigen is not sufficient to eliminate IgM
the developing autoreactive B cell, and it
escapes negative selection (FIG. 2b and BOX 2). Apoptotic cell B cell
One of the known roles of C4 in the
humoral immune response is the binding of C1q C4b
environmental antigens and, through its
interaction with CR1, the retention of these C1qR CR1
antigens on follicular dendritic cells (BOX 2).
Interestingly, deficiency in C3 did not alter
normal B-cell anergy, which is in accordance
with observations indicating that deficiency
in C3 is not an important susceptibility fac-
tor for SLE. Notably, although deficiency in Macrophage
C4 led to a partial loss of B-cell anergy, C1q b
Bone-marrow stromal cells Splenic stromal cells
does not seem to be required for full anergy
in the HEL-transgenic model51. One possible
explanation for this is that there are differ-
ences in the age and strain background of the
C1q-deficient double-transgenic mice and
the C4-deficient double-transgenic mice.
Alternatively, it is possible that C4 functions
independently of C1q in the HEL-transgenic
model. For example, as discussed earlier, C4
can be activated by either the classical (C1q- Receptor Receptor
dependent) or lectin (C1q-independent) editing editing
complement pathways52 (BOX 1). Anergy Anergy
A potential problem with generalizing Receptor Death
Death
about SLE using the results obtained from the editing
HEL-transgenic model is that the require- Anergy
ment for innate immunity probably varies Death
with the nature of the antigen and the way in
which it is recognized. For example, when the
model self-antigen — in this case, HEL — is
expressed at the surface of cells, HEL-specific Pre-B cell
B cells are deleted rather than anergized50. By
contrast, expression of a cytoplasmic form of
HEL in the HEL-specific immunoglobulin-
transgenic mice seems to lead to an absence of Immature Mature
B cell B cell
negative selection and an expansion of the
population of B1 cells53. Whether the innate Figure 2 | Hypotheses for the association of SLE with genetic deficiencies. Genetic deficiency
in components of the innate immune system — such as complement component 1q (C1q), C4, serum
immune system is involved in either of these
amyloid protein, natural IgM or complement receptor 2 (CR2) — leads to increased susceptibility to
models has not been determined. SLE anti- systemic lupus erythematosus (SLE). Two general hypotheses have been proposed to explain the genetic
gens reside mainly in the nucleus and, pre- association with disease. a | The clearance hypothesis states that failure to clear apoptotic bodies —
sumably, are exposed after the release of a principal source of SLE antigens — leads to inappropriate activation of mature, self-reactive B and
apoptotic blebs from dying cells. In this con- T cells. Accordingly, apoptotic bodies are usually sequestered from the adaptive immune system by
text, the requirement for innate immunity efficient recognition, binding and uptake by components of the innate immune system. So, SLE antigens
are effectively ‘hidden’ from self-reactive lymphocytes. Defects in clearance of apoptotic bodies, such as
could markedly differ between SLE and the
those that occur in the absence of C1q or C4, would lead to the exposure of self-antigens to autoreactive
HEL-transgenic mouse model. However, lymphocytes and the development of SLE. b | The tolerance hypothesis states that innate immunity is
given the known roles of SAP, C1q, C4 and important in the negative selection of self-reactive lymphocytes, especially B cells that are specific for SLE
natural IgM in the recognition and binding of antigens. The innate immune pathway functions to recognize, degrade and bind SLE antigens to stromal
chromatin and/or DNA, as described for the cells present in the bone marrow and spleen. Immature B cells that encounter concentrations of cognate
clearance hypothesis, it seems reasonable that antigen above a certain threshold are negatively selected; that is, they undergo receptor editing, clonal
these molecules could also participate in deletion or anergy. C1q and C4 function to enhance ‘presentation’ of SLE antigens to specific immature
B cells in the bone marrow. Alternatively, coupling of C4b to self-antigen could result in co-receptor
enhancing the availability of antigen for
stimulation of immature B cells displaying the CR1–CD19–CD81 co-receptor. The co-receptor
immature B cells that are undergoing selection is expressed at the surface of immature B cells during transitional stages in the spleen, in which co-ligation
either in the bone marrow or in the splenic with the B-cell receptor could result in enhanced negative selection and ‘escape’ of self-reactive B cells
compartment. into the peripheral mature compartment, where they encounter SLE antigens and become activated.

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Acknowledgements
I thank past and present members of the laboratory for thoughtful
discussions on the topic of innate immunity and B-cell tolerance.
Research was supported by the National Institutes of Health,
United States.
Competing interests statement
The author declares no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
C1q | C1r | C1s | C3 | C4 | C5 | CR1 | CR2 | DNase I | MASP2 |
SAP
OMIM:
http://www.ncbi.nlm.nih.gov/Omim/
SLE
FURTHER INFORMATION
Michael Carroll’s laboratory:
http://cbr.med.harvard.edu/investigators/carroll/lab/home.html
Access to this interactive links box is free online.
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