C3b covalently incorporated into immune complex lattices interferes with the interaction between antibody and antigen, limiting the formation of large complexes.
In addition, incorporation of C3b in circulating immune complexes, via its interaction with erythrocyte CR1, allows immune complexes to be transported to the fixed cells of the mononuclear phagocytic system, predominantly in the liver and spleen.
This has been tested experimentally. Despite enhanced hepatic uptake, immune complexes were retained in the liver inefficiently and slowly released back into the circulation. The observation that hypocomplementaemia is associated with defective clearance of immune complexes has led to the hypothesis that complement deficiency, as a consequence of this defective processing, results in increased tissue deposition of immune complexes.
Subsequent inflammation could then result in exposure of autoantigens, driving an autoantibody response and the development of autoimmunity. However, the presence of immune complexes in tissues with associated complement activation does not always result in tissue inflammation. It has been established that immune complexes, C1q and C3 may be present in tissues despite the absence of clinical and histological inflammation. This would suggest that inflammation in this model is independent of complement activation.
However, in some experimental models there are clear data showing a role for complement in the induction of inflammatory injury. For example. They serve to illustrate the complexity of mechanisms of inflammation in disease mediated by immune complexes. The size, composition and location of immune complexes may each modify whether and how inflammation ensues.
There is at present much interest in the hypothesis that a major source of the autoantigens driving the immune response in SLE is apoptotic cells. This has recently been reviewed in [95]. The role of apoptosis in SLE has been discussed in an earlier article in this series [96]. There is a small body of recent evidence that suggests that the complement system, particularly C1q, may be involved in the clearance of apoptotic cells. It has been demonstrated that, in vitro , human keratinocytes bind C1q in the absence of antibody when rendered apoptotic by UVB exposure [97].
Apoptotic keratinocytes exhibit surface blebs which have been shown to contain many lupus autoantigens e. It may also be that proteins that bind to apoptotic cells may become part of complexes of autoantigens. Another such binding protein to apoptotic cells may be C1q, which could explain the high prevalence of autoantibodies to C1q in SLE, although it is not yet known to what moiety on apoptotic cells C1q binds.
In addition, humans with homozygous C3 deficiency show mild impairment of antibody responses. The two principle mechanisms involve the covalent attachment of C3b in immune complexes which allows localization of antigen to the germinal centres of lymph nodes where it interacts with CR1 CD35 on follicular dendritic cells.
It has also been shown using a transgenic model to explore mechanisms of B cell tolerance that CR1, CR2 and C4, but not C3, are involved in the negative selection of autoreactive B cells [ , ]. However, the significance of this in relation to autoimmunity is uncertain and further work is needed. The links between complement and SLE are complicated and fascinating. After many years of study, hypotheses are developing which may begin to explain these apparent paradoxical findings.
It is becoming clear that complement, rather than being the villain in SLE as a mediator of inflammatory injury, may in fact play a predominantly protective role. The approach to therapy of the complement system in SLE may be replacement and not inhibition.
The authors gratefully acknowledge support for their work from the Arthritis Research Campaign and from the Wellcome Trust. Complement deficiency and disease. Immunol Today ; 12 : —6. C1q and systemic lupus erythematosus. Immunobiology ; : — Loos M, Heinz HP. Component deficiencies. The first component: C1q, C1r, C1s. Prog Allergy ; 39 : — Recurrent infections and staphylococcal liver abscess in a child with C1r deficiency.
J Allergy Clin Immunol ; 80 : —5. Scand J Immunol ; 40 : —8. Report of a case. Arthritis Rheum ; 35 : —9. Complement deficiencies and abnormalities of the complement system in systemic lupus erythematosus and related disorders.
Curr Opin Rheumatol ; 2 : —3. Hereditary complement factor I deficiency. Q J Med ; 87 : — Inherited structural polymorphism of the fourth component of human complement. Cloning of a human complement component C4 gene. Associations between systemic lupus erythematosus and the major histocompatibility complex: clinical and immunological considerations.
Clin Immunol Immunopathol ; 24 : — Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility.
Br Med J ; : —8. Am J Med ; 81 : — Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups. J Immunogenet ; 14 : — Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis Rheum ; 30 : — Tissue Antigens ; 35 : —7. Major histocompatibility complex MHC complement deficiency, ancestral haplotypes and systemic lupus erythematosus SLE : C4 deficiency explains some but not all of the influence of the MHC.
J Rheumatol ; 18 : —8. Clin Immunol Immunopathol ; 60 : 55 — J Rheumatol ; 18 : 14 —8. Major histocompatibility complex haplotypes and complement C4 alleles in systemic lupus erythematosus. Results of a multicenter study. J Clin Invest ; 90 : — Complement C4A gene deletion in patients with systemic lupus erythematosus in France. J Rheumatol ; 20 : —4. Br J Rheumatol ; 34 : —5. Tissue Antigens ; 46 : — Skarsvag S. The importance of C4A null genes in Norwegian patients with systemic lupus erythematosus.
Scand J Immunol ; 42 : —6. Family study of the major histocompatibility complex in HLA DR3 negative patients with systemic lupus erythematosus. Clin Exp Immunol ; 70 : — Strong association between the major histocompatibility complex and systemic lupus erythematosus in southern Chinese.
J Rheumatol ; 14 : — Partial C4A deficiency is associated with susceptibility to systemic lupus erythematosus in black Americans. Arthritis Rheum ; 31 : —5. Immunogenetics ; 30 : 27 — Lack of gene deletion for complement C4A deficiency in Japanese patients with systemic lupus erythematosus. J Rheumatol ; 17 : —7. J Rheumatol ; 21 : —7. Goldstein R, Sengar DP. Arthritis Rheum ; 36 : —7.
Hum Genet ; 91 : — Systemic lupus erythematosus in three ethnic groups: I. Lupus in minority populations, nature versus nurture. Arthritis Rheum ; 41 : — Hum Immunol ; 55 : 39 — Difference in the biological properties of the two forms of the fourth component of human complement C4. Clin Exp Immunol ; 63 : —7. Inherited deficiency of the second component of complement. Rheumatic disease associations. The internal thioester bond of C4A shows preferential binding to amino groups with the formation of covalent amide bonds between C4A and proteins.
Preferential binding to hydroxyl groups is shown by C4B, typically in carbohydrates, forming ester linkages [ ]. Following the discovery of the two isotypes of C4 and the existence of null alleles at both loci there have been many studies to attempt to determine whether null alleles of C4 might play a role in determining disease susceptibility. The literature abounds with case-control and family studies either confirming or refuting associations between C4 null alleles and SLE.
A definitive answer is likely to emerge in the next few years as large scale genotyping methods are applied to the very large family collections of patients with SLE that are being formed around the world. The traditional view of the pathogenesis of SLE is that immune complexes containing autoantigens and autoantibodies activate complement, and that this causes inflammatory injury to tissues.
Although this model is biologically plausible, it cannot account for all of the clinical observations that link the complement system and SLE. In particular, the observation that complement deficiency causes lupus is hard to reconcile with the concept that complement activation products are the major cause of inflammatory injury in the disease. The development of gene-targeted strains of mice that lack individual protein constituents of inflammatory pathways has led to a plethora of apparently inconsistent findings on mechanisms of immune-complex-mediated inflammation.
There is a large array of mice lacking complement proteins and Fc receptors, and an equally large array of studies of these mice. In this section the mechanisms of complement activation in SLE will be reviewed briefly and the pathogenesis of inflammation caused by immune complexes will be considered. The cause of complement activation in SLE is the formation of immune complexes, which in turn activate complement, predominantly by means of the classical pathway.
Complement activation is normally measured in clinical practice by estimation of antigenic levels of both C3 and C4, and measured functionally using the CH50 assay. In the majority of patients with moderate or active SLE, reduced levels of C4 are detected, with the level of C3 varying between normal to slightly reduced.
The CH50 is typically below normal. Three subsets of patients make up the majority of these individuals. There are those subjects who have evidence of autoimmunity to red blood cells. This may manifest as overt autoimmune haemolytic anaemia, but it may be more subtle and be detectable only by means of direct antiglobulin test Coombs' test positivity for IgG, C3 and C4 deposition on red cells. Some of these patients also have antiphospholipid also known as anticardiolipin autoantibodies.
A study in a murine model of the antiphospholipid syndrome has recently shown that antiphospholipid antibodies cause foetal resorption by means of complement activation in the decidua in the pregnant uterus [ ]. The complement activation at this site was shown to cause inflammatory injury, which appeared to be responsible for the foetal death and resorption. Another subset comprises patients with very systemic disease, typically associated with high levels of anti-dsDNA autoantibodies and, sometimes, with the presence of type III cryoglobulins [ ] in serum containing polyclonal IgG and C3.
The third group of patients comprises those individuals who have anti-C1q autoantibodies. These subjects often have the most severe evidence of classical pathway complement activation, with profoundly reduced C4 levels and moderate to substantial reductions in C3 levels. It is thought that anti-C1q autoantibodies are the cause and not the consequence of the complement activation measured in serum, and possible mechanisms were reviewed above.
Until very recently it was believed that tissue injury in SLE was caused by the formation of immune complexes that caused complement activation, which in turn caused inflammatory injury.
Tissue injury was thought to be mediated by the direct effects of activation of the triggered enzyme cascades of complement, coagulation and kinin pathways, coupled with an influx of inflammatory cells, including polymorphonuclear leukocytes and monocytes. The activities of complement in the mediation of inflammation include the ligation of complement receptors for the opsonic components of complement subcomponents C3b and C4b, the effects of the anaphylatoxins C5a and C3a, and the effects of insertion of sublethal amounts of the membrane attack complex into cell membranes.
The development of mice with null mutations in selected proteins of inflammatory pathways has enabled the precise dissection of their role in both host defence and the causation of inflammatory injury. There are many experimental models of injury caused by immune complexes and the use of these in gene-targeted mice has led to a reappraisal of the role of complement and Fc receptors in inflammatory responses to immune complexes. The major conclusions from these experiments are as follows.
Firstly, it is clear that all immune complexes are not equal in the manner in which they cause tissue injury. The site of immune complex formation [ ], the species [ ] and strain [ ] of animal, and the nature of the antigen [ ], as well as the antibody, may affect the inflammatory response.
Secondly, in many models it has been found that the ligation of Fc receptors by immune complexes is the dominant cause of tissue injury, and complement plays no important role in the induction of tissue injury [ ].
Indeed, in experimental models of complement deficiency, it has been shown that immune-complex-mediated glomerulonephritis can develop spontaneously in the presence of genetic deficiency of the complement activation pathways [ , ]. In other experimental models, however, complement activation, and in particular C5a production, have been found to be essential for the full expression of tissue injury [ ]; inhibition of C5a activity is therapeutic [ ].
Thirdly, it has been found that complement may provide some degree of protection against inflammatory injury induced by immune complexes in some models of experimental glomerulonephritis [ ]. We will consider possible mechanisms for this in a subsequent section of this chapter. Finally, it is clear that in mice and humans, inflammatory pathways that operate downstream from the activation of complement, and the ligation of Fc and complement receptors play crucial roles in the expression of inflammation that is mediated by immune complexes [ ].
The associations of complement deficiency with SLE have been reviewed in the Introduction. Here we shall consider three hypotheses that have been advanced to explain the mechanism of the association.
The first two of these are closely related, proposing mechanisms that could operate in tandem. These hypotheses are that complement prevents the development of SLE through a role in the processing and clearance from the body of immune complexes, and dying and dead cells. In the absence of these activities, autoantigens may be presented to the immune system in the context of inflammatory injury and this may drive the development of autoimmunity.
The third hypothesis invokes a role for complement in the development of self-tolerance to the autoantigens of SLE, and proposes that B cells with specificity for lupus autoantigens are not effectively silenced or eliminated in the absence of complement. Each of these hypotheses will be explored briefly in this section. Michael Heidelberger in the s demonstrated a role for complement in the modification of immune complex lattices [ ]. Since then there have been many studies that showed that complement promotes the inactivation and clearance of immune complexes by two main mechanisms.
One of these is the reduction in the size of immune complex lattices reviewed in [ , ]. This is achieved by the interaction of C1q with immune complexes, which interferes with Fc—Fc interactions that stabilize immune complexes, and by the covalent binding of C4b and C3b to antigens within the immune complexes.
This binding interferes with the binding of antigen to antibody by effectively reducing the valency of antigen for antibody. As well as reducing the size of immune complexes, complement provides additional ligands within the immune complex, promoting the clearance of immune complexes by complement as well as Fc receptors. As discussed in earlier in this chapter, immune complexes that have bound C4b and C3b can bind to CR1 on erythrocytes in the circulation that promote the clearance of immune complexes to the fixed mononuclear phagocytic system.
These observations led to the hypothesis that complement deficiency may promote the development of SLE by impairment of the normal mechanisms for clearance and processing of immune complexes. These could cause inflammatory injury in tissues, resulting in the release of autoantigens in an inflammatory context, promoting the development of an autoimmune response [ ].
There is abundant evidence that immune complex processing in SLE is abnormal and related to abnormal complement function [ — ]. Both the discovery that complement deficiency is compatible with the normal spontaneous development of glomerulonephritis in murine models of SLE [ , ] and the surprising finding that induced glomerulonephritis may be exacerbated in the presence of complement deficiency [ ] are compatible with this proposed role for complement in protection against immune-complex-mediated injury.
This hypothesis is complementary to and was the precursor of the 'waste disposal' hypothesis, developed in the next section, which advances the hypothesis that complement provides protection against the development of SLE by impairment of the physiological waste disposal of autoantigens released by dying and dead cells.
A central question about the aetiology of SLE is to understand how an autoimmune response develops to autoantigens that are found ubiquitously in cells of the body. There is abundant evidence that the established autoantibody response in SLE is driven by the actual autoantigens as opposed to being part of a polyclonal antibody response or driven by cross-reacting antigens. What is the source of these autoantigens? Cell death is an obvious potential source of autoantigens that are otherwise hidden from immune receptors in the heart of living cells.
However, cell death is a highly regulated process and the normal mechanisms of apoptosis ensure that dying cells are cleared without the induction of tissue inflammatory responses [ ].
One possible source is dead or dying cells from sites of inflammation and tissue injury. A possible connection between apoptotic cells and the autoantibody response of SLE was established by Rosen and his colleagues, who showed that a number of lupus autoantigens were located at the surface of apoptotic bodies and on apoptotic blebs [ ].
These observations have been followed by a series of studies of the mechanisms of apoptotic cell clearance in SLE. It was shown that macrophages derived from peripheral blood of patients with SLE showed defective uptake of apoptotic cells [ ].
The idea that complement might play a role in the clearance of apoptotic cells came from the observation that C1q bound to apoptotic keratinocytes [ ]. An excess of apoptotic cells was observed in kidneys from C1q-deficient mice [ ].
It was later shown that elicited peritoneal macrophages from C1q-deficient mice showed defective clearance of injected apoptotic thymocytes and the human lymphocyte cell lines known as Jurkat cells [ ]. Similarly, monocyte-derived macrophages from a small number of C1q-deficient humans showed defective clearance of apoptotic cells, a defect that could be reversed by the addition of purified C1q.
This work has led to the hypothesis that complement plays a role in the prevention of autoimmunity through a role in the disposal of dying and dead cells. Absence of this activity, possibly occurring in the context of an inflammatory environment, may promote the development of an autoantigen-driven autoimmune response [ , ].
It has also been shown that C4-deficient mice are prone to the development of lupus-like autoimmunity [ , ], which provides further evidence that complement-deficient mice are a useful model to study the association between complement deficiency and SLE, first described in humans.
The steps from defective clearance of apoptotic cells to the development of an autoimmune response remain unknown. It also causes disease acceleration in the lupus prone MRL. These data show the necessity for the presence of other disease-modifying genes that enable the potential autoimmune consequences of C1q deficiency to be expressed in mice. In humans, the strength of the contribution of C1q deficiency to disease appears higher than in mice, as the majority of humans with C1q deficiency express some manifestations of SLE [ ].
However, only approximately a third of patients develop glomerulonephritis, again indicating that C1q deficiency is not sufficient for the development of glomerular inflammation. Lupus in humans and mice is subject to the influence of multiple genetic and, probably also environmental, factors.
An alternative hypothesis to explain the link between complement deficiency and SLE is that complement plays a role in the induction of tolerance to autoantigens [ ]. Deficiency of this activity disturbs the normal tolerance mechanisms of lymphocytes leading to the induction of SLE. This hypothesis is difficult to reconcile with the observations that the complement system plays a physiological role in the augmentation of antibody responses. Pepys showed many years ago that depletion of complement C3 was associated with reduced primary and secondary antibody responses to T-cell-dependent antigens [ ], a finding that has subsequently been reproduced in complement genetically-deficient mice and guinea pigs [ , ].
The corollary of these observations was the engineering of complement as an adjuvant by the covalent attachment of oligomers of C3d to an experimental antigen [ ]. Using a transgenic model to study tolerance to hen egg lysozyme, expressed as an autoantigen, it was found that tolerance was disturbed in C4-deficient, but not C3-deficient, mice [ ]. In similar experiments with C1q-deficient mice, however, tolerance induction to hen egg lysozyme as an autoantigen was normal [ ].
This model of tolerance induction has important limitations as a model for exploring SLE, as in this disease, the majority of the autoantigens are cell-associated, as will be reviewed in the next section. Experimental studies are underway exploring the role of complement deficiency in tolerance induction in experimental animals expressing transgenic lupus autoantibodies, which may provide a clearer test of the hypothesis that complement is involved in the induction of tolerance.
A prominent feature of the autoantibody response in SLE is that it is directed not against isolated proteins but typically against whole complexes of proteins and nucleic acids [ — ]. Autoantibodies are found in clusters reactive against the different protein, nucleic acid and phospholipid components of these complexes.
For example anti-dsDNA autoantibodies are usually associated with antihistone autoantibodies and antibodies reacting with conformational determinants of chromatin. The autoantigens in this case are thought to be nucleosomes.
Anti-Sm and antiribonucleoprotein specificities are directed against different proteins in the spliceosome complex. Anti-Ro and anti-La are directed against the major protein component of a small cytoplasmic ribonucleoprotein complex.
These clinical findings point to actual autoantigenic particles in lupus being these large complexes and there is evidence that B cells play a key role as antigen-presenting cells in lupus [ — ].
A B cell bearing an antigen receptor for a component of one of these complexes can internalize the complex and then act as antigen-presenting cell for other peptides within the complex. In this way it is likely that the autoantibody response in SLE is diversified and amplified. The hypothesis has been reviewed above that C1q and other complement proteins prevent lupus by binding to apoptotic and necrotic cells and promoting their clearance.
The absence of C1q promotes autoimmunity by allowing these autoantigens to drive an autoimmune response. This hypothesis implies that C1q binds to the autoantigens of SLE.
In doing so, it may itself become part of the autoantigenic complexes that characterize the disease. Although it is unusual for plasma proteins to be targets for the autoimmune response in SLE, there is an important and informative analogy. Approximately a third of patients with SLE develop antiphospholipid autoantibodies.
These are directed against negatively charged phospholipids, especially phosphatidylserine, which normally reside on the inner lamella of cell membranes. However, they are translocated to the outer lamella of apoptotic cells, which reinforces the possible role of these cells as the source of the autoantigens that drive SLE [ , ].
Thus, the observation that C1q is itself an autoantigen in many patients with SLE reinforces the hypothesis that C1q and the complement system may prevent disease by binding to and promoting the clearance of autoantigens.
It is not straightforward to treat SLE by the manipulation of the complement system. On the one hand complement deficiency, as we have seen, is a powerful cause of SLE and this provides arguments for increasing complement activity by repletion of classical pathway proteins, at least in the case of the rare hereditary deficiencies. On the other hand, there is evidence that complement, especially the anaphylatoxins and the membrane attack complex, may be a cause of tissue injury and this raises the possibility of the treatment of SLE by therapeutic inhibition of the complement system.
Both approaches to therapy have been attempted in different contexts in SLE and will be reviewed in the next few paragraphs. Complement is a potent cause of tissue injury in ischaemia-reperfusion injury and therefore is a therapeutic target in patients with myocardial infarction and stroke.
Because these are highly prevalent and disabling diseases there have been many studies that have validated the potential importance of complement inhibition as a treatment for them. There are several reviews that illustrate the range of diseases that are under investigation and the many approaches to treatment by inhibition of the complement system [ — ].
There is increasing evidence that the key mediators of injury induced by the complement system are the anaphylatoxins, especially C5a, and the membrane attack complex. Thomas, and J. Sontheimer, P. Maddison, M. Reichlin, R. Jordon, P. Stastny, and J. View at: Google Scholar L. Lee, K. Alvarez, T. Gross, and J. View at: Google Scholar E. Chlebus, H. Wolska, M. Blaszczyk, and S. View at: Google Scholar M. Reid and R. Truedsson, A.
Bengtsson, and G. Manderson, M. Botto, and M. Davies, A. Peters, H. Beynon, and M. View at: Google Scholar P. Taylor, A. Carugati, V. Fadok et al. Ronnblom, M.
Eloranta, and G. Pascual, L. Farkas, and J. Tsao and H. Wallace and B. Hahn, Eds. View at: Google Scholar T. Vyse and B. Wu, G. Hauptmann, M. Viguier, and C. Mauff, B. Luther, P. Schneider et al. View at: Google Scholar C. Yu, E. Chung, Y. Patterns of disease activity in systemic lupus erythematosus. Prolonged serologically active clinically quiescent systemic lupus erythematosus: frequency and outcome. J Rheumatol. Erythrocyte bound C4d in combination with complement and autoantibody status for the monitoring of SLE.
The complex nature of serum C3 and C4 as biomarkers of renal flare. Are laboratory tests useful for monitoring the activity of lupus nephritis?
A 6-year prospective study in a cohort of patients with lupus nephritis. Ann Rheum Dis. Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares. The C3dg fragment of complement is superior to conventional C3 as a diagnostic biomarker in systemic lupus erythematosus. Front Immunol. Association of blood concentrations of complement split product iC3b and serum C3 with systemic lupus erythematosus disease activity.
A quantitative lateral flow assay to detect complement activation in blood. Anal Biochem. Plasma C4d as marker for lupus nephritis in systemic lupus erythematosus. Arthritis Res Ther. Plasma C4d correlates with C4d deposition in kidneys and with treatment response in lupus nephritis patients. The lectin pathway of complement activation in patients with systemic lupus erythematosus. Article PubMed Google Scholar. The role of mannose binding lectin in systemic lupus erythematosus. Clin Rheumatol.
Cell-bound complement activation products in SLE. Lupus Sci Med. Complement deposition, C4d, on platelets is associated with vascular events in systemic lupus erythematosus. Google Scholar. Gavrilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest. Complement activation in patients with primary antiphospholipid syndrome.
Blood cell-bound C4d as a marker of complement activation in patients with the antiphospholipid syndrome. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Advances.
A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy.
BMC Nephrology. C4d deposits on the surface of RBCs in trauma patients and interferes with their function. Crit Care Med. Complement fragment C3d is colocalized within the lipid rafts of T cells and promotes cytokine production. Complement and human T cell metabolism: location, location, location. Immunol Rev. Download references. Arthur Weinstein, Roberta V. You can also search for this author in PubMed Google Scholar. Correspondence to Arthur Weinstein. AW is a research consultant to Exagen Inc.
This article does not contain any studies with human or animal subjects performed by any of the authors. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
0コメント