molecules great and small: the complement system · bb, the active serine esterase that cleaves c3...

Molecules Great and Small: The Complement System

Douglas R. Mathern and Peter S. Heeger

AbstractThe complement cascade, traditionally considered an effector arm of innate immunity required for host defenseagainst pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complementcomponents produced by the liver and circulating in the plasma undergo activation through the classical and/ormannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection andautoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement mem-brane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, whichrequisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced byendothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressivekidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells andantigen-presenting cells, produce alternative pathway complement components during cognate interactions. Thesubsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to theirrespective 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 complementenhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to thepathogenesis of other T cell–mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionallybeen shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New trans-lational immunology efforts along with the development of pharmacologic agents that block human complementcomponents and receptors nowpermit testing of the intriguing concept that targeting complement in patientswithan assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

Clin J Am Soc Nephrol 10: 1636–1650, 2015. doi: 10.2215/CJN.06230614

IntroductionThe complement system, traditionally considereda com-ponent of innate immunity required for protection frominvading pathogens, has been implicated in the path-ogenesis of autoimmune kidney disease since the1960s (1). Fifty years later, the detailed complexities ofcomplement’s role in kidney injury are still being un-raveled. Building on early work indicating that mac-rophages and tubular cells produce complement (2,3),studies performed since the 2000s have altered for-mer paradigms by showing that tissue-derived com-plement and immune cell–derived complement caneach mediate local inflammation and that comple-ment acts as a bridge between innate and adaptiveimmunity in an array of kidney diseases. Herein, wewill review the physiology of the complement system,provide a framework for understanding complement’svaried roles in kidney disease pathogenesis, and high-light potential therapeutic targets.

Biology of the Complement SystemThe complement system is comprised of .30 soluble

and surface-expressed proteins, many of which arezymogens (inactive precursors that require cleavageto become active enzymes). In the latest nomencla-ture, the smaller cleavage fragments are designated

as a (e.g., C3a), and the larger cleavage fragments aredenoted as b (e.g., C3b). After they are activated, in-dividual enzymes have the ability to repeatedly cleavetheir substrates, yielding a self-amplifying cascade.The various components can be considered as princi-pally involved in (1) initiating complement activation,(2) amplifying complement activation, (3) performingeffector functions, and/or (4) regulating the cascade(Figure 1).

ActivationComplement activation can be initiated through three

pathways (Figure 1) (reviewed in ref. 4). The classicalpathway is activated when the hexameric C1q, as partof a C1qrs complex containing two C1r molecules andtwo C1s molecules, binds to the Fc regions of IgG orIgM. Complement activation through the classicalpathway is optimally activated by a hexameric orga-nization of antigen-bound antibodies, a configurationthat increases the avidity between C1q and the Fc re-gions by 20-fold (5). After an induced conformationalchange, the C1s component cleaves C4 to C4a1C4band then cleaves C2 to C2a1C2b. C4b can bind to cellsurfaces by a thio-ester bond, after which C2b is re-cruited to form the C4b2b classical pathway C3 conver-tase capable of cleaving C3 into C3a (an anaphylatoxin)plus C3b.

TranslationalTransplant ResearchCenter, Department ofMedicine, RecanatiMiller TransplantInstitute, ImmunologyInstitute, Icahn Schoolof Medicine at MountSinai, New York, NewYork

Correspondence:Dr. Peter S. Heeger,Icahn School ofMedicine at MountSinai, One GustaveLevy Place, Box 1243,New York, NY 10029.Email: [email protected]

www.cjasn.org Vol 10 September, 20151636 Copyright © 2015 by the American Society of Nephrology

mailto:[email protected]

mailto:[email protected]

In the lectin pathway, hexamers of mannose-binding lectins(MBLs) bind to bacterial carbohydrate motifs (includingmannose). MBL-associated serine proteases (MASPs) func-tion similarly to C1r and C1s to cleave C4 and then C2, gen-erating the C4bC2b C3 convertase.In the alternative pathway, complement activation occurs

spontaneously and continuously at a low rate (referred to astickover). The mechanism involves C3 associating with awater molecule to form C3 (H2O), which recruits factor B(fB) and factor D (fD). fD enzymatically cleaves fB, yieldingBb, the active serine esterase that cleaves C3 to C3a1C3b.C3b associates with Bb to form the C3bBb alternative path-way C3 convertase. The thio-ester bond on C3 covalentlyreacts with various residues on cell surfaces, localizing C3convertase formation predominantly to these sites. Proper-din has dual functions, directly binding to microbial targetsto provide a platform for assembly of the alternative path-way C3 convertase (6) and increasing the stability of theC3bB/C3bBb complexes (7).

AmplificationThe C3 convertases repeatedly cleave C3 molecules, yield-

ing multiple C3b products, each of which can interact with fBto form more C3 convertases. As consequences, C3 cleavageis the central amplification step of the cascade, and regard-less of the initial activation pathway, amplification at the C3convertase step occurs through the alternative pathway.Regulation of the C3 convertase amplification step is crucialto restrain complement activation so as to prevent patho-logic consequences (see below).

Effector FunctionsC4b2b and C3bBb form multimeric complexes with addi-

tional C3b molecules, yielding the C5 convertases C4b2bC3band C3bBbC3b. These enzymes cleave C5 to C5a (an an-aphylatoxin) plus C5b, the latter of which binds to C6 andsubsequently facilitates binding of C7 and C8 plus 10–16 C9molecules 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., bacteria andhuman red blood cells [RBCs]). Insertion of MACs into nu-cleated host cells generally does not result in lysis but caninduce 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 theirseven transmembrane-spanning G protein–coupled recep-tors C3aR and C5aR, respectively, transmitting proinflam-matory signals that induce vasodilation and cytokine andchemokine release. They also mediate neutrophil andmacrophage chemoattraction, activate macrophages topromote intracellular killing of engulfed organisms, andcontribute to T-cell and antigen-presenting cell (APC)activation, expansion, and survival (see below) (10–13).C3b and other bound cleavage products bind to varioussurface-expressed receptors, including complement recep-tor 1 (CR1), CR2, CR3, and CR4, functioning as opsonins.

RegulationComplement activation must be physiologically restrained

to limit damage to self-cells (4). Complement regulationoccurs at multiple steps through distinct mechanisms (Fig-ure 3). Regulation of C3 convertase activity is accomplishedby multiple molecules with overlapping but discrete func-tions. Decay accelerating factor (DAF; CD55) is a glyco-phosphatidylinositol (GPI)-anchored, membrane-boundregulator that accelerates the decay of cell surface–assembledclassical and alternative pathway C3 and C5 convertases(facilitating disassociation of Bb from C3bBb and C2b fromC4b, while also competitively inhibiting their reformation)(14), thereby preventing amplification, downstream cleav-age events, and formation of the MAC (15). This decayaccelerating activity functions intrinsically (i.e., restrainingcomplement activation only on the cell surface on whichDAF is expressed).Membrane Cofactor Protein (MCP; CD46) and its murine

homolog Crry are surfaced-expressed regulators with cofac-tor activity (16) functioning as cofactors for serum factor I(fI), which cleaves C3b to iC3b, thereby irreversibly prevent-ing reassembly of the C3 convertase. Crry also exhibits decayaccelerating activity (17). The cleavage product iC3b (an op-sonin) can be further broken down to C3c and C3dg

Figure 1. | Overview of the complement cascade. The complementcascade can be initiated by three pathways: (1) the classical pathway,(2) the mannose-binding lectin (MBL) pathway, and (3) the alternativepathway. The resultant C3 convertases can continuously cleave C3;however, after they are generated, the alternative pathway C3 con-vertase dominates in amplifying production of C3b (green loopingarrow). The C3 convertases associate with an additional C3b to formthe C5 convertases, which cleave C5 to C5a1C5b. C5b recruits C6,C7, C8, and 10–16 C9 molecules to generate the terminal membraneattack complex (MAC), which inserts pores into cell membranes toinduce cell lysis. C3a and C5a are potent signaling molecules, whichthrough their G protein–coupled receptors C3aR and C5aR, re-spectively, can promote inflammation, chemoattraction of leuko-cytes, vasodilation, cytokine and chemokine release, and activationof adaptive immunity. fB, factor B; fD, factor D; fP, factor P; MASP,mannose-binding lectin-associated serine protease.

Clin J Am Soc Nephrol 10: 1636–1650, September, 2015 Complement and Kidney Disease, Mathern et al. 1637

(through fI- and cofactor-dependent cleavage processes) (re-viewed in ref. 18), the latter of which interacts with CR2 onB cells to facilitate B-cell activation (19).Factor H (fH) is a plasma protein that also regulates com-

plement activation at the C3 convertase step (reviewed inref. 20). The carboxy terminus of this protein binds surface-deposited C3b and surface-expressed polyanionic glycos-aminoglycans, including sialic acid residues. After they arebound, the N-terminal domains of fH exhibit decay acceler-ating and cofactor activities (Figure 3). fH restrains comple-ment activation on host surfaces that do not express othercomplement regulators, including exposed basement mem-branes in the glomerulus (which express glycosaminogly-cans), explaining, in part, the association between mutationsin fH or fI and various C3 nephropathies (see below).Additional complement regulators (Figure 3) include the

GPI-anchored and surfaced-expressed protein protectin(CD59), which blocks formation of the MAC, the surface-

expressed CR1, which exhibits decay accelerating activityand cofactor activity for fI, and C1 inhibitor, a serine pro-tease that irreversibly binds to and inactivates C1r, C1s,MASP-1, and MASP-2, thereby limiting classical and MBLpathway activation. Ubiquitously expressed carboxypepti-dases rapidly inactivate the anaphylatoxins C3a and C5a(reviewed in ref. 4).

Sources of ComplementLiver-derived plasma complement is essential for pro-

tection from pathogens and contributes to antibody-initiated,complement-mediated autoimmune injury. Complementcomponents can be produced by tissue-resident (e.g., tubu-lar cells in the kidney [21]) and migratory/immune cells,including T cells and APCs (22–24). A thorough under-standing of complement-mediated kidney disease requiresconsideration of the source of complement production, thesite of complement activation, the specific complement

Figure 2. | Complement and adaptive immunity. (A) B cells express complement receptor 2 (CR2; CD21), which binds to C3dg, a C3 breakdownproduct that functions as an opsonin. C3dg-coated antigens recognized by antigen-specific B-cell receptors plus CR2 initiate engulfment and lowerthe threshold of B-cell activation, promoting antibody production. (B) Cognate interactions between T cells and antigen-presenting cells (APCs)(T-cell receptor [TCR]1CD28/80/86 orCD40/154) upregulate the expression ofmultiple alternative pathway components, includingC3, C5, fB, fD,C3aR, and C5aR, while simultaneously downregulating decay accelerating factor (DAF) expression (lifting restraint on complement activation).Locally produced C3a and C5a act in an autocrine/paracrine manner through AKT signaling to promote maturation and cytokine production ofAPCs, Th1/IFN-g expression, increased proliferation, and decreased apoptosis of T cells. (C) Regulatory T-cell generation, stability, and suppressivefunction are decreased by C3a and C5a signaling-induced AKT signaling, which impairs nuclear translocation of Foxo1, a transcription factor forFoxP3. AKT, phosphokinase B; pAKT, phosphorylated phosphokinase B; BCR, B cell receptor; iTreg, murine-induced regulatory T cell.

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effector components and receptors involved, and the func-tion of complement regulators in each situation.

Links between Complement and Adaptive ImmunityIt has been known for decades that complement deple-

tion impairs antibody production (25). The mechanism in-volves antigen-bound C3dg (an iC3b cleavage product)binding to B cell–expressed CR2 (CD21), which facilitatesantigen presentation to B cells and lowers the threshold forB-cell activation (26) (Figure 2).Work published since the early 2000s uncovered an un-

expected role for complement as a regulator of T-cell immu-nity. During cognate interactions between T cells and APCs,both partners upregulate and secrete alternative pathwaycomplement components C3, fB, and fD, produce C5, andupregulate surface expression of C3aR and C5aR (23,24)(Figure 2). These changes are a consequence of costimulatorymolecule signaling by CD28/CD80/CD86 and CD154/CD40 (24), which simultaneously and transiently reducescell surface–expressed DAF (thereby lifting restraint on com-plement activation). Locally produced C3a and C5a bind totheir receptors and function as autocrine and paracrine stim-ulators of the T cell and the APC (23,24). Signaling throughthese GPCRs in T cells activates phosphoinositide-3-kinase-gand induces phosphorylation of phosphokinase B (AKT)(22,24), upregulating the antiapoptotic protein Bcl-2 anddownregulating the proapoptotic molecule Fas. Together,these complement-dependent mechanisms enhance T-cellproliferation and diminish T-cell apoptosis (22). C3aR/C5aR signaling is also required for T-cell homeostasis, be-cause T cells deficient in both receptors spontaneously

undergo accelerated cell death in vitro and in vivo (24).The observations derived frommurine models also apply tohuman T cells (27). Building on these findings, a 2013 pub-lication showed that resting human CD41 T cells containC3 in granules that is rapidly cleaved by cathepsin-L to C3aand secreted after CD3 ligation. Evidence suggests that thisintracellular C3/C3a contributes to the aforementionedpromotion of T-cell survival and effector responses (28).Regulatory T cells (Tregs) are instrumental for allograft

tolerance induction and maintenance in rodents and as-sociated with improved long-term transplant outcomes inhumans (29). Data published in 2013 indicate that comple-ment also regulates Treg induction, function, and stability(12,30) (Figure 2). Our group showed that peripheral, mu-rine, natural regulatory T cells (nTregs) express C3aR andC5aR and that signaling through these receptors inhibitsTreg function (11). Genetic and pharmacologic blockade ofC3aR/C5aR signal transduction in nTreg cells augmentstheir in vitro and in vivo suppressive activity. Mechanismsinvolve C3a/C5a-induced phosphorylation of AKT and, as aconsequence, phosphorylation of the transcription factorFoxo1, which results in lowered nTreg Foxp3 expression.Two additional sets of data showed that genetic deficiencyor pharmacologic blockade of C3aR/C5aR signaling aug-ments murine-induced regulatory T cell (iTreg) generation,stabilizes Foxp3 expression, and resists iTreg conversion toIFN-g/TNF-a–producing effector T cells (12,30). Pharmaco-logic antagonists to human C3aR and C5aR also augment invitro generation and stability of human iTreg from naïveprecursors (12,30). These new results build on previouslypublished evidence that coengagement of the T-cell receptor

Table 1. Complement receptor functions

ComplementReceptor

AlternativeNames Ligand Effector

Functions Cell Type

CR1 CD35, immuneadherence receptor

C3b, iC3b,C4b, C1q

Clearance ofimmune complexes,enhancement ofphagocytosis, andregulation ofC3 breakdown

Many nucleatedcells and RBCs,B cells, leukocytes,monocytes, andfollicular dendriticcells

CR2 CD21, Epstein–Barrvirus receptor

C3dg, C3d, iC3b Regulation ofB-cell function,B-cell coreceptor,and retentionof C3d-taggedimmunecomplexes

B and T cells andfolliculardendritic cells

CR3 MAC1, CD11b-CD18,aMb2 integrin

iC3b, factor H iC3b enhancescontact of opsonizedtargets, resultingin phagocytosis

Monocytes,macrophages,neutrophils, NKcells, eosinophils,myeloid cells,follicular dendriticcells, and CD41and CD81 T cells

CR4 CD11c-CD18,aXb2 integrin

iC3b iC3b-mediatedphagocytosis

Monocytes andmacrophages

Modified from reference 130, with permission. CR1, complement receptor 1; RBC, red blood cell; MAC1, membrane attack complex 1.


and the complement regulator CD46 promotes regulatoryIL-10 production (31) to delineate a crucial role for comple-ment in modulating the balance between pathogenic andprotective adaptive T-cell responses.

Complement and Kidney DiseaseAntibody-Initiated Activation of Serum ComplementAutoantibodies reactive to kidney-expressed self-antigens

and/or antibody/antigen complexes deposited in the kidney

are considered causative of various human kidney diseases.Increasingly available evidence links the pathogenesis ofmany of these antibody-initiated kidney pathologies tocomplement-derived effector mechanisms, in which plasmacomplement is activated through the classical or MBLpathways (Figure 4).Membranous Nephropathy. Membranous nephropathy

(MN), a common cause of nephrotic syndrome in adults, ischaracterized by a fine granular deposit of IgG with C3 inthe peripheral capillary loops (32,33). IgG4 reactive to the

Figure 3. | Complement regulation. (A–D) Schematics depicting decayaccelerating activity of (A andC) decayaccelerating factor (DAF)/CD55and factor H (fH), (B) CD59, which inhibits membrane attack complex formation, and (D) Membrane Cofactor Protein (MCP)/CD46 and fH,which display cofactor activity for factor I (fI). Cofactor-mediated fI activity irreversibly cleaves C3b to iC3b and subsequently cleaves iC3b toC3c and C3dg. (E) Schematic depicting the mechanism of C1-inhibitor (C1-inh), a protease that inactivates C1r, C1s, and mannose-bindinglectin-associated serine proteases (MASPs), irreversibly preventing reformation of the classical and mannose-binding lectin (MBL) pathwaysinitiating complexes. C1-inh also inhibits the kallikrein-kinin and coagulation cascades, two other mechanisms of complement activation.


M-type phospholipase A2 receptor, a transmembrane gly-coprotein expressed on the glomerular podocyte, is pres-ent in 70%–98% of patients with MN (34,35). AlthoughIgG4 does not efficiently activate complement throughthe classical pathway, deposition of C4d, a breakdownproduct of C4b, is detectable in essentially 100% of patientswith primary MN (36,37). Together with the observations thatMBL and hypogalactosylated IgG (including IgG4) can bedetected in subepithelial deposits in primary MN and thathypogalactosylated IgG can bind to MBL and activate com-plement through the MBL pathway, the data suggest thatMBL-initiated complement activation is pathogenic in MN.MACs are detectable in the urine of patients with MN andconsidered a dynamic marker of ongoing injury, supportingan integral role for complement in MN (reviewed in ref. 38).Mechanistic studies in animal models, including Heymann

Nephritis, indicate that antipodocyte antibodies lead to in-sertion of MAC into podocytes and that blocking MAC for-mation prevents phenotypic expression of disease (39). Theresultant sublytic podocyte activation alters cytoskeletalstructure crucial for foot process and slit diaphragm integrityand function, leading to proteinuria (40,41). Associated pro-motion of extracellular matrix results in the characteristicthickened glomerular basement membranes (GBMs) observedin this disease (42).Although one report in abstract form (G. Appel et al.,

unpublished data) suggested that anti-C5 mAb had no ef-fect on proteinuria in patients with MN, additional studies

are needed to determine if targeting complement is an ef-fective therapy for this disease.Anti-GBM Disease. Autoantibodies targeting the NC1

domain of type IV collagen are pathogenic mediators ofanti-GBM disease (43). The proliferative GN observed inanti-GBM disease is characterized by linear deposition ofIgG and various complement components along the GBM(44). The classical and alternative pathways are implicated,because MBL, C1q, fB, properdin, C3d/C4d, and C5b-9have been detected in GBM. An observed correlation be-tween intensity of fB deposition and glomerular crescentformation supports a pathogenic link (45). Evidence indi-cates that local complement activation results in C3a- andC5a-mediated inflammation as well as MAC-dependentsublytic activation of cells within the glomerulus, whichtogether promote nephropathy and extracellular matrixformation (46). Together, these mechanistic findings sup-port the need to test whether complement inhibition pos-itively affects outcomes in patients with anti-GBMdisease.Immune Complex-Initiated Glomerular Diseases. Cir-

culating immune complexes that are deposited in the sub-epithelial or subendothelial compartments of the glomeruluscan also mediate complement-dependent glomerular in-jury, including GN associated with streptococcal infec-tion, cryoglobulinemia, and lupus. These disease processesare commonly characterized by neutrophils and C3 depos-its in glomeruli and systemic C3 depletion, suggestive of a

Figure 4. | Mechanisms through which complement mediates antibody-initiated kidney diseases. (A) Complement and membranous ne-phropathy (MN): autoantibodies reactive to podocyte-expressed phospholipase A2 receptor 1 (PLA2R1) activate complement through themannose-binding lectin (MBL) pathway. Cascade amplification promotes membrane attack complex (MAC) formation, which induces sublyticsignaling and dedifferentiation of the podocyte to impair its filtration capacity, leading to proteinuria. (B) Complement and immune com-plex disease: circulating or in situ–formed immune complexes from kidney disease initiated by lupus, streptococcal infections, andcryoglobulinemia are deposited in the subepithelial and/or subendothelial space of the glomerulus. Classical pathway activation inducesinflammation and recruitment of neutrophils andmacrophages (MF), promoting tissue injury. (C) Complement andANCAvasculitis. Cytokine-induced neutrophil activation results in surface expression of myeloperoxidase (MPO; among other cytoplasmic antigens). On binding toANCA and cross-linking FcR, local complement activation results in C5a production, which induces vascular inflammation by ligating itsreceptor C5aR. GBM, glomerular basement membrane; PMN, polymorphonuclear leukocyte.


pathogenic role of complement-mediated inflammation andimmune cell recruitment (47).Animal model data supporting complement activation as

pathogenic in lupus nephritis include the observation thatfH-deficient MRL/lpr mice died with severe, diffuse GN(48). Conversely, administration of a CR2-Crry fusion pro-tein that targets complement regulation to C3b deposits(CR2 binds C3b) prevented expression of disease (49). InMRL/lpr mice, C5aR blockade decreased glomerular in-flammation (50). Anti-C5 mAb ameliorated GN in the mu-rine NZB/W(F1) lupus model (51), indicating a role forterminal complement. A phase 1 human trial with eculizu-mab (anti-C5) suggested preliminary efficacy, but the treat-ment period was too brief to draw definitive conclusions(52). Despite these observations, complement is not thesole pathogenic mediator of lupus nephritis, because FcRdeficiency but not C3 deficiency prevented phenotypic ex-pression of disease in one model (53).The complexities of complement’s effects on lupus are

illustrated by the seemingly paradoxical observation thatgenetic absence of C4 or C1q in mice (54) and humans (55)increases the risk of developing lupus nephritis. The mech-anism is likely related to an absence of complement-derivedopsonins, preventing clearance of immune complexes thatdeposit in the glomerulus and promote FcR-dependent in-flammation.ANCA-Induced Vasculitis. ANCAs contribute to small

vessel vasculitis, which is characterized by a paucity of Igdeposits (56) but with complement component deposition(Bb, C3d, C3c, and C5b-9) at sites of acute vascular andglomerular inflammation (57). Cytokine-primed neutro-phils display ANCA-binding antigens (myeloperoxidase[MPO] and proteinase 3) on their surfaces and participatein vascular injury. Complement depletion protected anti–MPO-treated mice from developing necrotizing crescenticGN (58). fB deficiency was protective, but C4 deficiency wasnot protective, implicating the alternative pathway. WhereasC5 deficiency or blocking anti-C5 mAb was protective (59),C6 deficiency was not protective (60), indicating that C5cleavage but not MAC formation is pathogenic. Additionalanimal studies showed that ANCAs stimulate neutrophils toproduce and release C5, and blockade or deficiency of C5aR(60) prevented disease expression. Together, the data suggestthat pathology is mediated by ANCA-induced, neutrophil-derived complement release and leads to C5a/C5aR-inducedproinflammatory signaling, particularly in neutrophils andneutrophil-associated vasculature (61), rather than by MACformation. A small molecule C5aR inhibitor limited expres-sion of a murine model of anti–MPO-induced kidney disease(60), and C5aR antagonism is being tested as a therapy forpatients with ANCA vasculitis (European Union ClinicalTrials Register ID EUCTR2011–001222015-GB).Other Glomerular Diseases. IgA nephropathy, char-

acterized by recurrent bouts of GN, focal mesangial cellexpansion, and IgA deposition, is likely mediated by MBL-dependent and/or alternative pathway-dependent, anti-body-initiated complement activation (62). Deposits of C3and C5b-9 are detectable in the diseased glomeruli andcorrelate with disease severity and prognosis. Experimen-tal evidence suggests that sublytic MAC activates mesan-gial cells, yielding mesangial proliferation and matrixexpansion (62).

The pathogenesis of FSGS remains unclear, but IgM andC3 deposits are commonly observed in the affected glo-meruli (63). Mutations in fH and C3 have been describedin cases of FSGS (64), and a murine model of IgG-initiatedFSGS in DAF-deficient mice (65) supports a role for com-plement dysregulation in some cases. Complement inhibi-tion has not been carefully studied as a therapy for FSGS.Postinfection GN, classically after Streptococcal pyogenes

infection, is characterized by proliferative GN and deposi-tion of C3 with or without Igs (reviewed in ref. 66). Al-though the majority of patients achieve complete remissionof the associated nephritic syndrome, some experience de-layed resolution or chronic GN, resulting in ESRD. A recentstudy published on 11 patients at the Mayo Clinic foundmultiple underlying causes of alternative pathway dysregu-lation in these chronic patients, including mutations in fH orCFHR5 and/or the presence of C3 nephritic factors (67).Monoclonal gammopathy has also been associated with

the activation of the alternative pathway and subsequentinduction of membranoproliferative GN. Circulating l–light-chain dimers were found to bind to fH and inhibit its controlfunction, thus lifting restraint over alternative pathway reg-ulation, but they differed from C3 nephritic factor in that thedimers were unable to bind and stabilize the alternativepathway C3 convertase (68).Antibody-Initiated Injury to a Kidney Transplant. Donor-

reactive anti-HLA antibodies are considered pathogenic me-diators of acute and chronic transplant injury (69). Theycan bind to donor tissue and mediate damage through mul-tiple mechanisms, including complement activation (70,71).A mechanistic link between antibody-mediated injury and

terminal complement activation was documented throughexperiments performed in rodents: whereas heart allograftstransplanted into sensitized (with preexisting antidonorantibodies) wild-type rats were rejected in 6–7 days, graftsurvival was prolonged to .30 days in sensitized C62/2

recipients (72). Documentation of impaired MAC complex(C5b-9) formation in the C62/2 recipients (73) supports theconclusion that terminal complement is a key effector mech-anism. In work by others, anti-C5 mAb (inhibits C5 cleav-age) plus cyclosporin and short-term cyclophosphamideresulted in prolonged heart allograft survival in presensi-tized mice, despite persistent antidonor IgG in the seraand the graft (74).In 2013, studies in a humanized mouse model (8) showed

that antidonor HLA antibodies bind to human aortic en-dothelium to initiate complement activation, resulting inMAC insertion into aortic endothelial cells. This inducedendothelial cell activation, characterized by noncanonicalNF-kB activation and upregulated production of chemo-kines, cytokines, and adhesion molecule expression, whichin turn, facilitated T cell–mediated injury to the aortic allo-graft (8). The findings support the conclusion that comple-ment bridges pathogenic humoral and cellular alloimmunityto mediate tissue damage.Clinical studies have begun to test the efficacy of complement-

targeted strategies to treat human antibody-mediated trans-plant rejection. Anti-human C5 mAb plus plasma exchangereduced the incidence of antibody-mediated rejection in 26sensitized recipients of kidney transplants (75) and success-fully reversed established antibody-mediated rejection in asmall cohort (76).


Complement-Based Diagnostics Relevant to Transplan-tation. The recognition that complement participates inantibody-initiated allograft rejection suggested that iden-tifying serum anti-HLA antibodies capable of binding C1qwould enhance their prognostic use after kidney transplan-tation (77). A 2013 paper, indeed, suggests that, among pa-tients with serum anti-HLA antibodies, those binding toC1q1 had the worst kidney graft survival (78). In anotherexample of complement-based diagnostics, C4d staining ofkidney transplant tissue is currently considered one key crite-rion for diagnosing antibody-mediated allograft rejection (79).

Kidney Injury Mediated by Serum Complement in theAbsence of AntibodyEmerging evidence suggests that unrestrained C3 conver-

tase activity underlies the pathogenesis of several diseasesinvolving the kidney, including paroxysmal nocturnal he-moglobinuria (PNH), forms of C3 nephropathy, and atypicalhemolytic uremic syndrome (aHUS) (Figure 5).PNH. PNH is a hematologic disorder characterized by

bone marrow failure, thrombophilia, complement-mediatedintravascular hemolysis, and hemoglobinuria. It is causedby a clonal expansion of RBC precursors that contain a mu-tation in the X-linked phosphatidylinositol glycan anchorbiosynthesis, class A gene (PIGA) that encodes for a proteininvolved in GPI anchor synthesis (80). DAF and CD59 areGPI-anchored molecules that require posttranslational addi-tion of GPI anchors to guide them to cell surfaces. The PIGAmutation prevents DAF and CD59 surface expression on theaffected RBCs. The inability to regulate alternative comple-ment activation/amplification at the C3 convertase step (ab-sent DAF) and prevent MAC formation (absent CD59)causes spontaneous lysis of the mutant RBCs. Therapeuti-cally inhibiting MAC formation with an anti-C5 antibodythat prevents C5 cleavage reduces morbidity and increasesquality of life for patients with PNH (81). Although effectivein preventing lysis, the anti-C5 mAb does not affect the un-regulated upstream production and deposition of C3b onRBC surfaces resulting from the absence of DAF. Evidenceindicates that this C3b deposition functions as an opsonin,causing macrophage-dependent RBC destruction in theliver/spleen, despite anti-C5 therapy (82). Alternative treat-ment strategies, including those targeting C3 activation (83),require additional study.C3 Nephropathies. C3 nephropathies are nephritic kidney

diseases characterized by low serum C3 and glomerular C3deposits without IgG. Subsets of C3 nephropathies areassociated with serum C3 nephritic factors (Figure 5): ac-quired autoantibodies that impair complement regulation bybinding directly to the C3bBb C3 convertase or its compo-nents, enhancing properdin-mediated stabilization of the com-plex, and/or inhibiting fH-mediated C3b degradation (84).C3 nephropathies can also occur in association with genetic

mutations in complement components and/or regulators thatresult in impaired complement regulation (Figure 5) (84).Loss-of-function mutations in fH, gain-of-function mutationsin C3 (conferring resistance to fH-mediated cleavage), andgain-of-function mutations in complement fH regulatory pro-teins (which compete with fH for binding to C3b and impairthe function of fH) have been described (84).Regardless of the specific molecular basis for the com-

plement dysregulation, the resultant complement acti-

vation likely predominantly causes glomerular disease,because the glomerulus contains fenestrated endotheliumwith exposed GBM that requires functional fH and fI toprevent local complement activation. Supporting thisconcept, fH-deficient mice develop membranoproliferativeGN with low serum C3 levels (85), and recombinant fHrestores plasma C3 levels with resolution of C3 depositionin the GBM (86). Mice deficient in both fH and fB do notdevelop disease, confirming a pathogenic role for alternativepathway activation (85). fH2/2/C52/2 mice and fH2/2

mice treated with anti-C5 mAb developed less severe dis-ease, whereas C6-deficient mice were not protected,inferring a role for C5a/C5aR in immune cell recruitment(87).Effective therapy for C3 nephropathies remains enig-

matic, but limited studies in animal models and patientshave suggested that restoration of alternative pathwayregulation may prove effective. Infusions of fresh frozenplasma containing fH may benefit patients deficient in fH(88), and therapy targeting C5 showed some success inpatients with forms of C3 nephropathies (89,90).aHUS. The current concept is that aHUS, characterized

by hemolysis and renal failure associated with kidneyendothelial cell injury, typically in the absence of detectablecomplement deposition in the glomerulus (91), is also aresult of complement dysregulation. Inherited loss-of-function mutations in fI, MCP, and fH as well as acquired,blocking, anti-fH antibodies have been associated withcases of aHUS (92). Gain-of-function mutations in C3and/or fB, which promote accumulation of the C3bBb con-vertase and overwhelm/resist complement regulation,have been described (93).Additional insights derived fromwork using mice with a

mutated fH were that they lack the ability to bind to cellsurfaces but maintain its complement-regulatory capacity(Figure 5). Although complement activation in the plasmawas controlled, the animals developed C5-dependent fea-tures of thrombotic microangiopathy (94,95), indicatingthat fH must regulate complement activation while boundto surfaces in the kidney to prevent disease.Most humans with inherited mutations associated with

aHUS or C3 nephropathy are heterozygotes. Current conceptsare that common allelic variants in complement regulatorspresent in the general population confer a complotype thatpredisposes to disease (96) and that additional immuneinsults unmask complement regulatory deficiencies. Asone illustration supporting this concept, poststreptococcalGN, generally a self-limited disease, resulted in progres-sive C3 nephropathy in a patient with a complement regu-lator mutation (97).Control of complement activation using eculizumab

(anti-C5) has revolutionized treatment of aHUS. Approx-imately 85% of treated patients have achieved remission(98). Those refractory to eculizumab may have diseasedriven by C3 cleavage products (which would not be af-fected by anti-C5 mAb), raising the possibility that target-ing C3 and/or C3a/C3aR may ultimately prove to bemore effective.

Kidney-Derived Complement and DiseaseIschemia-Reperfusion Injury. Ischemia-reperfusion (IR)

injury results from tissue hypoxia, mitochondrial damage,


and ATP depletion followed by the generation of free oxygenradicals on reperfusion, which initially damage endothelium(99). Ensuing inflammation is driven by Toll-like receptorsignaling, and cytokines, chemokines, and complement am-plify the inflammation, resulting in tubular injury and kid-ney dysfunction (Figure 6).To summarize findings reviewed elsewhere (100), comple-

ment deposition and loss of membrane-bound complementregulators occur during murine kidney IR injury, and

overexpression of Crry (murine homolog of MCP) amelio-rated IR injury. IR injury was dampened in complement-de-pleted mice and C3-deficient, fB-deficient, or C5-deficientmice. Conversely, DAF-, Crry-, or fH-deficient mice aremore susceptible to IR injury. Reciprocal transplant studiesshowed that donor kidney–derived C3 and not systemicrecipient C3 is the predominant mediator of IR injury(101). Using C3aR-, C5aR-, or C3aR/C5aR-deficient mice(102), investigators observed that deficiency of either or

Figure 5. | Kidney diseases caused by abnormalities in complement regulation. (A, upper panel) Healthy red blood cells (RBCs) express CD59and decay accelerating factor (DAF), preventing complement activation on their surfaces. (A, lower panel) Paroxysmal nocturnal hemoglo-binuria (PNH) is caused by mutation of the X-linked phosphatidylinositol glycan anchor biosynthesis, class A gene, resulting in a loss ofglycophosphatidylinositol (GPI) anchor biosynthesis that prevents surface expression of GPI-anchored DAF (CD55) and CD59. An inability toregulate alternative pathway activation/amplification at the C3 convertase step (DAF; amplification loop) and prevent MAC formation (CD59),results in spontaneous RBC lysis (membrane attack complex [MAC]). (B) C3 nephropathies. Factor H (fH) normally binds to polyanionicglycosaminoglycans on glomerular basement membranes (GBMs) to restrain complement activation (Normal). Mutations in the C-terminalregion of fH (depicted as red regions of the protein) impair fH’s physiologic ability to bind to the basement membrane, lifting restraint on localcomplement activation and contributing to glomerular inflammation and injury (mutant fH). C3 nephritic factors (right panel) can promote stabilityof C3, and properdin (factor P [fP]) can stabilize the C3bBb C3 convertase or inhibit fH-mediated decay/degradation, lifting restraint on C3 con-vertase-mediated amplification (looping arrow). (C)Atypical hemolytic uremic syndrome (aHUS). Among severalmechanisms,mutations in fH thatimpair its ability to bind to basement membranes (red regions of protein) permit complement regulation in the fluid phase (plasma regulation; leftpanel) but prevent local complement regulation on surfaces (right panel), predisposing to vascular inflammation and hemolysis.


both of these receptors protected mice from kidney IR in-jury and that their expression on either renal tubular epi-thelial cells or circulating leukocytes contributes to thepathogenesis. Together, the data indicate that IR injury up-regulates production of complement components by kid-ney endothelial and tubular cells and infiltrating immunecells. Local activation through the alternative pathwayyields C3a/C5a, which amplifies local inflammationthrough autocrine/paracrine ligations with their kidneycell–expressed receptors (102). Confirmatory evidence inhumans includes detection of soluble C5b-9 after reperfu-sion of deceased donor but not living donor kidneys (103)and higher expression of complement genes in deceasedversus living donor kidneys on reperfusion (104).An analog of the human complement-regulatory pro-

tein CD35 (CR1; blocks C3 convertase) was conjugated to amyristoylated peptidyl tail, such that, when administeredby intravenous perfusion of the harvested organ ex vivo, itwill self-insert into the lipid bilayer of the endothelial cellmembranes. This reagent was effective in preventing post-transplant kidney IR injury in rats (105). The human re-agent, mirococept (APT070), is being studied in a clinicaltrial for prevention of DGF (100). Eculizumab is also beingtested for efficacy in preventing post-transplant DGF(NCT01403389 and NCT01919346).

Chronic Kidney Injury and Fibrosis. Mechanisms ofkidney fibrosis, including late kidney transplant failure,involve immune and nonimmune mechanisms (106). Thefunctional and structural changes of chronic renal allograftfailure share similarities with those observed in otherforms of chronic progressive kidney disease, in which de-cline of functioning nephron mass has been considered thekey event (107). Emerging evidence suggests that intragraftcomplement activation contributes to this progressive kid-ney injury (108). C3 is implicated in the activation of therenin-angiotensin system and the epithelial-to-mesenchymaltransition (109,110). Together with observations that ab-sence/blockade of C5/C5aR (but not blocking MAC forma-tion) limited kidney fibrosis in several animal models(111,112), the data suggest that kidney-derived complementparticipates in fibrosis of native and transplanted kidneys(Figure 7).Associative evidence linking complement to progressive

human kidney transplant injury derives from studies of com-plement gene polymorphisms and transplant outcomes.Specific C5 polymorphisms in both the donor and recipienthave been associated with worse late graft function but notrisk of acute rejection (113). Although controversial, donorkidney expression of a specific polymorphic variant of C3 isassociated with worse post-transplant outcomes (114,115).Additionally, proteomic studies of kidney allograft tissuerevealed strong associations between chronic injury and alter-native pathway but not classical pathway complement com-ponents (116). An ongoing study of chronic anti-C5 mAbtherapy in kidney transplant recipients (NCT01327573) couldpotentially provide additional insight into the role of comple-ment as a mediator of progressive graft dysfunction and in-terstitial fibrosis and tubular atrophy.

Figure 6. | Complement in ischemia-reperfusion (IR) injury. IR in-jury results from tissue hypoxia and reperfusion, promoting reactiveoxygen species (ROS) production, which causes endothelial injury.Inflammation drives Toll-like receptor (TLR)–mediated signalingand cytokine production as well as complement production andactivation, which drives additional cytokine and chemokine pro-duction and immune cell recruitment through C3aR and C5aRsignaling. DAMP, damage associated molecular pattern; HMGB1,high mobility group protein B1.

Figure 7. | Chronic kidney injury and fibrosis. Chronic injury causedby toxins or transplant-related immune responses upregulates com-plement production and activation within the kidney. C3 has beenimplicated in the activation of the renin-angiotensin system andthe promotion of the epithelial-to-mesenchymal transition, includingfibrosis. IR, ischemia reperfusion; RAS, renin-angiotensin system.


Complement and T Cell–Mediated Transplant RejectionExtending from the fundamental discoveries that absence

of donor C3 prevents murine kidney transplant rejection(117) and that immune cell–derived complement augmentseffector T-cell differentiation and survival (23,24), studiesperformed in transplant models revealed that wild-typemice reject DAF-deficient heart allografts with acceler-ated kinetics (118). The accelerated rejection is causedby a complement-dependent augmentation of antidonorT-cell immunity. Donor or recipient DAF deficiency accel-erated skin graft rejection (23), bypassed the requirementfor CD4 help in murine heart transplant rejection (119), andovercame immune privilege of the eye to cause rapid cor-neal transplant rejection (120). Local complement produc-tion and C5a/C5aR interactions also influence effectorCD81 T-cell responses to allogeneic vascular endothelialcells (121) in in vitro culture systems and in vivo in responseto a heart transplant (8,121) as well as T cell–dependentkidney transplant rejection in rodents (122). Togetherwith the findings that anti-C5 mAb synergizes withCTLA4–Ig to prevent T-cell priming, limits T-cell traffick-ing to an allograft, and prolongs transplant survival in mice(123), the work supports the conclusion that complementis a physiologic regulator of pathogenic T-cell immunitythat causes allograft rejection (as well as various autoim-mune diseases) in animal models.Confirmatory human experiments published in 2013 show

that C3a and C5a are generated during in vitro cultures ofhuman T cells responding to allogeneic dendritic cells (DCs)(27). Both partners express the receptors for C3a and C5a(124–127), and C3aR- and C5aR-antagonists inhibit humanT-cell proliferation, whereas recombinant C3a/C5a pro-motes alloreactive human CD41 T-cell expansion. Varioussubsets of human DCs produce complement, and C5aR/C3aR signaling regulates DC activation and function (27).Pharmacologic C5aR blockade reduced human anti-mousegraft-versus-host disease scores, inhibited T-cell responses inNOD/SCID/gcnull mouse recipients of human PBMCs, andenhanced stability of iTreg, verifying that the C5aR-dependenteffects on human T cells apply in vivo (12,27). In furthersupport of a role for local complement in human transplan-tation, the quantity of RNA message for alternative pathwaycomplement components and receptors is higher in humanallograft biopsies with histologic evidence of rejection com-pared with noninjured control tissue (122,128). Together,these translational findings provide proof-of-concept thatC3a/C3aR and C5a/C5aR ligations are viable targets forfacilitating prolonged survival of human transplants.

ConclusionThe complement system is a pathophysiologic mediator

of kidney disease in humans. Building on the notion thatplasma complement functions as an effector mechanismof antibody-initiated kidney injury, the recognition thatkidney-derived and immune cell–derived complementparticipates in innate and adaptive immune responsesand the appreciation that disorders of complement regu-lation underlie multiple kidney diseases have altered fun-damental paradigms of complement biology. Ongoingtranslational immunology efforts along with the developmentof pharmacologic agents that block human complement

components and receptors (129) now permit testing of theintriguing concept that targeting complement in patientswith an assortment of kidney diseases has the potential toabrogate disease progression and improve patient health.

AcknowledgmentsThe authors thank P. Cravedi and J. Leventhal for their critical

comments.The work was supported by National Institutes of Health (NIH)

Grant R01-AI071185 (to P.S.H.). D.R.M. is supported byNIHMedicalScientist Training ProgramGrant T32-GM007280 (to the Icahn Schoolof Medicine at Mount Sinai).

DisclosuresP.S.H. receives grant funding from Alexion Pharmaceuticals.

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