(Journal of Leukocyte Biology. 2002;72:249-261.)
© 2002
by Society for Leukocyte Biology
Complement’s participation in acquired immunity
Claus Henrik Nielsen* and
Robert Graham Quinton Leslie
* Institute for Inflammation Research, Rigshospitalet, University Hospital Copenhagen; and
Department of Immunology and Microbiology, University of Southern Denmark, Odense
Correspondence: Graham Leslie, Associate Professor, Ph.D., Department of Immunology and Microbiology, Institute of Medical Biology, University of Southern Denmark (Odense), Winsløwparken 21-I, 5000 Odense C, Denmark. E-mail: gleslie{at}health.sdu.dk
ABSTRACT
The preliminary evidence for the involvement of complement in
promoting primary humoral responses dates back over a quarter
of a century. However, it is only in the course of the past
decade or so that the detailed mechanisms underlying complement’s
influence have been characterized in depth. It is now clear
that complement serves as a regulator of several B cell functions,
including specific antibody production, antigen uptake, processing
and presentation, and shaping of the B cell repertoire. Of key
importance, in this respect, is the role played by the B cell-signaling
triad consisting of the B cell receptor for antigen (BCR), a
complex composed of the iC3b/C3d fragment-binding complement
type 2 receptor (CR2, CD21) and its signaling element CD19 and
the IgG-binding receptor Fc
RIIb (CD32). The positive or negative
outcome of signaling through this triad is determined by the
context in which antigen is seen, be it alone or in association
with natural or induced antibodies and/or C3-complement fragments.
The aim of this review is to describe the present status of
our understanding of complement’s participation in acquired
immunity and the regulation of autoimmune responses.
Key Words: B cell receptor • follicular dendritic cells • classical pathway • immune complexes
INTRODUCTION
The role of complement as a component of the innate immune system,
dedicated to the eradication of infections, has been known for
decades. The functions of complement in innate immunity range
from chemoattraction of leukocytes to the site of an infection
and the enhancement of phagocyte effector activities, on the
one hand, to direct destruction of certain microorganisms by
the assembly of membrane attack complexes (MAC) in the cell
wall, on the other (
Table 1
). Complement’s promotion
of leukocyte activity occurs via specific receptors for active
fragments of various complement components. Thus, receptors
for the complement fragments C5a and C3a direct chemotaxis,
whereas phagocytic effector functions are stimulated by the
interaction of fragments of complement components 3 and 4 (C3
and C4), attached to complement-activating surfaces, with the
complement receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18).
In recent years, evidence has accumulated for a contribution
by complement to the development and regulation of adaptive
immunity, and our understanding of the mechanisms underlying
this regulation is in a state of rapid growth. In this review,
we will address the question of the complement system’s
functional diversity with respect to this role.
THE IN VIVO EVIDENCE FOR COMPLEMENT’S INFLUENCE ON THE ACQUIRED HUMORAL IMMUNE RESPONSE
Complement’s involvement in the induction and regulation
of humoral immunity was first established over a quarter of
a century ago with the pioneering studies of Mark Pepys, who
showed that depleting mice of C3 with injected cobra venom factor
markedly impaired their antibody responses to primary antigen
[
1
,
2
], and with the observations that deficiencies of C2,
C4, or C3 [
3
4
5
6
7
] result in a similar impairment of immune
responsiveness to that seen with the C3-depleted mice. Support
for the implication of the classical pathway of complement activation
in this process was gained from the finding that the humoral
response enhancement seen with immunoglobulin (Ig)M class antibodies
of appropriate specificity—administered concurrently with
the immunizing antigen—failed to occur when a mutant IgM
monoclonal antibody (mAb) lacking complement-activating ability
was used [
8
]. Somewhat paradoxically, deficiencies of C1q and
C4 in humans [
4
] (reviewed in ref [
9
]) and guinea pigs [
10
]
were also found to predispose for autoimmune conditions (see
below), indicating that the complement system may, moreover,
be involved in the induction and/or maintenance of tolerance
at the humoral level.
In vivo studies of the mechanism(s) underlying complement’s contribution to acquired immunity initially focused on its role in promoting antigen retention by the follicular dendritic cells (FDC) in germinal centers [11
12
13
14
15
] to provide a constant source of antigenic stimulus to activated, antigen-specific B cells. More recent investigations have provided clear evidence that the complement receptor type 2 (CR2/CD21), which binds the C3 cleavage products, iC3b and C3dg, and is expressed on B cells as well as FDC, is instrumentally involved in the induction of a primary humoral response (Table 1)
. Thus, it was demonstrated that:
- Blockade of murine CD21 with a mAb, which interfered with C3 fragment binding, abrogated the primary immune response to T-dependent [16
] and T-independent antigens [17
] without impairing T helper cell (Th) induction [18
].
- Neutralization of CD21 function by competing soluble CD21 diminished the primary humoral response to T-dependent antigens [19
], and coupling C3d fragments to the immunizing antigen enhanced the response. Thus, immunization of mice with the chimeric protein, hen egg lysozyme (HEL)-C3d3, resulted in a 10,000-fold enhancement in response compared with immunization with HEL alone and a 100-fold greater response than that obtained with HEL in Freund’s complete adjuvant [20
].
- Cr2-/- mice, lacking the receptors CR1 and CR2 [21
, 22
], in common with their C3- and C4-knockout counterparts [23
], displayed marked inhibition in the production of Ab arising from class switching (i.e., IgG2a, IgG2b, and IgG3), as well as the generation of fewer and smaller germinal centers. Furthermore, Cr2-/-mice are unable to sustain antibody production over a longer period of time, although the affinity maturation of the antibodies they produce is enhanced [24
].
The above-mentioned studies, although demonstrating unequivocally the implication of CD21 in the development of a humoral response, do not shed any light on the relative contributions of CD21 expressed on B cells and FDC, respectively, to this process. To do this, two reconstitution mouse models were used in which recombination-activating gene-2 (RAG-2)-deficient mice were reconstituted with B cells from Cr2-/- mice to provide mice with CD21-negative B cells against a CD21-positive FDC background [25
], and Cr2-/- mice were implanted with wild-type bone marrow to create the reverse situation [26
] (Table 2
). In mice with the B cell CD21 deficiency, the response pattern resembled that of the total Cr2-/-, i.e., impaired initial response and failure of class-switch. Conversely, mice with selective CD21 deficiency on their FDC displayed a normal, initial response, although the long-term IgG antibody response was depressed and there was a lack of memory induction.
A feature common to many of the above-mentioned studies was
that complement’s role in the induction of humoral responses
was most apparent upon immunization with low doses of antigen
and could be diminished or even abolished by administering the
antigen at higher doses. However, it is feasible that the low
doses of antigen used may well reflect the type challenge arising
from naturally occurring infections and thus be more closely
representative of the physiological situation.
COMPLEMENT’S INTERACTION WITH ANTIGEN—THE PIVOTAL STEP
As with other the elements of the innate response, complement’s
effectiveness in initial defense and as a stimulator of acquired
immunity is determined by its ability to link itself physically
to the antigens of invading microorganisms. This can be achieved
in three ways via triggering the respective complement pathways:
the lectin pathway (LP), the classical pathway (CP), and the
alternative pathway (AP). The common outcome of activation of
all three pathways is the covalent attachment of the C3 split
product, C3b, to the target surface. C3b, or its subsequent
degradation products, iC3b and C3d, thereby provide the opsonic
handle that is recognized by the complement receptors (CR1/CD35,
CR2/CD21, and CR3/CD11b-CD18) expressed by leukocytes.
Activation via the LP is mediated by mannan-binding lectin or proteins of the Ficolin family and involves specific recognition of carbohydrate motifs contained in bacterial coat polysaccharides [27
, 28
] in a manner analogous to that seen with the mannose receptors on myeloid cells [29
]. CP activation, in the nonimmune condition, may be induced directly by invading microorganism, such as Pseudomonas aeruginosa [30
], group B streptococci [31
], or Klebsiella pneumoniae [32
], but more generally is initiated via so-called natural antibodies, which have formed immune complexes (IC) with the microbial antigens. Natural antibodies (NA) are polyreactive Igs of IgM, IgG, or IgA isotypes, which recognize a great variety of self- and foreign antigens with low affinity and are present in the serum of all individuals without previous immunization (for reviews, see refs [33
34
35
]). These antibodies express immunoglobulin heavy-chain variable regions encoded by genes in a virtually nonmutated configuration [36
] and are often directed against public epitopes and antigens that are well-conserved during evolution. By virtue of their polyreactivity, NA are important components in the innate "first line defense" that confers protection against bacteria and viruses before an efficient, adaptive immune response is mounted [37
] (for review see ref [38
]). However, there is now clear evidence that they may also be involved in immune regulation by forming complement-activating IC with antigen, which subsequently bind to antigen-presenting cells (APC) via complement receptors [39
, 40
] (see below).
In contrast to the foregoing pathways, activation of the AP does not involve a recognition event as such. On the contrary, the AP is an ongoing process leading to the spontaneous and indiscriminate deposition of C3b on target surfaces, where it can form a further C3 convertase by binding factor B. On host cells, this development is held in check by the inhibitory factor H, which exerts its inhibitory effect upon binding to the cell surface adjacent to C3b via heparin and sialic acid residues present on the outer membrane [41
]. When C3b binds to microbial targets lacking these moieties, amplification of the AP goes unhindered, and the target becomes effectively opsonized. Thus, the AP-mediated labeling of target microbes with C3 fragments can be described as a process of "recognition by default" and, as such, provides for a very broad spectrum of target identification.
THE MECHANISMS FOR COMPLEMENT ENHANCEMENT OF THE IMMUNE RESPONSE
The attachment of C3 to an antigen has been demonstrated to
affect various phases of the acquired immune response. With
respect to the function of B cells, it appears to be involved
in the promotion of antigen uptake, processing, and presentation
by B cells to antigen-specific T cells, in the direct activation
of B cells and in the facilitation of B cell interactions with
FDC.
Complement-mediated promotion of antigen processing and presentation by B cells
In addition to producing antibodies, B cells also serve an important physiological role as APC. The first evidence for a role of complement in antigen presentation by B cells came from the demonstration by Arvieux et al. [42
] that coupling of C3b or C4b to an antigen, tetanus toxin (TT), enhanced the proliferative and cytotoxic responses of antigen-specific Th cell clones. In this connection, the role of complement was to target the antigen to CD21 and CD35 on Epstein-Barr-transformed B cells. More recently, it has been observed that the binding, processing, and presentation of antigens in the form of IC are substantially enhanced by incorporation of C3 fragments into the complexes [40
]. Furthermore, CD35 and particularly CD21 on the B cells were shown to be of key importance for the binding of the opsonized IC [40
, 43
, 44
]. Studies with C3b-TT [45
] and opsonized IC [38
, 39
, 42
] have indicated that the interaction of C3 fragments with CD21 (and CD35) allows nonspecific B cells to participate in antigen presentation to specific T cells, albeit less efficiently than antigen-specific B cells [40
], thereby greatly enhancing the efficiency of antigen presentation. Subsequently, it was shown that only the antigen-specific B cells were reciprocally stimulated for antibody synthesis upon cultivation of peripheral blood mononuclear cells with IC, indicating that regulatory mechanisms exist to prevent polyclonal B cell activation [39
].
It should be noted that in two of the studies mentioned above [39
, 40
], a primary antigen, keyhole limpet haemocyanin, was used, and the formation of complement-activating IC was achieved by the incubation of the antigen with sera containing NA. In analogy, the synergistic action of natural autoantibodies and complement promotes the uptake, via CD21 and CD35, by B cells and stimulate a subset of CD4+ T cells for proliferation [46
].
Recent studies indicate that attachment of C3 to antigens not only enhances the antigen uptake by B cells, but also modulates downstream events such as endosomal targeting of antigen, as well as the processing and binding of peptides to major histocompatibility complex (MHC) class II molecules. Thus, the speed and efficiency of the production of antigen-MHC class II complexes are increased by C3d-tagging to the antigen and coengagement of the CD19/CD21 complex as compared with B cell receptor (BCR)-mediated processing alone, an effect that is mediated by signaling through the CD19/CD21 complex rather than involvement of the complex in targeting antigen for processing [47
]. Moreover, covalent attachment of C3b to TT results in enhanced and prolonged stimulation of specific T cells by nonspecific and TT-specific B cell clones, presumably as a result of delayed proteolysis of C3b-TT by the endosomal enzyme cathepsin D [48
]. It has been suggested that the delayed endosomal proteolysis results in an improved peptide loading on MHC class II molecules and an increased stability of these molecules in the lysosomes [49
]. Consistent with this observation is the finding that attachment of C3b to the heavy chain of murine IgG results in a 100-fold reduction in the amount of IgG required for human B cell lines to stimulate heavy chain-specific T cell clones without enhancing antigen presentation to light chain-specific T cell clones [50
].
Apart from facilitating antigen presentation, IC may play an additional enhancing role by inducing the expression of costimulatory molecules. Thus, the costimulatory molecule CD80 [40
], which binds to CD28 on T cells, has been demonstrated to be up-regulated by the ligation of IC-associated IgG to the B cell Fc receptor for IgG (FcR)II (CD32), with CD21 playing a synergistic role. Similarly, IC ligation to CD21 or FcRII can activate another costimulatory molecule, lymphocyte function-associated antigen-1 (CD11a/CD18), which binds to intercellular adhesion molecule-1 (CD54) on T cells [39
]. (This enhancing role of FcRII in immune regulation is in contrast with the down-regulatory signaling through this receptor seen in relation to B cell activation; see below.) It has also been shown that the expression of CD86, which also binds CD28, could be induced by cross-linking CD21 [51
].
Finally, it should be noted that complement also plays a role in modulating the cytokine profile of Th cells. Thus, it has been demonstrated that interferon- (IFN-) synthesis is reduced in C1q-deficient mice [52
], and interleukin (IL)-4 production remains normal. This deficiency has a dual effect. It blocks the switch to IgG2a and IgG3 production, which is under IFN- control [53
], and it ablates the induction of localized C3 synthesis in lymph nodes activated by antigen challenge, thereby diminishing the potency of the amplification mechanisms described above. In other words, it would appear that complement exerts a comprehensive and integrated influence on all aspects of the acquired immune response.
Direct activation of B cells
A major advance in understanding the mechanisms that underlie the enhancing effect on complement on B cell function was achieved from studies in which CD21 and membrane IgM (the BCR) were co-cross-linked with mAb directed against these receptors in a manner that mimicked their binding of antigen covalently associated with C3d. The recruitment of CD21 in this manner enhanced BCR-mediated signaling by one to two orders of magnitude [54
]. Shortly after, it was demonstrated that the T cell-independent, proliferative response of B cells, induced by BCR aggregation, was enhanced by co-cross-linking of the BCR with CD21 [55
] and that polyvalent ligands for CD21 primed the B cells for enhanced response to stimulation via the BCR [56
, 57
], while monovalent ligands proved to be inhibitory [57
]. Of crucial importance in this regard, was the finding that CD21, which possesses only a short cytoplasmic tail (of 34 or 35 amino acids for human and murine CD21, respectively; refs [58
, 59
]), associates noncovalently with the CD19/TAPA(CD81)/Leu-13 signaling complex [60
, 61
]. In this complex, CD21 serves as the ligand-binding subunit, and CD19 is responsible for the intracellular signaling. The significance of the complex, with respect to immune regulation, was unequivocally demonstrated by direct coligation of CD19 with the BCR, which resulted in a marked lowering of the threshold for stimulation via BCR [62
, 63
].
The signaling process
Intracellular signaling via the BCR and CD19 involves distinct means of activating a range of common signaling elements, and the synergy between the two is achieved through mutual stimulation and the parallel activation of these elements. This activation process is kept under control by the concerted action of CD22, CD72, and the low-affinity receptor for IgG, FcRIIb (CD32).
The promotion of BCR signaling by the CD19/CD21 complex appears to operate at two levels: (i) by enhancing the recruitment of BCR to detergent-insoluble lipid rafts, which are the centers for activation processes on the B cell surface (reviewed in ref [64
]), and by prolonging the retention of BCR in these localities and (ii) through synergistic activation of intracellular messengers themselves.
Lipid rafts and BCR-mediated signaling
Lipid rafts or membrane microdomains are terms used to describe organized foci in the plasma membranes of mammalian cells, characterized by their high concentrations of cholesterol and sphingolipids, which render them insoluble in detergents such as Triton X-100. The outer surface of the rafts provide anchorage sites for glycosylphosphatidylinositol-anchored proteins, such as CD59, CD55, CD48, CD24, and CD14 [65
], and the inner leaflet provides docking sites for doubly acylated protein tyrosine kinases (PTKs) of the Src family such as Lyn. The rafts perform a dual function, acting as centers for the initiation of intracellular signaling and as organelles for the internalization and endocytic transport of raft-associated proteins (reviewed in refs [66
67
68
]).
Upon aggregation via a multivalent ligand (antigen), the BCR translocates from the detergent-soluble plasma membrane to the lipid rafts, where it is activated by the PTK, Lyn [69
, 70
] (Fig. 1
). With antigen alone as the recruiting agent, the efficiency of translocation may be relatively low, resulting in only ca. 30% BCR recruitment to the lipid rafts [71
]. Conversely, coligation of BCR and CD19/CD21 with complement-tagged antigen was shown to markedly enhance the process, leading to virtually complete translocation of the receptor to these sites. Furthermore, the period of residency of BCR in the rafts was more than doubled from ca. 30 min, seen with BCR cross-linking alone, to over 1 h [71
]. Thus, the enhancing effect of the CD19/CD21 complex on BCR recruitment to signaling is not only a question of amplitude but also of duration.
BCR-mediated signaling and CD19/CD21-mediated enhancement
Lyn activates the BCR by phosphorylating the immunoreceptor
tyrosine-based activation motifs (ITAMs) in the cytoplasmic
tails of the Ig-
(CD79a) and Ig-ß (CD79b) components
of the BCR complex (reviewed in ref [
72
];
Fig. 1
). The phosphorylated
ITAMs act as a docking site for the cytosolic PTK, Syk, which,
upon phosphorylation itself, plays a key role in initiation
of downstream pathways by recruiting the adapter molecule BLNK/SLP-65.
The phosphorylated BLNK/SLP-65 serves as a platform for the
assembly of a signaling module consisting of Bruton’s
tyrosine kinase (Btk) [
73
], phospholipase C-
2 (PLC-
2), the
guanidine nucleotide exchange factors Vav and Sos, and phosphatidylinositol-3
kinase (PI-3K). A key role of Btk is to activate PLC-
2, which
then cleaves PI to inositoltriphosphate (IP3) and diacylglycerol,
thereby promoting the mobilization of intracellular-free calcium
ions and activation of protein kinase C (PKC). Vav and Sos,
meanwhile, serve to activate GTPases of the Rho and Ras families,
respectively. The combined actions of calcium ions, calcineurin,
PKC, and the GTPases, in turn, lead to activation and nuclear
translocation of the nuclear factors (NF), NF-
B and NF-AT, and
the mitogen-activated protein kinases (MAPK), p38, JNK, and
ERG. Thereby, gene expression is initiated. PI-3K plays a critical
supporting role in this process by generating phosphatidylinositol-3,4,5,-trisphosphate
at the cell membrane, which provides tethering sites for Btk
and PLC-
2 and an activation site for Vav [
72
].
The CD19 component of the CD19/CD21 complex, by contrast, appears to act in its own right as an adaptor protein for a wide range of signaling elements. It associates constitutively with Lyn [74
] and the nucleotide exchange factor, Vav [75
]. These interactions are strengthened upon tyrosyl phosphorylation by BCR-associated PTK [74
75
76
]. The phosphorylation of tyrosines throughout the cytoplasmic tail generates a further string of docking sites for the recruitment of the Src-family PTK, Fyn (at Y403/Y443) [77
], PI-3K (at Y492/Y513) [78
], PLC--2 and Vav (both at Y391/Y421), as well as Sos, complexed with its adaptor protein, Grb2 [77
] (at Y330; Fig. 1
).
Down-regulation of BCR-CD19/CD21-mediated signaling
B cell activation via BCR and CD19/CD21 complex is controlled through the actions of a number of regulatory membrane proteins, including CD22 [79
], CD72 [80
], and CD32 [81
]. Common to these regulators is the presence, in their cytoplasmic domains, of tyrosine-based inhibitory motifs (ITIMs) [82
83
84
], which, upon phosphorylation by Lyn, recruit the SH2 domain-containing inositol polyphosphate 5-phosphatase SHIP [85
] and the protein tyrosine phosphatases SHP-1 [79
, 81
] and in humans, SHP-2 [86
] (Fig. 1)
. Activation of SHIP results in down-regulation of BCR signaling through dephosphorylation of IP3 [85
] and thereby inhibition of calcium mobilization [87
] and MAPK activation [88
], while SHP-1 and -2 act upon a variety of phosphorylated signaling components, including Syk [89
], Vav [90
], and BLNK [91
].
In terms of responses to antigenic stimuli, of particular relevance is the role played by FcRIIb (CD32). B cell activation by complement-opsonized IC can be considered as being under the control of a signaling triad, consisting of the BCR and CD19/CD21 complex as stimulatory components, and FcRIIb as a negative regulator of the activation process (Fig. 1)
. IgM-containing complexes will, when opsonized, engage CD21 alone (in the case of nonspecific B cells) or the BCR and CD21, providing stimulatory signals to varying degrees. On the other hand, in the case of antigen-specific B cells, the binding of IgG-containing, opsonized IC will result in engagement of the full triad, whereas nonspecific B cells will be engaged only via CD21 and FcRIIb. The as-yet limited, in vitro data available on the dynamics of signaling via the triad suggest that whereas engagement of FcRIIb markedly inhibits signaling via BCR or CD21 alone, triple engagement results in a similar degree of activation to that attained by single stimulation via the BCR [92
]. However, it is likely that the nature of the B cell response will be determined not only by the types of receptor engaged, but also on the degree to which the various receptors are represented in the final signaling complex.
Finally, it should be noted that excessive signaling via the CD19/CD21 complex might, in itself, prove counterproductive. Thus, use of a CD21 cross-linker at a concentration 12.5-fold greater than that required for maximal enhancement of a suboptimal BCR stimulus was found to virtually abrogate the calcium flux induced by BCR stimulation, even when this was performed optimally [93
]. The mechanism underlying this regulatory effect appeared to be based on the ability of CD19/CD21 to sequestrate the key PTK, Lyn, from the BCR and to engage Lyn in promoting the recruitment of SHP-1 to another negative regulator of BCR signaling, CD22 [94
]. The authors of this study propose that negative regulation via CD19/CD21 may play a role in limiting bystander B cell activation under circumstances where complement-bearing immune complexes are present in excessive amounts and that lack of this control might partly explain the proclivity of CD21-deficient animals to develop autoimmune responses (see below). Conversely, it has also been demonstrated that CD19 amplification of B lymphocyte Ca2+ responses may arise as a consequence Lyn of sequestration by CD19 from CD22 [95
], thus illustrating the complex, quantitative interplay among the various signaling elements.
The functional consequences of BCR signaling
Although the initial intracellular signaling processes that form the basis for synergy between BCR and CD21 in the development of a humoral immune response are now well characterized, less is known about the particular aspects of B cell function, which are influenced by this synergistic activity. However, the data presently available suggest that the influence of CD21 on B cell function is far-reaching in its diversity. Thus, it has been demonstrated that coligation of CD21 with BCR by C3d-tagged antigen promotes trafficking of the antigen to processing compartments in the B cell and to more rapid and efficient production of antigenic-peptide/class II complexes, although the precise signaling mechanisms involved in this process remain to be established [96
]. CD21 is also shown to have a direct influence on B cell-T cell signal exchange by simultaneous up-regulation of CD80 and CD86 on murine splenic B cells [97
]. The enhancing effect of CD21 on B cell proliferation appears to operate at two levels: it promotes T cell-independent proliferation induced by cross-linking membrane IgM [54
, 55
] and reduces the BCR stimulation threshold for proliferation to a variety of T cell cytokines, in particular IL-4 [98
]. The mechanism involved in the latter instance appears to be synergism between the IL-4R and BCR-CD21 signaling pathways in promoting the progression of resting B cells past an early G1 checkpoint. Finally, CD21 may play a key role in determining B cell survival by limiting apoptosis induced through ligation of membrane IgM (BCR) [99
]. A mechanistic basis for this rescue from apoptosis has subsequently been established with the observation that signaling via CD21 promotes accumulation of the survival protein, Bcl-2, in the B cell [100
].
The CD19/CD21 complex also seems to play a role in the early B cell development. In mice, two different subsets of B cells, B-1 and B-2, react differently to signaling through CD19/CD21. The B-1 cell subset is abundant in fetal life but constitutes a minor population in adult mice. They are IgMhiIgDlo and may express CD5 (B-1a) or not (B-1b) and localize to the peritoneal cavity where they also express CD11b (reviewed in ref [101
]). They are long-lived and frequently produce NA, mainly of the IgM and IgG3 classes [102
] and are the major producers of serum IgM. B-2 cells, on the other hand, are phenotypically IgMloIgDhi,CD5- and are the predominant, adult B cell phenotype, characterized by the production of somatically hypermutated antibodies [103
]. A normal function of the CD19/CD21 complex appears to play an essential role in the development and maintenance of B-1 cells [104
105
106
]. Thus, mice in which the Cd19 or Cr2 genes have been disrupted exhibit diminished numbers of B-1 cells [107
, 108
], and treatment of mice with antibody to CD19 leads to a reduction in B-1 cell numbers as a result of decreased replication rather than accelerated death [106
]. In this connection, it is noteworthy that the CD19 knockout displays a more severe phenotype with respect to B-1 cell reduction than Cr2-/- mice [108
], reflecting the capacity of CD19 to act independently of CD21 [109
]. Thus, CD19 has recently been shown to bind IgM and heparan sulfate/heparin on stromal cells independently of complement [110
]. This finding has led to the proposal that CD19 can be co-opted to signaling by IC containing IgM alone, without the involvement of CD21 and that this interaction is facilitated through engagement of CD19 by heparan sulfate/heparin in developing germinal centres [110
]. Conversely, B-2 cells exhibit relatively normal development and numbers of B-2 cells in the absence of functional CD19 [107
], but do require CD19 for the development of memory cells [111
]. In humans, 10–30% of peripheral B cells in adults [112
, 113
] and an even higher, predominant fraction in newborns [114
] produce NA. However, the role of CD19/CD21 in their selection and development is not as yet clear.
Facilitation of B cell interactions with FDC
FDC of the spleen and lymph nodes express three receptors for C3 fragments (CD35, CD21, and CD11b/CD18) [115
] as well IgG-binding receptor, CD32 [116
]. These receptors enable the FDC to take up and retain opsonized IC on their surfaces, in a process primarily involving CD21 and CD35 [15
, 116
, 117
], for presentation to activated antigen-specific B cells. The consequences of the interaction appear to be twofold: first, rescue of the antigen-activated B cells from apoptosis [118
, 119
] and second, the promotion of somatic hypermutation [120
, 121
] and class switch [25
, 122
, 123
] concomitant with the development of a memory B cell population. With regard to rescue from apoptosis, at least, it would appear that CD21 plays a central role in the process [99
, 124
]. This occurs via a pathway independent of that involving CD40 [125
], and the required activation of CD21 on B cells takes place by its association with C3 fragments deposited on the FDC or through association with Fc
RII (CD23) borne on the FDC [126
].
Recently, it has been demonstrated that antigen presentation may be enhanced by direct C3 fragment deposition on murine B lymphoblasts or macrophages [127
]. It had previously been established that B cells [128
] and FDC [129
, 130
], which constitutively express CD21 as well as non-CD21-expressing murine and human macrophages [127
, 131
, 132
], are the targets for the covalent deposition of C3 fragments. In the case of human B cells, it has been shown that this deposition is mediated by CD21 [133
, 134
], which, by virtue of its capacity to bind the hydrolyzed form of C3 (iC3), assembles an AP convertase at its ligand binding site [135
]. Nascent C3b fragments, generated by the convertase, then attach themselves to secondary acceptor sites on the B cell surface [136
]. Furthermore, it has recently been demonstrated that activation of the alternative pathway via CD21 also leads to the formation of C9-containing, membrane-attack complexes at the B cell surface [137
, 138
]. Although the full significance of these events for the development of an immune response is not yet established, there is some evidence to suggest that C3 deposition may play a subsidiary role by promoting intercellular interactions involving the binding of C3 fragments deposited on one cell to CD21 expressed on another [127
]. Thus, covalent C3 deposition on B cells may enhance their interaction with CD21 on FDC (and vice versa), which expresses this receptor [139
], or on the subset of T cells. The role of MAC formation in this connection remains to be clarified.
COMPLEMENT IN THE REGULATION OF AUTOIMMUNITY
At the root of autoimmune disease lies deficient immune regulation,
leading to attack on self-tissue by the adaptive immune system.
Autoimmune diseases are often characterized by high levels of
circulating autoantibodies and/or the presence, in affected
organs, of T cells with reactivity against self-antigens. It
is well established that complement plays a detrimental role
in the acute inflammatory response following attack on self-tissue
by autoantibodies or deposition of complement-activating IC
in glomeruli and small vessels [
140
141
142
]. An additional
harmful role of complement has recently been demonstrated by
Rose and colleagues [
143
], who demonstrated that autoimmune
myocarditis induced by inoculation of mice with virus or cardiac
myosin is abrogated by depletion of C3 and markedly reduced,
in terms of prevalence and severity, by blockade of CD21 and
CD35. The authors demonstrate an effect of complement on autoantibody
production and the synthesis of tumor necrosis factor and IL-1,
and they propose that a subset of CD44
hiCD62
lo T cells expressing
CD21 and CD35 plays a regulatory role in disease development.
It is now clear, however, that complement also provides protection against chronic inflammatory damages in relation to autoimmune disease [142
, 144
, 145
]. The different levels at which complement may exert its protective effect(s) are best described in relation to systemic lupus erythematosus (SLE; lupus), a systemic, autoimmune disease with clinical features, including glomerulonephritis, haemolytic anaemia, thrombocytopenia, and central nervous system involvement (reviewed in refs [146
, 147
]). Lupus is characterized by polyclonal B cell activation [148
, 149
] and the excessive production of autoantibodies against ubiquitous self-antigens such as double-stranded DNA (dsDNA), the spliceosome complex, and the Ro/La small nuclear ribonucleoprotein particles [150
]. Somewhat surprisingly, expression of surface Ig, but not the secretion of autoantibodies, is necessary for disease expression in MRL/lpr mice [151
], indicating an important role for B cells as APC in the development of lupus. A similar role for B cells has also been described in connection with diabetes [152
153
154
] in mice and rheumatoid arthritis in humans [155
, 156
].
Defects in the components of the CP of complement activation C1q and C4 confer a high risk of developing lupus on humans [146
], and the presence of autoantibodies against C1q correlates with the development of glomerulonephritis in lupus [157
].
Our knowledge of the role of CP components in protection against lupus has recently been extended by observations in several murine-transgenic models. Two mutually nonexclusive models have been proposed for the protective effect of CP components against the development of lupus: that complement plays a role in the clearance of IC and/or apoptotic debris, and that the innate immune system, including complement, enhances negative selection of self-reactive B cells.
It has been known for decades that complement plays an important role in facilitating the clearance of IC from the circulation [158
]. In humans and other primates, erythrocytes (E) bear clusters of CD35 [159
, 160
] that mediate multivalent binding of C3 and/or C4 fragments deposited on IC, which in normal circumstances, enables E to take up IC at peripheral sites and transport the complexes to the liver and spleen where transfer to fixed macrophages takes place [161
, 162
]. In SLE, on the other hand, disposal of IC fails as a consequence of a disease-induced reduction in the number of CD35 on E [163
164
165
], resulting in deposition of IC in glomeruli and small vessels followed by inflammatory reactions. Moreover, due to their low CD35 numbers, E from lupus patients display diminished capacity to compete for IC and thereby prevent complex uptake, oxidative burst activity, and granule release by circulating neutrophils [166
, 167
]. In addition to acting as a buffer in this manner, E, by virtue of the cofactor activity of CD35 [168
], also process C3 fragments attached to the IC past the iC3b stage to C3dg, and thus divert the IC from the CD11b/CD18-bearing neutrophils to CD21-bearing B cells [43
, 167
].
Many of the autoantigens that are characteristic of SLE are present in surface blebs of apoptotic cells [169
], and this observation led to the hypothesis that deficient disposal of apoptotic cell constituents might predispose to the development of the disease. The demonstration that C1q binds directly to surface blebs of apoptotic human keratinocytes [170
] strongly suggested a role for complement in the clearance process. Indeed, mice deficient in C1q exhibit impaired clearance of apoptotic cells injected in vivo [171
] along with increased glomerular deposition of apoptotic bodies, increased incidence of glomerulonephritis, elevated titers of autoantibodies, and increased mortality [172
].
It is also possible that that autoreactive NA of IgM type are involved in the complement-mediated clearance of cellular debris, as suggested more than 25 years ago by Grabar [173
] and later demonstrated for the clearance of E [174
]. In keeping with this model, mice deficient in the expression of secreted IgM are prone to the development of lupus-like disease [175
, 176
]. Thus, the polyclonal activation of B cells and production of autoantibodies in lupus may be explained in terms of the accumulation of self-antigens, which, upon self-aggregation and activation of the AP, stimulate circulating, self-reactive B cells in the presence of T cell help [177
]. A role for C3 deposition in the inappropriate activation of B cells would account for the finding that individuals deficient in C3 are not predisposed for lupus.
The failure of regulation of self-reactive B cells is directly addressed by a second theory linking complement deficiencies with impaired B cell tolerance and escape of autoreactive B cells from the bone marrow [177
, 178
]. In mice expressing transgenes for HEL and a corresponding HEL-specific membrane Ig receptor, Cr2-/- mice exhibit impaired induction of tolerance in comparison with Cr2+/+ mice [179
]. In keeping with this observation (and with the predispostion of C4-deficient individuals for the development of autoimmunity), C4null double-tg chimeric mice also break tolerance in this model. Taken together, these findings imply a role for the CP of complement and CD35/CD21 in the regulation of tolerance against soluble self-antigens. It is proposed that C1q and other complement-activating recognition proteins, such as natural IgM, C-reactive protein (CRP), and serum amyloid protein (SAP), promote the localization of dsDNA and nuclear proteins on bone marrow stromal cells [177
, 178
] and thereby enhance recognition of self-antigen by immature B cells. An interesting aspect of this theory is that the inherent recognition pattern of natural autoantibodies provides a mean for targeting self-antigens to the sites of B cell selection. It has recently been demonstrated that thyroglobulin binds to the bulk of B cells in human peripheral blood in a manner that is dependent on NA [46
]. This binding could be completely abrogated by blockade of CD21 and CD35. Although a role for this finding in maintenance of peripheral tolerance remains to be investigated, it demonstrates that natural antibodies are instrumental in the attachment of C3 fragments to self-antigens, which may have important implications for negative selection of B cells, as discussed above. It should be noted that transgenic mice, in which the majority of B cells are specific for dsDNA, exhibit differential regulation of B-1 and B-2 cells, in that anti-Sm-specific B cells are found in the peritoneum, whereas B-2 cells with this specificity are eliminated in the spleen [180
181
182
]. Thus, B-1 cells secreting low-affinity, self-reactive, natural IgM apparently are permitted, whereas potentially pathogenic, self-reactive B-2 cells are deleted. Recent studies indicate that B-1 cells are positively selected on the basis of reactivity with self-antigens [183
, 184
]. Selection of B cells producing NA reactive with highly conserved epitopes on self-antigens might ensure the production of antibodies recognizing similar epitopes on microbial antigens, which is likely to be important for the appropriate complement opsonization, clearance, and/or uptake of foreign antigens by APC. One may be led to speculate that microbial infections can, reciprocally, induce loss of tolerance. The notion of the induction of autoimmunity by infection has received a lot of attention in connection with a number of diseases and has been supported by demonstrations of cross-binding of certain self- and viral peptides with human leukocyte antigen molecules (reviewed in ref [185
]). With respect to presentation of self-antigens, it is noteworthy that B cells are critical APC in the development of diabetes and lupus in mice [151
152
153
154
] and rheumatoid arthritis in humans [155
, 156
].
The amount and context of self-antigen presented by B cells are likely to be determined by the degree to which it is opsonized by complement. As mentioned above, natural autoantibodies and complement enhance the uptake of self-antigens, via CD21 and CD35, by B cells [46
]. The formation of complement-activating IC between self-antigens and natural autoantibodies (or cross-reactive, hypermutated antibodies) may occur when the self-antigen:antibody ratio is raised as a consequence of self-tissue attack by cytotoxic T cells in the course of an infection. Supporting a role for IC formation in the induction of autoimmunity is the finding that the autoantigen in a murine B cell transgenic model of RA, IgG2aj, only elicited B cell activation and rheumatoid-factor production when administered in the context of IC [186
].
CONCLUSIONS
The relationship between the elements of the innate and the
acquired immune systems is symbiotic. Thus, the innate system
is engaged not only in the identification and destruction of
invading microorganisms, but also in the processing and presentation
of their antigens and the provision of stimulatory signals in
this connection. Correspondingly, the acquired immune system,
by providing more effective and specific target recognition
in the form of antibodies and activating signals in the form
of cytokines, enhances the destructive capacity of the innate
immune system.
In these terms, complement is a highly representative element of the innate immune system in most respects. It is involved in the detection and destruction of the invading microorganism, in the recruitment of other effector elements for this purpose, and in the promotion of a B cell response in a similar manner to the myeloid cell stimulation of T cell immunity. Also, like other elements of innate immunity, complement identifies, via the LP, foreign microorganisms by specific recognition of their carbohydrate moieties. However, the complement system is also unique in the sense that it can, through the AP, act in a completely nondiscriminating manner based on absence of the down-regulation, which is exerted in the context of AP initiation on host cells—in other words, "recognition by default." In this sense the "recognition" capacity of the complement system can be regarded as exceptionally flexible.
Complement’s influence on the B cell response operates at various levels: in the recruitment of B cells as APC for T cells, in the provision of antigen to FDC in a context that promotes specific B cell survival and proliferation, and in the direct activation of the B cells themselves. In the last named circumstance, the identification of the CD19/CD21 complex as a costimulatory element for signaling via the BCR and CD32 as a negative regulatory element provides new insight into the complexity of the B cell activation process. Thus, the context in which the antigen is recognized by B cells—alone or in association with Ab and/or C3 fragments—will be of crucial importance in determining whether the resulting signal is stimulatory or down-regulating. In this connection, natural antibodies, being primarily of IgM class, would tend to provide activating signals upon IC formation with antigens by virtue of their highly effective activation of the CP, whereas acquired antibodies, after class switch to IgG, would tend to have a negative, regulatory influence through their interaction with CD32.
It is now clear that signaling through the CD19/CD21/BCR complex plays a key role in positive as well as negative selection of developing B cells and in the setting of B cell activation thresholds. Thereby, complement—and complement-activating recognition proteins such as IgM, CRP, and SAP—is potentially involved in shaping an appropriate B cell repertoire on one hand and regulating autoreactivity on the other. Indeed, deficiency of C1q, C4, CD21/CD35, as well as secreted IgM and SAP [187
] predisposes for the development of autoimmunity in mice. The implications of our current understanding of complement’s influence on acquired humoral immunity for therapeutic intervention are legion, stretching from the possibility of preparing highly effective vaccines with inbuilt C3d fragments as molecular adjuvant [188
189
190
191
], on the one hand, to the induction of tolerance to relevant self-antigens in relation to autoimmune disease, on the other.
Received March 1, 2002;
accepted April 3, 2002.
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