And C5-Binding Proteins in Renal Injury

The Many Effects of Complement C3- and C5-Binding Proteins in Renal Injury

Tipu S. Puri, MD, PhD, and Richard J. Quigg, MD

Summary: The complement system is an important component of the innate immune system and a modulator of adaptive immunity. The entire complement system is focused on C3 and C5. Thus, there are proteins that activate C3 and C5, those that regulate this activation, and those that transduce the effects of C3 and C5 activation products; each can affect the kidney in renal injury. The normal kidney has the inherent capacity to protect itself from complement activation through cellular expression of decay-accelerating factor, membrane cofactor protein (in human beings), and Crry (in rodents). In addition, plasma factor H protects vascular spaces in the kidney. Although the main function of these proteins is to limit complement activation, there is now considerable evidence that they can transduce signals on engagement in immune cells. The G-protein–coupled 7-span transmembrane receptors for C3a and C5a, and the integral membrane complement receptors (CR) for C3b, iC3b, and C3dg, are expressed outside the kidney, particularly in cells of hematopoietic and immune lineage. These are important in renal injury through their infiltration of the kidney and/or by affecting kidney-directed immune responses. There is mounting evidence that intrinsic glomerular and tubular cell C3aR and C5aR expression and activation also can affect renal injury. CR1 on podocytes and the ␤2 integrins CR3 and CR4 in kidney dendritic cells have functions that remain poorly defined. Cells of the kidney also have the capacity to produce and activate their own complement proteins. Thus, intrinsic renal cells express decay- accelerating factor, membrane cofactor protein, Crry, C3aR, C5aR, CR1, CR3, and CR4. These can be engaged by C3 and C5 activation products derived from systemic and local pools in renal injury. Given their capacity to provide signals that influence kidney cellular behavior, their activation can have substantial effects in renal injury. Defining these in a cell- and disease-specific fashion is an exciting challenge for future research. Semin Nephrol 27:321-337 © 2007 Elsevier Inc. All rights reserved. Keywords: Complement, innate immunity, regulators of complement activation, ␤2 integrins

he complement system contains more optotic cells; in so doing, they can shape the than 30 plasma and cell-associated pro- immune response to diverse antigens, including Tteins, many of which are alike as a con- those derived from self and allogeneic tissue.1-3 sequence of gene duplication events during The complement system has 3 main path- evolution. Complement is the ﬁrst line of de- ways of activation: the classic, alternative, and fense against some microorganisms and an in- mannose-binding lectin (MBL) pathways. All tegral component of innate and adaptive im- proteins in these pathways come from the liver mune responses to many others. Complement and circulate in plasma. Nonetheless, cells proteins also are important to clear immune throughout the body, including those in the complexes (ICs) and material derived from ap- kidney, have the capacity to produce complement proteins for local or even systemic use.4,5

Section of Nephrology, University of Chicago, Chicago, IL The circumstances behind this, including par- Supported by National Institutes of Health grant R01DK041873 and the Na- ticular stimuli, cells, and produced proteins, tional Kidney Foundation of Illinois. Address requests for reprints to Richard Quigg, MD, Chief, Section of Ne- can be relevant to kidney disease. phrology, Department of Medicine, University of Chicago, 5481 S. Mary- Each complement pathway has its own initi- land Ave, Chicago, IL 60637. E-mail: [email protected] 0270-9295/07/$ - see front matter ators. Initial activation of the classic pathway © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2007.02.005 occurs through binding of C1 to immunoglob-

Seminars in Nephrology, Vol 27, No 3, May 2007, pp 321-337 321 322 T.S. Puri and R.J. Quigg

Table 1. Receptors for Activation Products Derived From C3 and C5 Principal Site Class Protein Ligand Human Beings Rodents Renal 7TM GPCR C3aR C3a Leukocytes Same Podocytes, PTECs C5aR C5a Leukocytes Same Endothelium, PTECs RCA CFH C3, C3b Plasma Plasma ϩ Podocytes (rodent) platelets DAF C3, C3b Widespread Widespread Podocytes, endothelium MCP C3b Widespread Testis only Glomerulus, tubules (human beings) Crry C3, C3b N/A Widespread Mesangium, endothelium, PTECs CR1 C3b, iC3b Leukocytes, Es, B cells, DCs Podocytes (human beings) B cells, DCs CR2 iC3b, C3dg B cells, DCs, Same None some T cells ␤2 integrins CR3 iC3b Leukocytes Same Resident DCs CR4 iC3b Leukocytes Same Resident DCs Abbreviations: PTEC, proximal tubular epithelial cell; E, erythrocyte.

ulin M or immunoglobulin G antibodies (Abs) in membrane (7TM) proteins of the rhodopsin re- ICs, activation of the MBL pathway occurs by ceptor family, whereas C3b-binding proteins the binding of MBL to terminal carbohydrate are in the regulators of complement activation groups on certain microbes, and activation of (RCA) and ␤2 integrin families. The events that the alternative pathway occurs through the follow binding of these various protein pairs spontaneous hydrolysis of C3. Activated C1 (as can have considerable relevance to renal dis- the multiprotein C1qr2s2 complex) and MBL- eases. associated serine proteases cleave both C4 and C2 to generate the C4b2a C3 convertase. Hy- RECEPTORS FOR THE C3a AND C5a drolyzed C3 binds factor B in the fluid phase, ANAPHYLATOXINS: C3aR AND C5aR leading to a conformational change in factor B, allowing its cleavage by factor D, thereby form- Structure/Function ing an initial alternative pathway C3 convertase. C3aR and C5aR have 21 and 30 amino acid This then can amplify itself to generate many extracellular N-termini, respectively, 7TM re- copies of the alternative pathway C3 conver- gions, 3 extracellular and intracellular loops, tase, C3bBb. and intracellular C-termini.9-11 The extracellular Activation through each complement path- regions confer the specificity of binding to their way leads to the cleavage of C3 and C5. In so respective C3a and C5a ligands and couple sub- doing, C3a, C3b, C5a, and C5b are generated. sequent activation events through other por- C5b can combine with C6, C7, C8, and C9 to tions of the molecules.12,13 Removal of just the form C5b-9 in any receptive cell membrane; single arginine at the C-terminus of C3a or C5a, although this is fairly promiscuous, the effects which occurs physiologically by carboxypepti- of such C5b-9 formation appear to have some dase N, eliminates C3a binding to C3aR and specificity in terms of cellular pathways that considerably decreases the binding affinity of become activated.6-8 In contrast, C3a, C3b, and C5a to C5aR.14 C5a have specific partners in the complement C3aR and C5aR can be up-regulated by bac- system (Table 1). The receptors for C3a and terial lipopolysaccharide (LPS) in a variety of C5a are G-protein–coupled (GPC) 7-span trans- cells,15-18 including those of the kidney.19,20 Complement C3- and C5-binding proteins 323

From promoter analyses, this appears to require cells.36,39,40 C5aR also is present on mouse mi- activator protein 1 (AP-1) and v-ets erythroblas- crovascular endothelial cells,16,17 including tosis virus E26 oncogene homologue (Ets) sites those derived from the kidney (our unpub- in the C3aR promoter,18 and CCAAT box pro- lished data). In MRL/lpr lupus mouse kidneys, moter elements and transcription factor CP2 C3aR and C5aR expression was up-regulated sites in the C5aR promoter,17 thereby indicating significantly at both the mRNA and protein lev- an underlying specificity behind their transcrip- els and was accompanied by a wider cellular tional regulation. distribution.36,41 This up-regulated expression As is true for all G-protein coupled receptors started before the onset of kidney disease, sup- (GPCRs), the effects of C3aR and C5aR occur porting that C3aR and C5aR may be involved in from their associated specific heterotrimeric G- the development of disease, rather than simply proteins (␣␤␥). Typically, C3aR/C5aR are cou- a consequence. In the case of renal expression, 21 pled to G␣i (pertussis-sensitive) and/or G␣16 an elegant series of studies have shown that (pertussis-resistant) GPCRs.22 Ligand binding C5aR expression in mesangial cells is up-regu- leads the ␣ subunit to acquire guanosine triphos- lated by activation of receptors for urokinase- phate in exchange for guanosine diphosphate and type plasminogen activator and interleukin its separation from ␤␥ subunits. The subsequent (IL)-6 (gp130), which converge to activate sig- downstream events mediated by the free ␣ and nal transducers of activation 3.20 ␤␥ subunits involve phosphorylation of intermediates and ultimate transcriptional events, which Role in Renal Diseases are shared by other cellular signals (eg, receptor The anaphylatoxins C3a and C5a have long tyrosine kinases).22 For instance, activation of been considered to play a role in leukocytic phospholipase C, mitogen-activated protein ki- accumulation, which occurs in various inflam- nases, nuclear factor ␬ B, and signal transducers of matory diseases including glomerulonephritis activation can ensue on C3aR or C5aR engage- (GN).42 The presence of C3aR and C5aR on ment and activation.16,22-28 The intermediates and inflammatory cells such as neutrophils and ultimate cellular effects can vary considerably monocytes and the alteration of several disease from cell to cell, and in a given cell depending on models in mice in which C3aR43,44 and its prevailing state.16,27 Even in the same cell, C5aR45,46 were deleted is further evidence for a activation of C3aR and C5aR can lead to similar or role of these proteins in inflammatory diseases. disparate actions, thus reflecting a specificity to Evidence for the role of C5aR in glomerular C3a and C5a.29,30 diseases has come from cryoglobulinemia and nephrotoxic serum nephritis models in which Location Relevant to Renal Diseases neutrophil infiltration was C5-dependent but C3aR and C5aR are on most hematopoietic C6-independent.47,48 cells, including neutrophils, monocytes/macro- Chronic administration of a specific C3aR phages, and basophils/mast cells. The former 2 antagonist to MRL/lpr lupus mice significantly are certainly relevant to inflammatory renal reduced kidney disease, prolonging their sur- diseases, whereas the latter are more relevant vival.36 Similarly, when C5a signaling was to immediate hypersensitivity diseases (eg, blocked in our studies with a specific antago- asthma) that are not typical in renal disease nist,41 MRL/lpr mice displayed attenuated renal pathophysiology. It also is appreciated that T disease and prolonged viability. The effects of cells, B cells, and dendritic cells (DCs) bear blocking C3aR and C5aR in lupus mice had C3aR and C5aR.11,31-35 The influence of signals certain features in common, including a reduc- through these receptors can affect how these tion in renal neutrophil and macrophage infil- cells respond to a given antigenic stimulus.33 tration, apoptosis, and IL-1␤ expression.36,41 Both C3aR and C5aR are present in intrinsic The effects on chemokine expression were dis- cells of the kidney. C3aR is on podocytes36 and tinct, with C3aR- and C5aR-inhibited MRL/lpr C5aR is on mesangial cells,20,37,38 although both mice having reduced chemokine (C-C motif) are present on proximal tubular epithelial ligand 5 (CCL5) [regulated upon activation, nor- 324 T.S. Puri and R.J. Quigg mally T-expressed, and presumably secreted sion of activating Fc␥ receptors by lung and (RANTES)] and chemokine (C-X-C motif) ligand liver macrophages.59,60 Interestingly, intrave- 2 (CXCL2) [macrophage inflammatory protein nous immunoglobulin can reverse these effects 2 (MIP-2)] expression, respectively. C3aR-inhib- of C5aR, potentially explaining the therapeutic ited mice also had increased phosphorylation of efficacy in certain disease states.61 Inflamma- protein kinase B, which may have accounted tory cells also can produce60 and cleave their for the protection from apoptosis with receptor own C5,62,63 completely bypassing the need for antagonism.36 Consistent with these studies, plasma complement proteins. Although, as C5aR-deficient MRL/lpr mice had attenuated re- noted earlier, C5aR engagement can promote nal disease and prolonged survival.49 In these the development of a Th1 immune response in mice, there was a reduction in CD4ϩ T-cell T cells, there are also instances in which it can renal infiltration, lower titers of anti–double- suppress Th1 responses. This is true in macro- stranded DNA Abs, and inhibition of IL-12 p70 phages, in which C5a potently suppresses LPS- and interferon (IFN)-␥ production, supporting and/or IFN-␥–induced IL-12 production in a that C5aR signaling links Th1 responses in lu- dose-dependent fashion.64 Defining some of pus nephritis.49 these nuances in a site- and disease-specific Relevant to the capacity of LPS to induce manner is one of the exciting prospects for C5aR expression are Ab-mediated renal dis- upcoming research in complement pathobiol- ease models in which LPS pretreatment gen- ogy. erated a C5aR-dependent process. In a model of glomerular thrombotic microangiopathy THE FLUID PHASE COMPLEMENT induced by nephrotoxic serum, a specific REGULATOR: FACTOR H C5aR antagonist blocked disease expression.50 This has similarities to the model of Structure/Function antiphospholipid Ab-induced fetal loss, in All members of the RCA family are composed which complement activation led to C5aR- primarily of short consensus repeat domains dependent placental infiltration with neutro- (SCRs; also termed complement control pro- phils.51 In addition to its chemotactic effects, tein or sushi domains). These have a high activation of neutrophil C5aR results in extra- degree of relatedness within and between spe- cellular signal-regulated kinase activation and cies. Structurally, the SCR is a globular ellipsoid production of Bad, which can protect these approximately 3.5 nm in length created by 5 cells from apoptosis.24 Yet, in other circum- short antiparallel ␤-strands dictated by 2 invari- stances, C5a can be proapoptotic.52 For ex- ant intra-SCR disulfide bonds.65,66 Complement ample, in a model of IC-mediated glomerular factor H (CFH) is composed of 20 SCRs ar- disease, the simultaneous administration of ranged in tandem, with a high degree of simi- LPS led to a C5aR-dependent tubulointerstitial larity among human, mouse, and rat CFH.67-69 nephritis, with prominent apoptosis occur- By best-fit models, CFH is approximately 38 nm ring through activation of up-regulated tubu- in length, which is nearly half that of a fully lar cell C5aR.53 extended molecule of 20 SCRs, reflecting that The often disparate effects of C3aR/C5aR ac- the native molecule is folded back on itself (like tivation extend to the adaptive immune sys- the Greek letter ␴).70,71 tem.54-56 In models of sepsis, T cells are stimu- CFH is unique among RCA members in that it lated to increase expression of C5aR; given the contains solely SCRs, which it puts to good use co-existent systemic complement activation, to provide its complement inhibitory functions these C5aRs are activated leading to down- as well as specificity of binding to host surfaces. stream events culminating in T-cell apoptosis.57 This distinguishes CFH from other RCA mem- Although C5aR activation appears to be detri- bers with C-terminal transmembrane and intra- mental in sepsis,58 activation of C3aR can con- cytoplasmic regions (membrane cofactor pro- fer protection from downstream inflammatory tein, CR1, CR2), or points of attachment to the events.43 C5aR activation can promote expres- membrane (decay-accelerating factor) or neigh- Complement C3- and C5-binding proteins 325 boring molecules in multimers (C4-binding pro- temic alterations in individuals with defective tein). CFH has 3 C3b-binding sites,72-75 with the CFH.92,93 CFH also appears to be uniquely ex- first in SCRs 1-4 also responsible for factor I pressed on the rodent platelet and podocyte, cofactor activity,76 and 3 heparin/sialic acid– where it functions in place of CR1 (discussed binding sites, which allows CFH to attach to the later).88,93-95 receptive surfaces.77-79 In particular, the high Besides the key role of hepatic-derived density of positively charged residues in SCRs plasma CFH to limit systemic alternative path- 19 and 20 confers its binding to corresponding way complement activation, it is very clear that negatively charged residues in molecules such CFH is necessary to limit local complement as heparin.79,80 It appears that when native CFH activation within organs such as the kidney and binds to a surface bearing C3b and/or heparin eye.82,83 This is attributable to the specific bind- (or related anions) it can straighten out, thereby ing of CFH to anionic sites in cellular and acel- revealing its multiple binding sites and permit- lular regions of blood vessels, particularly those ting full functionality.70,71 of the glomerular and choroidal capillaries.96-98 Because CFH has affinity for C3b and not C4b, CFH inhibits the formation and acceler- Role in Renal Diseases ates the decay of the alternative pathway C3 Abnormalities in CFH can underlie membrano- convertase, C3bBb, and also serves as cofac- proliferative (MP) GN type II (dense deposit tor for factor I–mediated cleavage and inacti- disease) and atypical hemolytic uremic syn- vation of C3b to iC3b.81 Because it is the drome (aHUS).99,100 Both typical HUS and aHUS predominant fluid-phase alternative pathway are characterized by acute kidney injury to- complement regulator, abnormalities in CFH gether with consumptive anemia and thrombo- quantity or function result in uncontrolled cytopenia, but are different because aHUS is not alternative pathway activation.82,83 The C3 associated with diarrheal infections (as caused convertases of each of the complement acti- by Shiga toxin–producing Escherichia coli) and vating pathways are converted to C5 conver- its propensity to recur.101 A substantial propor- tases by the addition of C3b molecules, which tion of aHUS cases are attributable to defects in localize C5 for cleavage by C2a or Bb. By complement regulation.101-105 Thus, genetic de- virtue of its actions on C3b, CFH is an effec- fects in genes for CFH, factor I, and membrane tive inhibitor of C5 convertases.84 cofactor protein (MCP, CD46), as well as inhibitory autoAbs to CFH are associated with Location Relevant to Renal Diseases MPGN.105-110 As a general rule, MPGN type II is CFH is produced primarily in the liver and cir- attributable to type I mutations in CFH, leading culates in human and rodent plasma at rela- to its altered appearance in plasma and the tively high concentrations (ϳ500 ␮g/mL or 3.3 ensuing unrestricted systemic alternative path- mmol/L).69,85 This fact underlies attempts at way activation, whereas aHUS is attributable to liver transplantation to treat genetic CFH de- type II mutations clustering in the terminal fects (discussed further later).86 Although there SCRs. These lead to impaired ability of CFH to is evidence for CFH production by other cells of bind anionic sites such as on endothelium and the mononuclear phagocyte lineage, bone mar- to provide local protection against complement row–derived cells do not contribute substan- activation.83 Overall, aHUS occurs under the tially to the circulating CFH pool.87,88 right genetic and environmental conditions, Similar to many complement proteins that with excessive complement activation occur- are synthesized in the liver and circulate in ring on endothelia.101 Exactly what initiates this plasma, there is evidence that CFH also is pro- complement activation has been elusive. duced by intrinsic cells of the human kid- CFH also is necessary in mice to limit spon- ney.89-91 Nonetheless, this is not sufficient to taneous and Ab/IC-dependent complement ac- impact local or systemic complement regula- tivation. Thus, CFH-deficient mice have unre- tion; thus transplantation of a kidney with nor- stricted activation of the alternative pathway of mal CFH genes does not reverse local or sys- complement, with systemic complement con- 326 T.S. Puri and R.J. Quigg sumption.82 These mice developed factor B- Although DAF, MCP, and Crry have similar and C5-dependent glomerular disease with fea- structures, they have distinct functions as com- tures of MPGN type II later in life, which was plement regulators. DAF has decay-accelerating fatal in some animals.47,82 Complement deposi- activity toward C3 and C5 convertases of all tion in the glomerular capillary wall (a feature pathways, whereas MCP is a cofactor for the of MPGN type II) preceded IC deposition factor I cleavage and inactivation of C3b. Inter- (which is a feature of MPGN type I but not type estingly, Crry has the features of DAF and MCP, II). In an accelerated model of nephrotoxic and hence is a versatile and potent complement serum nephritis using relatively low (subnephri- regulator.116 togenic) doses of Ab, CFH-deficient mice had a There has been considerable interest in de- greater extent of disease compared with con- fining the roles of these proteins outside of trols; similar to the spontaneous disease, this their regulating complement activation, such as was factor B- and C5-dependent.47,82 In a model their capacity to generate cellular signals and to of chronic serum sickness, C57BL/6 mice did serve as receptors for the binding and uptake of not develop GN unless deficient in CFH.111 microorganisms. Related to the latter, in the 12 years between the findings that CD46 and DAF are receptors for measles virus117 and Helico- INTRINSIC CELLULAR COMPLEMENT bacter pylori,118 respectively, the list has ex- REGULATORS: DECAY-ACCELERATING panded to include a number of viral and bacte- FACTOR, MEMBRANE COFACTOR rial pathogens.119,120 PROTEIN, AND COMPLEMENT RECEPTOR– When Abs are used to cross-link DAF on the RELATED PROTEIN Y surface of T cells, there is subsequent src family Structure/Function tyrosine kinase-mediated cellular activation.121,122 The proteins of the RCA family that provide The potential that DAF can modulate T-cell func- intrinsic cellular complement regulation in hu- tion in vivo has been supported by studies in DAF man beings are decay-accelerating factor (DAF, knockout mice.123 Although C3b is a natural li- CD55) and MCP. DAF is a glycosylphosphatidyl gand for DAF, the binding affinity is several logs inositol–anchored membrane protein, whereas lower than that of Abs. This has led to a search for MCP is a type 1 transmembrane protein. De- other natural ligands of DAF, one of which is spite these differences in cell attachment, they CD97, a 7TM protein with 3 to 5 epidermal are alike in their extracellular 4 SCRs and mem- growth factor repeats in its N terminus.124,125 The brane proximal O-glycosylated sites. question remains whether the functions of DAF in As is apparent throughout this issue, the use T-cell immunity are related to signals through en- of rodents has been invaluable to developing gagement of DAF by ligand and/or are a conse- human disease models and obtaining an in- quence of its complement inhibition. The study depth understanding of disease pathophysiol- by Heeger et al126 showed augmented mouse pri- ogy. Those of us interested in complement are mary T-cell responses in the absence of DAF, a aided by the high degree of similarities among phenomenon that appears to require intrinsic human and rodent complement activation path- production of complement alternative pathway ways and constituent proteins. There are, how- constituents (eg, factor D) and C5. This has simi- ever, some important differences in the regula- larities to previously discussed studies in liver tory proteins, particularly those in the RCA macrophages, which have an apparent autocrine family. Rodents, but not human beings, have loop of C5a production-C5aR stimulation.60,127 the type 1 transmembrane protein Crry (CR1- However, recent studies with a human T-cell sys- related y), named for its similarity to human tem have shown that DAF engagement with Abs 112 CR1. Structurally, Crry is relatively small, sim- or recombinant (CD97)2-Fc provides a costimula- ilar to DAF and MCP, with 5 to 7 SCRs.112-114 tory signal to those delivered through CD3; this There are also 2 Daf genes in mice; the product appeared to be independent of complement acti- of Daf1 has the most relevance to human DAF vation products.128 Thus, the current understand- and disease states of the kidney.115 ing is that DAF limits generation of C5a and its Complement C3- and C5-binding proteins 327 potential stimulatory effects on T cells, and it also formly in all 3 intrinsic glomerular cells,144,145 can provide a productive second signal to CD3, at whereas DAF is highly expressed in the juxtaglo- least when cross-linked by fluid phase CD97 or merular apparatus.146 Functional DAF is also on anti-DAF Abs. cultured human podocytes,147 which is relevant Similar fascinating yet confusing issues to studies with rodent podocyte DAF (discussed present themselves for MCP. Cross-linking MCP later). Other sites in human kidneys served by with Abs can provide a costimulatory signal to DAF and/or MCP include endothelial and tubular anti–CD3-treated T cells.129-131 These are spe- cells.145 cific to those with a T-regulatory 1 (Tr1) phe- In rodent kidneys, DAF is primarily a podo- notype.132 Under more physiologic conditions, cyte and vascular endothelium protein.148,149 costimulation of CD3 and MCP generated Unlike in human beings in which MCP has poorly proliferative Tr1 cells, which could be widespread distribution throughout the body, attributed to defective protein kinase B/survivin MCP expression in mice is limited to spermato- signals.133 Overall, this phenotype of Tr1 cells is zoa, making its absence in knockout mice of no more reflective of their state in vivo. Further consequence to renal disease models.150 Over- evidence for the relevance of CD46 and Tr1 all, it is likely that the rodent uses Crry in place cells has come from recent studies in patients of MCP and/or DAF in many sites as its comple- with multiple sclerosis, in whom there was ment regulator, which is not surprising because altered Tr1 cell–associated IL-10 secretion in Crry combines the functions of both.116 In the response to CD46 (but not CD28) costimula- rodent kidney, this appears to be true in endo- tion.134 CD46 is associated with Discs Large 4 in thelial, mesangial, and tubular cells. epithelial cells135,136 and the microtubule orga- nizing center in T cells.137 In the latter, ligation Role in Renal Diseases of CD46 can be dominant in polarization of the Clearly podocyte DAF is important to restrict immunologic synapse, which can be produc- complement activation locally, such as can oc- tive or subvertive, depending on the circum- cur in nephrotoxic serum nephritis,151-153 and stances.138 recovery from puromycin aminonucleoside ne- Consistent with its limited distribution in ro- phrosis, in which complement proteins are ac- dents, MCP is not present on rodent immune cessible to the apical portion of podocytes.149 cells. Instead, Crry is present with DAF on ro- Consistent with this limited role, studies from dent T cells.139 Strategies to examine MCP func- Wenchao Song in MRL/lpr mice showed that tions in rodent models have included the use of there was no effect of DAF deficiency on the transgenic expression of human MCP, which inflammatory lupus nephritis.154 revealed comparable results with those of hu- In disease states in which there is comple- man T cells ex vivo.129 In addition, the role for ment deposition, DAF and MCP are present in Crry on T cells, as a surrogate for MCP, also has increased intensity,144,146 perhaps owing to been examined through the use of cross-linking an appropriate protective response of cells to Abs.140-143 These studies have shown results complement activation.155 The regulatory in- comparable with those with MCP, in that cross- fluences on DAF and MCP expression have linking of Crry can activate mitogen-activated been defined further. For instance, DAF has protein kinases and Vav, thereby facilitating constitutive, cell-specific, and stimulated ex- events through CD3 engagement, as well as pression,148,156-159 which largely can be attrib- providing independent costimulatory signals.143 uted to 2 cytosine-guanine dinucleotide (CpG)-rich regions within its proximal pro- Location Relevant to Renal Diseases moter to which Sp1 binds.160 As with C3aR DAF, MCP, and Crry protect the kidney from and C5aR, the expression of DAF can be up- complement activation. Each of these proteins regulated by LPS and cytokines,157,159,160 once tend to have their distinct localization patterns by again illustrating the interrelationships immunohistochemical techniques. In human be- among different arms of the immune system. ings, MCP appears to be distributed fairly uni- Given its widespread distribution in glomer- 328 T.S. Puri and R.J. Quigg uli and tubules,139,161-163 Crry is likely to be very distinct functional domains contributed by both important in renal diseases. This has proven to subunits.176,177 The integrin ectodomain con- be difficult to study directly because Crry leads sists of head, upper leg, and lower leg segments to embryonic death owing to unrestricted acti- formed by the noncovalent association of the vation of maternal complement.164 Nonethe- ␣␤ subunits. Under basal circumstances, inte- less, it is quite clear that Crry is a very important grins are expressed as inactive forms character- complement regulator, as shown by a series of ized by a bent structure in which the head studies by Seeichi Matsuo in which Crry func- segment contacts the lower leg. Activation in- tion-neutralizing Abs exacerbated diseases of duced by inside-out signals rapidly and revers- the mesangium,165 podocyte,166 and tubuloint- ibly switch the integrin to a ligand-binding erstitium.167 A fascinating series of studies from state, most typically characterized by a linear Josh Thurman163,168,169 showed that the normal form, although this is not essential for high- polarization of Crry to the basolateral aspect of affinity binding.176,177 mouse tubules is lost in ischemia, which leads The ligands for CR1-4 include C3b and its 2 to unrestricted alternative pathway activation factor I cleavage products: iC3b and C3dg. The and acute kidney injury on reperfusion. This highest-affinity binding interactions are C3b appears to be relevant to acute kidney injury with CR1, iC3b with CR3 and CR4, and C3dg (tubular necrosis) in human beings.170 Consis- with CR2. These receptors are somewhat pro- tent with this work are our studies in which miscuous in their binding because CR2 also transplantation of Crry-deficient kidneys into binds Epstein-Barr virus gp350/220, the immu- wild-type recipients led to marked complement noregulatory CD23 protein, and IFN-␣,178-180 activation in the tubulointerstitium, and the whereas CR3 and CR4 also bind intercellular rapid development of scarring and failure of the adhesion molecule (ICAM)-1 and fibrinogen. kidney.171 Unlike DAF, MCP, and Crry, for which the evidence is circumstantial only, engagement of CR1-4 with their C3 ligands can lead directly to RECEPTORS FOR C3: COMPLEMENT cellular signaling events. However, similar to RECEPTORS 1 THROUGH 4 the former, activation appears to involve acces- Structure/Function sory plasma membrane molecules rather than direct effects of these proteins. This is not sur- CR1 (CD35) and CR2 (CD21) are type 1 trans- prising because CR1, CR2, ␣ , ␣ , and ␤ pro- membrane proteins with extended extracellular M V 2 teins each have short intracytoplasmic domains domains made up of tandemly arranged SCRs.172 ranging from 24 to 46 amino acids. Among the Their intracytoplasmic domains are relatively best studied are the costimulatory signals pro- short (43 and 34 amino acids, respectively). Hu- vided by CR2 to B cells. In this setting, antigen- man and mouse CR2 contain 15 SCRs. Similar to C3dg complexes are bound by the B-cell recep- CFH, the SCR arrangement in CR2 is flexible, tor and CR2 in proximity, the latter recruiting facilitating interactions with its ligands.173 Human CD19 and CD81 into lipid rafts, leading to the CR1 is the product of a separate gene, whereas phosphorylation of CD19 tyrosine residues, mouse CR1 is generated by alternative splicing which provides a costimulatory signal to B-cell from the Cr2 gene, leading to the addition of 6 receptor activation.181-185 SCRs to the N-terminus of CR2.174 There are 4 human CR1 allotypes, distinguished by the number of 7 SCR-containing long homologous repeats, Location Relevant to Renal Diseases ranging from 3 to 6.172,175 As can be appreciated from Table 1, CR1-4 are CR3 and CR4 are members of the ␤2 integrin expressed primarily on cells of hematopoietic family of heterodimeric transmembrane pro- and immune lineage. One clear exception to teins, containing the ␤2-subunit (CD18) and ␣M- this is the expression of CR1 on human podo- 186 (CD11b) or ␣x-subunit (CD11c). As opposed to cytes, on which it is capable of binding C3b. the relatively simple make-up of RCA proteins The quantities of CR1 on podocytes can vary consisting of SCRs, integrins contain a variety of considerably in glomerular diseases, with loss Complement C3- and C5-binding proteins 329 of the entire CR1 molecule occurring in a vari- Fc␥ receptor, or any combination thereof. As ety of disparate glomerular diseases.187,188 Al- noted, CR1 in mice is not expressed to the same though these circumstantial findings have been extent as it is in human neutrophils and mono- established for decades, the exact role of podocytes,191,202 making it difficult to fully study the cyte CR1 remains undefined. role for leukocyte CR1 in experimental renal A major obstacle to defining the functions of diseases. CR1 in human beings is that rodent CR1 is not Because platelet and podocyte CFH in mice its equal. This is true for its gene and protein are surrogates for human erythrocyte and podo- structure, as discussed earlier, as well as its cyte CR1, respectively, studies of CFH in mice cellular distribution, which is much more re- have provided circumstantial evidence for the stricted in rodents.189-192 The vast majority of roles of human E and podocyte CR1. To dissect CR1 in human beings is present on erythro- the roles of plasma and platelet-associated CfH, cytes, which simply reflects the numeric pre- we created bone marrow (BM) chimeras be- dominance of these cells.172 On erythrocytes, tween CFHϪ/Ϫ and wild-type C57BL/6 mice.88 CR1 binds C3b in ICs, which is necessary for Plasma and platelet CFH protein largely tracked proper delivery of ICs to the mononuclear with the CFH status of recipient and BM do- phagocyte system.193 In rodents, platelet CFH nors. We also examined the role of CFH intrin- serves this purpose,88,94 which is not totally sic to the kidney through the use of renal trans- surprising given that erythrocytes and platelets plants between wild-type and CFHϪ/Ϫ mice.93 are each present in blood in large numbers, and These have shown that wild-type kidneys in a CR1 and CFH are C3b-binding proteins with CFH-deficient host bear CFH in the glomerular factor I–cofactor activities. A similar switch ap- capillary wall, which by several lines of evi- pears to occur in rodent podocytes, in which dence is likely to originate from the podocyte. 93,95 CFH takes the place of CR1. These results with BM and kidney transplants The normal kidney contains a sizable pool of ϩ ϩ were consistent with those from cultured cells expressing CR3 (CD11b ), CR4 (CD11c ), megakaryocytes and platelets in showing the major histocompatibility class II molecules, and intrinsic origin of their CFH.88,94,95 Fc␥ receptors.194,195 Although some of these are ϩ Further studies were performed in these tissue resident macrophages (eg, F4/80 ), many transplanted mice by actively inducing chronic 195 express CX3CR1 typical of resident DCs. serum sickness characterized by the presence of circulating ICs. Wild-type mice with CFHϪ/Ϫ Role in Renal Diseases BM had extensive glomerular deposition of Ϫ Ϫ Much of the work on CRs in renal disease has complement-activating ICs. In contrast, CFH / focused on their roles in inflammatory cells. For mice reconstituted with wild-type BM had sub- example, nephrotoxic serum nephritis has a stantially less glomerular deposition of ICs and dependence on CR3.196,197 Although CR3 is complement activation than mice with global present and functional on both neutrophils and or platelet CFH deficiency.88 Impaired glomer- monocyte/macrophages, the predominant cell ular IC processing occurred when extrarenal or affected in this model was the neutrophil, given podocyte-associated CFH were absent.93 These that early glomerular accumulation of these were taken as evidence that podocyte-associ- cells was reduced.198 The conclusions regard- ated CFH is necessary for the directed move- ing CR3-iC3b interactions were limited in these ment of ICs across the glomerular capillary studies because CR3 has an affinity for ICAM-1, wall,203 such that in its absence, subepithelial up-regulated in this model,199 and CR3 also can and subendothelial ICs persisted. function to facilitate Fc␥ receptor func- These studies with mouse platelet and podo- tions,197,200 which clearly can be important in cyte CFH were likely to be reflective of human this model.201 Thus, an effect of CR3 deficiency erythrocyte and podocyte CR1. By virtue of to limit glomerular injury could be ascribed to their capacity to bind C3b in ICs, they facilitate preventing leukocyte binding to iC3b or IC processing in the circulation and subepithe- ICAM-1, or to impaired signaling through the lial space. It is notable, however, that in all 330 T.S. Puri and R.J. Quigg experimental conditions, absence of plasma signals transduced by complement. Mol Immunol. CFH had the strongest bearing on the develop- 2004;41:583-97. ment of GN.88,93,111 The reason behind this was 8. Cybulsky AV, Quigg RJ, Salant DJ. Experimental membranous nephropathy redux. Am J Physiol. shown by Western blotting studies examining 2005;289:F660-71. isolated glomeruli for C3b activation prod- 9. Wetsel RA. Structure, function and cellular expres- ucts.88 Even with excessive IC deposition as sion of complement anaphylatoxin receptors. Curr occurred in mice lacking platelet CFH, the large Opin Immunol. 1995;7:48-53. quantities of C3b were inactivated; in contrast, 10. Gerard C, Gerard NP. C5a anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev active C3b remained when plasma CFH was Immunol. 1994;12:775-808. absent. Interestingly, mild disease also resulted 11. Guo RF, Ward PA. Role of C5a in inflammatory in CFH-deficient kidneys, which could be attrib- responses. Annu Rev Immunol. 2005;23:821-52. utable to CFH on podocytes serving as an in- 12. Klco JM, Wiegand CB, Narzinski K, et al. Essential trinsic complement regulator.93 Most of the de- role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol. 2005;12:320-6. tails behind this and whether the function of 13. Klco JM, Nikiforovich GV, Baranski TJ. 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