CJASN ePress. Published on January 8, 2015 as doi: 10.2215/CJN.06230614 Molecules Great and Small: The Complement System Douglas R. Mathern and Peter S. Heeger Abstract The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and Translational autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement mem- Transplant Research brane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which Center, Department of requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 Medicine, Recanati nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by Miller Transplant Institute, Immunology endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive Institute, Icahn School kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and of Medicine at Mount antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The Sinai, New York, New subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their York respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell–derived complement Correspondence: Dr. Peter S. Heeger, enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the Icahn School of pathogenesis of other T cell–mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally Medicine at Mount been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New trans- Sinai, One Gustave lational immunology efforts along with the development of pharmacologic agents that block human complement Levy Place, Box 1243, New York, NY 10029. components and receptors now permit testing of the intriguing concept that targeting complement in patients with Email: peter.heeger@ an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health. mssm.edu Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.06230614 Introduction as a (e.g., C3a), and the larger cleavage fragments are The complement system, traditionally considered a com- denoted as b (e.g., C3b). After they are activated, in- ponent of innate immunity required for protection from dividual enzymes have the ability to repeatedly cleave invading pathogens, has been implicated in the path- their substrates, yielding a self-amplifying cascade. ogenesis of autoimmune kidney disease since the The various components can be considered as princi- 1960s (1). Fifty years later, the detailed complexities of pally involved in (1) initiating complement activation, complement’s role in kidney injury are still being un- (2) amplifying complement activation, (3) performing raveled. Building on early work indicating that mac- effector functions, and/or (4) regulating the cascade rophages and tubular cells produce complement (2,3), (Figure 1). studies performed since the 2000s have altered for- mer paradigms by showing that tissue-derived com- Activation – plement and immune cell derived complement can Complement activation can be initiated through three fl each mediate local in ammation and that comple- pathways (Figure 1) (reviewed in ref. 4). The classical ment acts as a bridge between innate and adaptive pathway is activated when the hexameric C1q, as part immunity in an array of kidney diseases. Herein, we of a C1qrs complex containing two C1r molecules and will review the physiology of the complement system, two C1s molecules, binds to the Fc regions of IgG or ’ provide a framework for understanding complement s IgM. Complement activation through the classical varied roles in kidney disease pathogenesis, and high- pathway is optimally activated by a hexameric orga- light potential therapeutic targets. nization of antigen-bound antibodies, a configuration that increases the avidity between C1q and the Fc re- gions by 20-fold (5). After an induced conformational Biology of the Complement System change, the C1s component cleaves C4 to C4a1C4b The complement system is comprised of .30 soluble and then cleaves C2 to C2a1C2b. C4b can bind to cell and surface-expressed proteins, many of which are surfaces by a thio-ester bond, after which C2b is re- zymogens (inactive precursors that require cleavage cruited to form the C4b2b classical pathway C3 conver- to become active enzymes). In the latest nomencla- tase capable of cleaving C3 into C3a (an anaphylatoxin) ture, the smaller cleavage fragments are designated plus C3b. www.cjasn.org Vol ▪▪▪▪,2015 Copyright © 2015 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology Amplification The C3 convertases repeatedly cleave C3 molecules, yield- ing multiple C3b products, each of which can interact with fB to form more C3 convertases. As consequences, C3 cleavage is the central amplification step of the cascade, and regard- less of the initial activation pathway, amplification at the C3 convertase step occurs through the alternative pathway. Regulation of the C3 convertase amplification step is crucial to restrain complement activation so as to prevent patho- logic consequences (see below). Effector Functions C4b2b and C3bBb form multimeric complexes with addi- tional C3b molecules, yielding the C5 convertases C4b2bC3b and C3bBbC3b. These enzymes cleave C5 to C5a (an an- aphylatoxin) plus C5b, the latter of which binds to C6 and subsequently facilitates binding of C7 and C8 plus 10–16 C9 molecules to form the C5b-9 membrane attack complex (MAC) (Figure 1). The MAC forms a pore in cell membranes, which promotes lysis of non-nucleated cells (e.g.,bacteriaand human red blood cells [RBCs]). Insertion of MACs into nu- cleated host cells generally does not result in lysis but can induce cellular activation (8) and/or promote tissue injury (9). Various complement cleavage products have other effec- tor functions (Figure 2, Table 1). C3a and C5a ligate their – Figure 1. | Overview of the complement cascade. The complement seven transmembrane-spanning G protein coupled recep- fl cascade can be initiated by three pathways: (1) the classical pathway, tors C3aR and C5aR, respectively, transmitting proin am- (2) the mannose-binding lectin (MBL) pathway, and (3) the alternative matory signals that induce vasodilation and cytokine and pathway. The resultant C3 convertases can continuously cleave C3; chemokine release. They also mediate neutrophil and however, after they are generated, the alternative pathway C3 con- macrophage chemoattraction, activate macrophages to vertase dominates in amplifying production of C3b (green looping promote intracellular killing of engulfed organisms, and arrow). The C3 convertases associate with an additional C3b to form contribute to T-cell and antigen-presenting cell (APC) 1 the C5 convertases, which cleave C5 to C5a C5b. C5b recruits C6, activation, expansion, and survival (see below) (10–13). C7, C8, and 10–16 C9 molecules to generate the terminal membrane C3b and other bound cleavage products bind to various attack complex (MAC), which inserts pores into cell membranes to surface-expressed receptors, including complement recep- induce cell lysis. C3a and C5a are potent signaling molecules, which through their G protein–coupled receptors C3aR and C5aR, re- tor 1 (CR1), CR2, CR3, and CR4, functioning as opsonins. spectively, can promote inflammation, chemoattraction of leuko- cytes, vasodilation, cytokine and chemokine release, and activation Regulation of adaptive immunity. fB, factor B; fD, factor D; fP, factor P; MASP, Complement activation must be physiologically restrained mannose-binding lectin-associated serine protease. to limit damage to self-cells (4). Complement regulation occurs at multiple steps through distinct mechanisms (Fig- ure 3). Regulation of C3 convertase activity is accomplished In the lectin pathway, hexamers of mannose-binding lectins by multiple molecules with overlapping but discrete func- (MBLs) bind to bacterial carbohydrate motifs (including tions. Decay accelerating factor (DAF; CD55) is a glyco- mannose). MBL-associated serine proteases (MASPs) func- phosphatidylinositol (GPI)-anchored, membrane-bound tion similarly to C1r and C1s to cleave C4 and then C2, gen- regulator that accelerates the decay of cell surface–assembled erating the C4bC2b C3 convertase. classical and alternative pathway C3 and C5 convertases In the alternative pathway, complement activation occurs (facilitating disassociation of Bb from C3bBb and C2b from spontaneously and continuously at a low rate (referred to as C4b, while also competitively inhibiting their reformation) tickover). The mechanism involves C3 associating with a (14), thereby preventing amplification, downstream cleav- water molecule to form C3 (H2O), which recruits factor B age events, and formation of the