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vascular permeability and the infection. The second category Primer extravasation of plasma. This is in which there is persistent accompanied by the adhesion of formation of immune complexes is leukocytes to vascular endothelium autoimmune disease, in which, by The complement and their emigration into definition, the antigen is a system surrounding tissue. Complement permanent feature of the host. plays an important part in An understanding of how immune Philip Taylor, Marina inflammation, in helping to recruit complexes cause tissue injury effector cells and in promoting the developed from study of such Botto and Mark Walport killing and clearance of pathogens. diseases in humans and animals, and But complement can be both from the induction of experimental The system of plasma proteins called friend and foe. In some immune complex disease. In these complement was so-named because circumstances the activation of situations, immune complexes were it complements the activity of complement in response to immune shown to cause tissue injury through antibody in the lysis of bacteria. It complexes may cause harm: acutely activation of complement, as opsonin has a central role in host defence in the context of massive (binding to complement receptors on against many micro-organisms and in complement activation occurring in leukocytes) and as the source of the modulation of inflammatory patients with overwhelming Gram- anaphylatoxins (stimulating leukocyte reactions, an activity that has been negative bacterial sepsis, and chemotaxis and degranulation). But illuminated by the study of humans chronically, when an antibody the development of gene-targeted with naturally occurring deficiencies response develops in the context of mice with deficiencies of complement of complement. antigens that cannot be cleared. proteins and of receptors for the Fc Complement is activated by three Examples of this are infections at part of antibodies has led to pathways: the classical, alternative and anatomically-protected sites — such re-appraisal of the role of complement mannan-binding lectin (MBL) as heart valves in bacterial and antibodies in inflammatory injury. pathways (Figure 1 and Table 1). The endocarditis — or infections by Some studies of the formation of classical pathway is primarily activated certain viruses, such as hepatitis C, immune complexes in the skin of by antibody bound to antigens in patients who are unable to clear these animals (the Arthus reaction) (immune complexes). The alternative pathway is activated by the direct Figure 1 binding of complement component C3 to pathogens in the absence of Classical Mannan-binding Alternative antibody. The recently discovered pathway lectin pathway pathway MBL pathway is initiated by the Mannan-binding lectin binding of MBL to mannose groups, Antigen–antibody complex binds mannose on Pathogen surfaces present on many bacterial cell walls. pathogen surface All three pathways lead to the C1q MBL C3 cleavage of C3, the central component C1r–C1s MASP1–MASP2 B of complement, which functions as an C4 C4 opsonin, tagging pathogens and C2 C2 D immune complexes for recognition C3 convertase and uptake, mediated by specific complement receptors on phagocytic C3a cells. Subsequent activation of the C3 terminal complement pathway, C3b known as the membrane attack C5 convertase complex (MAC), leads to cell lysis. C5b An important current focus of C6 complement research is the C7 physiological activities of C8 complement in vivo, on which we C9 will concentrate in this primer. Membrane-attack complex Complement and inflammation Current Biology Inflammation is a complex process The main pathways and components of the complement activation system. involving vasodilation, increased R260 Current Biology, Vol 8 No 8

Table 1 addition of increasing numbers of C3 molecules to each antigen molecule Effector activities of the complement system dramatically reduced the threshold Activity Complement protein Complement receptor for activation of B lymphocytes. mediating effect Evasion of complement by pathogens Opsonin for phagocytosis C3b, iC3b CR1, CR3 C4b CR1 One of the most fascinating aspects C1q, MBL C1q receptor of the study of complement is the exploration of the mechanisms that Peptide mediators of inflammation C5a C5a receptor C3a C3a receptor pathogens have evolved to evade and, in some cases, exploit the Lytic membrane attack complex C5b, C6, C7, C8, C9 complement system. Pathogens that Processing and clearance of C1q C1q receptor cause disease are pathogenic by antigen–antibody immune complexes C3b, iC3b CR1, CR3 virtue of their ability to escape, at C4b CR1 least in part, the primary mechanisms Localization of antigen in the C3b, iC3b, C3dg CR1, CR2, CR3 of defence of the innate immune form of immune complexes on antigen-presenting cells system. To evade complement pathogens have stolen and mimicked Activation of B lymphocytes C3dg CR2 regulatory molecules of the Clearance of apoptotic cells C1q? C1q receptor? complement system (Figure 2).

The activites of the complement system are complement proteins that bind covalently to Complement and autoimmunity shown in the left-hand column. In the centre the targets of complement activation.) The Homozygous deficiency of classical are shown the complement proteins that column on the right shows the receptors that pathway proteins is very strongly mediate the effects. (C3b, iC3b and C4b are are bound by the relevant complement large activation products of these ligands in the centre column. associated with the development of the autoimmune disease systemic showed that ligation of Fc receptors mice. Complement activation was lupus erythematosus (SLE). There is — which bind to antibodies shown to mediate the initial release a hierarchy of susceptibility and complexed with antigens — on mast of the pro-inflammatory cytokine severity of autoimmune disease cells is critical for the induction of TNFα by mast cells, and the according to the position of the inflammatory injury by immune subsequent neutrophil influx. deficient protein in the classical complexes, and that complement pathway, with C1q deficiency showing plays little or no part. This view has Complement and adaptive immunity the highest prevalence and causing been supported by the study of the It has been known since the seminal the most severe disease. These effects of Fc receptor deficiency in experiments of Pepys in 1974 that clinical observations imply that there a spontaneous mouse model of an complement is involved in the is a, so far unknown, physiological autoimmune disease, systemic induction and maintenance of activity of the early proteins of the lupus erythematosus, in which antibody responses. Recently, there classical pathway that protects against immune complexes are prominent. has been an increasing appreciation of the development of SLE. Fc receptors were shown to be the importance of the role of Some recent data point to the required for the development of complement at the interface between discovery of a possible new severe renal disease. innate and adaptive immunity. Here, physiological activity of the It is probably too early, however, complement plays a part in the complement system that could link to dismiss completely the role of localization of antigens to antigen- complement deficiency and SLE. complement in inflammation in presenting cells — cells specialized to There is evidence that apoptotic immune complex-mediated disease. present antigens to lymphocytes and cells might be the source of the Studies of immune complex to activate them — and to B cells, autoantigens that stimulate formation in mice deficient in both of which bear receptors for major autoimmunity in SLE and that C1q complement component C5, or in the cleavage products of C3. might be involved in the processing receptor for the anaphylatoxin C5a, This activity of complement was of apoptotic cells. If these findings demonstrated a more substantial role beautifully demonstrated by are confirmed, then failure of for complement in the mediation of experiments in which antibody clearance of apoptotic cells could inflammatory reactions in the lungs responses were measured in animals perhaps explain the link between and peritoneum. Similar results were immunized with antigens covalently complement deficiency and SLE. obtained in studies of peritoneal linked by genetic engineering to the The development of C1q-deficient infection in C3- and C4-deficient relevant cleavage product of C3. The mice will help to resolve this. Magazine R261

Therapeutic inhibition of complement complement when transplanted into in cheek, by a distinguished Transplantation of organs between non-human primates. Professor of Medicine that species that are distantly related in A clinically-important example of complement research was dead. We phylogenetic terms — such as complement-mediated tissue injury hope this primer will persuade that humans and pigs — is followed by is that following infarction. For professor that the complement rapid organ rejection, which is example, the MAC might be found system is alive and well and that the mediated by massive complement in the heart following myocardial study of complement continues to activation, caused by antibody infarction. Soluble fragments of the make major and surprising binding to abundant carbohydrate complement receptor and regulatory contributions to our understanding epitopes on the pig tissues. Because protein CR1 (CD35) reduce the of immunobiology. xenotransplantation is an attractive infarct size in experimental models option (if ethical and viral issues of myocardial infarction. This has yet Acknowledgements permit) for overcoming the severe to be translated into clinical practice, Work in the authors’ laboratories is supported by grants from the Arthritis and Rheumatism shortage of human organs for but complement activation in Council and the Wellcome Trust. transplantation, there has been infarction and ischaemic-reperfusion much interest in inhibiting injury remains a very attractive Key references complement-mediated injury to target, especially if a small molecule Clynes R, Dumitru C, Ravetch JV: Uncoupling of immune complex formation and xenotransplants. Pigs have been could be discovered with efficient kidney damage in autoimmune developed that are transgenic for inhibitory activity for complement. glomerulonephritis. Science 1998, the expression of human 279:1052-1054. Dempsey PW, Allison ME, Akkaraju S, complement regulatory proteins. Conclusion Goodnow CC, Fearon DT: C3d of Organs from such animals show When one of the authors of this complement as a molecular adjuvant: significant protection from article, MW, entered complement bridging innate and acquired immunity. Nature 1996, 271:348-350. hyperacute rejection mediated by research he was told, possibly tongue Fischer MB, Ma M, Goerg S, Zhou X, Xia J, Finco O, Han S, Kelsoe G, Howard RG, Rothstein TL, et al.: Regulation of the B Figure 2 cell response to T-dependent antigens by classical pathway complement. J Immunol 1996, 157:549-556. (a) (b) Hazenbos WL, Gessner JE, Hofhuis FM, Kuipers H, Meyer D, Heijnen IA, Schmidt RE, Sandor M, Capel PJ, Daeron M, et al.: Impaired IgG-dependent anaphylaxis and B cell Arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity 1996, 5:181-188. Hopken UE, Lu B, Gerard NP, Gerard C: Impaired inflammatory responses in the EBV reverse Arthus reaction through genetic deletion of the C5a receptor. J Exp Med 1997, 186:749-756. Korb LC, Ahearn JM: C1q binds directly and (c) (d) specifically to surface blebs of apoptotic CD59-like Bb human keratinocytes: complement molecule deficiency and systemic lupus C2a erythematosus revisited. J Immunol 1997, 158:4525-4528. C9 C3b Lachmann PJ, Davies A: Complement and DAF immunity to viruses. Immunol Rev 1997, 159:69-77. C5b,6,7,8 Molina H, Holers VM, Li B, Fung Y, Mariathasan Schistosome Schistosome C4b S, Goeller J, Strauss-Schoenberger J, Karr R, Chaplin D: Markedly impaired humoral immune response in mice deficient in Current Biology complement receptor 1 and 2. Proc Natl Acad Sci USA 1996, 93:3357-3361. Four strategies by which pathogens use the (blue) via C3 receptors (pink) on the cell Prodeus AP, Zhou X, Maurer M, Galli SJ, Carroll complement system as part of their surface. (c) Schistosomes synthesize an MC: Impaired mast cell-dependent pathogenesis. (a) The Epstein–Barr virus endogenous protein (purple) that mimics a natural immunity in complement C3- (EBV) uses a B lymphocyte receptor for host complement regulatory protein, CD59, deficient mice. Nature 1997, 390:172-175. complement, CR2 (pink), to gain entry to the and inhibits the formation of the MAC (red) Schorey JS, Carroll MC, Brown EJ: A cell. (Cell-surface immunoglobulin is shown on the parasite. (d) Schistosomes absorb a macrophage invasion mechanism of pathogenic mycobacteria. Science 1997, in yellow.) (b) A mycobacterium (green) fixes complement regulatory protein, decay 277:1091-1093. a complement enzyme, C2a, to its surface. accelerating factor (DAF; green), from the The C2a cleaves C3, resulting in the binding host plasma that protects against the of C3b (red) to the mycobacterial surface. activation of complement by inhibiting the Address: Rheumatology Section, Division of The mycobacterium then enters macrophages formation of the C3 convertase enzyme. Medicine, Imperial College School of Medicine, Du Cane Road, London W12 0NN, UK.