COMPLEMENT ACTIVATION AND REGULATION

In animals and humans, the complement system, which comprises more than 30 individual components, represents one of the most powerful defenses against invading pathogens Figure 1.

Figure 1.

A schematic view of complement activation and its regulation.

Full figure and legend (29K)

The classical pathway is activated by the binding of C1q to antibody/antigen complexes, while the alternative pathway can be initiated when spontaneously activated complement components bind to the surface of a pathogen. Once complement activation is initiated by either pathway, the C3 convertases (C4b2a and C3bBb) are generated that cleave the intact C3 molecule into C3a and C3b fragments. The newly generated C3b molecule forms another C3 convertase by the reaction of factor B and factor D. Thus, the complement activation is accelerated at C3 level by this amplification loop. Active C3b forms the C5 convertase and initiates the formation of the membrane attack complex (MAC) C5b-9, which is common to all these pathways. Another pathway is the recently discovered lectin activation pathway⁷, which is initiated by the binding of mannose-binding lectin (MBL) to carbohydrates on the surface of microorganisms. The lectin pathway, like the classical pathway, involves the generation of a C3-converting complex, C4b2a, and contributes to efficient antimicrobial immunity and protection, not only during the physiological window of vulnerability in early childhood following the decay of maternal antibody, but also in the early phase of every primary contact with a sugar-rich pathogen.

While the complement system works as an effective host defense, inappropriate complement activation leads to tissue injury through various mechanisms^8,9. Glomerular injury mediated by complement was once thought to occur primarily as a consequence of the generation of chemotactic factors such as C3a and C5a that attracted inflammatory cells as effectors. However, subsequent studies have shown that the nephritogenic effect of complement activation may result from formation and insertion of MAC in the resident glomerular cells^1,4. Although non-nucleated cells may be lysed by C5b-9, nucleated cells are usually resistant to lysis and may become activated by insertion of sublytic quantities of C5b-9 [reviewed in¹⁰. The consequences of this process are multiple and include cell proliferation¹¹, generation of inflammatory mediators such as oxidants, proteases, growth factors and prostanoids, and increased production of extracellular matrix. Although the role of MAC is best established in experimental membranous nephropathy where the primary target is GEC, more recent studies have implicated the pathogenic roles of MAC in the glomerular mesangial and endothelial cell as well^12,13,14. In addition, it is recognized that complement activation causes glomerular injury not only by recruitment of inflammatory cells and induction of inflammatory mediators, but also by other mechanisms including decreasing renal plasma flow as demonstrated by Stahl's group¹⁵ and direct stimulation of glomerular cell proliferation as shown in Shankland et al's studies¹¹.

To prevent undesirable complement activation, rigorous regulatory mechanisms are exhibited by host cells [reviewed in^3,16,17,18. Control of complement activation is focused at two stages in the pathway, the formation of the C3/C5 convertase and the assembly of the membrane attack complex (C5b-9) Table 1. While there are fluid-phase and membrane-bound complement control proteins acting at both of these stages, the membrane-bound inhibitors play a vital role in limiting damage at the cell surface. The glomerulus is particularly well endowed with complement regulatory proteins expressed by all three resident glomerular cells. Here I will focus primarily on the membrane bound complement regulatory proteins.

Table 1 - Complement regulatory proteins in humans.

Full table (76K)

FLUID PHASE COMPLEMENT REGULATORY PROTEINS

Many investigators have shown that clusterin and S-protein are detected in immune complexes formed in glomerulonephritis^{19,20,21,22,23,24,25,26,27,28}. These soluble complement regulatory proteins may inactivate at least part of locally activated C5b-9 in glomeruli Table 1. Experimental approaches to elucidate the in vivo role for fluid phase complement regulatory proteins in kidney disease have only been attempted with clusterin. Perfusion of isolated kidneys with anti-Fx1A antibody resulted in enhanced glomerular MAC formation and increased proteinuria when clusterin-depleted plasma was utilized by Saunders et al²⁹.

Jansen, Hogasen, and their colleagues showed that factor H deficiency causes hereditary MPGN type II in pigs^30,31, which can be reversed by full-substitution therapy with factor H concentrate³². While factor H deficiency is rare in humans, it was repeatedly found in association with various forms of glomerular diseases including MPGN^33,34. Furthermore, it was recently shown that mutations in the factor H gene are associated with familial hemolytic uremic syndrome³⁵.

MEMBRANE BOUND COMPLEMENT REGULATORY PROTEINS

The first group of these complement regulatory proteins acts by inactivating C3/C5 convertase via either of two different mechanisms. DAF displaces C2a from C4b and Bb from C3b. In contrast, MCP binds to membrane-associated C3b and C4b and catalyzes their degradation by factor I, serine protease in plasma. CR1 has both decay accelerating activity and cofactor activity for factor I. Many cells express more than one of these molecules, which may work synergistically with different mechanisms of action.

DAF, CR1, and MCP belong to the gene superfamily known as the regulators of complement activation (RCA), located on the q32 band of chromosome 1. The encoded genes in this genomic region of approximately 900 kb are ordered C4BP, DAF, CR2, CR1, MCP-like, CR1-like, and MCP in a 5' to 3' orientation, while the factor H gene lies at a distance of more than 500 kb away from this region. MCP-like and CR1-like are genomic elements that represent partial duplications of their respective genes, while it is not known whether they are true genes that yield protein products or pseudo-genes. The members of RCA have a strikingly similar motif structure. This motif, called SCR or a complement control protein (CCP) repeat, is a tightly packed structure of approximately 60 amino acids held together by two internal disulfide bridges formed by four invariant cysteine residues.

Activation of the complement cascade is also regulated at its final step, formation of MAC, by another membrane bound complement regulatory protein, CD59.

In the human glomerulus, all four membrane-bound complement regulatory proteins (MCP, DAF, CR1, and CD59) are present Table 2. The structures of these proteins are shown in Figure 2, and more detail about each of these complement regulatory proteins is provided below. I will also mention a rodent protein, Crry, which has been intensively studied in rodent models of renal disease.

Figure 2.

Schematic structures of human membrane-bound complement regulatory proteins. Decay accelerating factor (DAF) and membrane cofactor protein (MCP) are composed of four short consensus repeat (SCR) structures. This is followed by an STP segment, which is rich in serines, threonines, and prolines and is extensively O-glycosylated. In MCP this region is followed by a segment of unidentified function, a transmembrane domain, and one of two alternatively spliced cytoplasmic tails. DAF is tethered to the cell membrane by a glycosyl-phosphatidylinositol (GPI)-anchor that is added post-translationally. Complement receptor type 1 (CR1) has an interesting structural arrangement in which contiguous blocks of every seven SCR form a larger highly homologous repeating array called a long homologous repeat (LHR). Thus, the extracellular domain of the common form of CR1 is composed of four LHR with two additional SCR (a total of 30 SCR).

Full figure and legend (27K)

TABLE 2 - Distribution of complement regulatory proteins in the kidney.

Full table (28K)

Decay accelerating factor

Decay accelerating factor (DAF, CD55) acts by inhibiting formation and accelerating decay of the C3/C5 convertase, thereby limiting activation and deposition of C3. Cloning of DAF cDNA has revealed a structure with four contiguous SCRs^36,37. DAF is anchored to the plasma membrane by a carboxy-terminal GPI linkage, while the other two C3/C5 convertase inhibitors, CR1 and MCP, are classical transmembrane proteins.

DAF is expressed on a wide variety of circulating cells and tissues, and has been demonstrated in human glomeruli by immunoprecipitation³⁸. DAF isolated from cultured mesangial cells by Shibata, Cosio and Birmingham demonstrated a molecular mass of 83 kD³⁹, while immunoprecipitation of protein derived from human glomeruli showed a single band at 67 kD³⁸. These results clearly demonstrated DAF expression in glomerular cells. Although DAF was barely detectable in glomerular cells immunohistochemically^{4041,42,43,44}, technical difficulty in detecting DAF by immunohistochemistry could explain the discrepancy.

The functional importance of DAF on glomerular cells has been demonstrated by neutralizing it with antibody and showing that GEC became more susceptible to complement mediated cytotoxicity³⁸. DAF contained in mesangial cell extracts was also shown to be functionally active and inhibited complement mediated hemolysis³⁹.

Membrane cofactor protein

Membrane cofactor protein (MCP, CD46) is also a regulatory protein that is widely distributed on almost every cell and tissue, with the curious exception of the erythrocyte. MCP serves as a cofactor for the factor I-mediated degradation of C3b and C4b. Cloning of MCP cDNA, performed by Lublin from Atkinson's group, revealed that it was a typical type 1 membrane glycoprotein with four SCRs⁴⁵.

MCP is clearly seen in all three different types of human glomerular cells by immunohistochemical analysis^40,42,46. As seen in most tissues, glomerular MCP showed molecular weight heterogeneity consisting of two major components with 45 to 65 kD on SDS-PAGE⁴⁰, a distinguishing structural characteristic of MCP. The two distinct forms result from alternative splicing in the region of O-glycosylation.

Nakanishi et al showed that cofactor activity in the extracts of cultured GEC and mesangial cells assessed with fluorescence-labeled substrate C3 and purified factor I was completely blocked by anti-MCP antibody⁴⁰.

Complement receptor type 1

Complement receptor type 1 (CR1, CD35) is a polymorphic membrane protein of 190 to 280 kD that is expressed on the surface of various circulating cells and, interestingly, podocytes. CR1 has four allotypes: A (or F), B (or S), C, and D. Fearon's group showed that the most common A allotype has a molecular mass of 250 kD when analyzed by reducing SDS-PAGE, and has 30 SCRs^47,48.

CR1 mediates phagocytosis of particles opsonized with C3b and acts as cofactor for the breakdown of C3b and C4b by the fluid-phase regulator Factor I. Decay accelerating activity has also been attributed to CR1. Aside from these functions, CR1 on erythrocytes has a unique role in the transport and clearance of immune complexes from the circulation.

In glomeruli, CR1 is localized exclusively on podocytes^40,49,50,51. CR1 was also detected only in cultured GEC^40,52,53 in contrast to the other membrane-bound complement regulatory proteins that were present in any cultured glomerular cells^39,40,54,55. Quigg et al demonstrated that cultured rat glomerular epithelial cells express 4.5 kb CR1 mRNA which encodes a 200 kD protein^52,53. However, the precise functional role of CR1 in podocytes remains to be determined.

Complement regulatory protein, CD59

CD59 is also known as membrane inhibitor of reactive lysis (MIRL), homologous restriction factor-20 (HRF-20), or protectin. CD59 is an 18,000 20,000 molecular weight GPI-anchored glycoprotein, and binds to the -subunit of C8 and the C9b domain of C9, preventing formation of a lytic lesion by limiting incorporation of C9 into C5b-9 complexes. The mature protein consists of 77 amino acids with no significant similarities to any of the other complement regulatory proteins^56,57,5859.

CD59 is also ubiquitously expressed on all three glomerular cells^{40,42,44,60,61,6263}. Cultured glomerular epithelial, endothelial, and mesangial cells have been shown to have increased susceptibility to complement-mediated lysis in the presence of neutralizing antibody to CD59 in vitro^54,55,60,64. An important role of CD59 in vivo was demonstrated utilizing two different models of complement-dependent glomerulonephritis. Matsuo et al perfused anti-CD59 antibody into kidneys of rats with experimental mesangial proliferative glomerulonephritis induced with a lectin as a planted antigen⁶⁵. Neutralization of CD59 resulted in more severe glomerular damage in their model. Nangaku et al also performed selective renal artery perfusion of anti-CD59 in a thrombotic microangiopathy model in rats induced with antibody to endothelial cells⁶⁶. Rats perfused with anti-CD59 showed more glomerular C5b-9 formation and more severe endothelial damage associated with more platelet and fibrin deposition in glomeruli and a decrease in renal function⁶⁷. These studies suggest that CD59 has an important protective role in glomeruli subject to complement attack.

Rodent protein, Crry

In humans, DAF and MCP work at a C3/C5 convertase step by different mechanisms. In addition to DAF and MCP, rodents have a single protein known as Crry that serves the complement regulatory role of both these proteins. Cloning of rat cDNA for Crry revealed a structure composed of a signal peptide, six or seven SCRs, a transmembrane, and an intracytoplasmic domain^68,69.

In rats Crry is expressed on the membrane of glomerular mesangial, endothelial, and epithelial cells^54,55,70. Crry has been demonstrated immunohistochemically in glomerular capillary walls and mesangial cells in normal rats⁷⁰ and mice⁷¹.

Quigg et al showed the functional importance of Crry in cultured glomerular cells utilized neutralizing antibody to Crry^54,55. Matsuo and his colleagues have elucidated protective roles of Crry in vivo through animal studies. Their elegant studies suggested that normal vascular permeability is maintained by Crry through controlling complement activation on endothelial cells^72,73. Renal artery perfusion of Fab2 fragments of anti-Crry in normal rats resulted in marked renal tubulointerstitial damages, implying that Crry protects normal kidneys from spontaneous complement activation⁷⁴. Suppression of glomerular Crry by antibody in the anti-thymocyte serum (ATS) model of glomerulonephritis in rats also resulted in more severe mesangiolysis and microaneurysm formation⁷⁵.

EXPRESSION OF COMPLEMENT REGULATORY PROTEINS

Human studies

Expression of complement regulatory proteins can be changed by complement attack itself and other factors such as cytokines.

Cosio, Shibata and their colleagues demonstrated that early complement components increased DAF mRNA⁷⁶, while they also showed that C5b-9 formation caused an increase of DAF at the protein levels in cultured mesangial cells³⁹. An increase of MCP and CD59 protein levels was also induced by complement activation in cultured mesangial cells^76,77. The up-regulation of CD59 was controlled by at least two steps of the complement pathway, C5 and C8.

Treatment of cultured GEC with various cytokines did not change the expression levels of MCP, DAF, and CR1, while CD59 was up-regulated by IL-1 and TGF-⁷⁸.

REGULATION OF COMPLEMENT REGULATORY PROTEINS

In vivo studies

Some reports have analyzed the expression levels of complement regulatory proteins in human diseased kidneys in vivo.

MCP was up-regulated in some diseased kidneys such as membranoproliferative glomerulonephritis, IgA nephropathy, and lupus⁴⁶. The enhanced staining for MCP colocalized with C3b/C3c, an indicator of on-going complement activation, and it was speculated that up-regulation of MCP was stimulated by nascently generated complement fragments. Up-regulation of MCP in IgA nephropathy was also reported recently by Ootaka et al with a mild correlation with proteinuria⁷⁹.

DAF, which was barely detected in normal kidneys except in the juxtaglomerular apparatus, was up-regulated in the glomerular mesangium and renal interstitium of diseased kidneys, and correlated with C1q and C3 deposition⁴¹.

CR1 expression in podocytes was lost in some glomerular diseases such as rapidly progressive glomerulonephritis, membranous nephropathy, diabetic glomerulosclerosis, and lupus nephritis^{51,80,81,82,83,84,85,86,87,88}. This may be explained by the loss of podocytes or a metabolic abnormality of the podocytes.

Expression of CD59 in glomerular capillary walls was increased in diffuse lupus nephritis, which might be a protective response against the complement mediated injury in this disease⁶². Although a slight increase of CD59 expression was also reported in minimal change disease and IgA nephropathy in the same study, the differences in these disorders from normal kidneys did not reach statistical significance. In contrast, Lehto from Meri's group showed that the expression of CD59 in glomeruli was decreased in patients with membranous nephropathy, accompanied by an increase of urinary CD59 excretion⁸⁹. The mechanism of increased urinary CD59 is unclear and may reflect shedding of CD59 from GEC induced by complement attack.

Genetically engineered animals overexpressing or lacking genes of complement regulatory proteins (transgenic animals or knock-out mice) will be great tools to investigate their roles in glomerulonephritis in vivo. Recent studies utilizing transgenic mice that overexpress soluble Crry under the control of the inducible promoter demonstrated a significant reduction in albuminuria in the nephrotoxic serum nephritis model (R.J. Quigg, personal communication).

POTENTIAL THERAPEUTIC APPLICATIONS OF COMPLEMENT REGULATORY PROTEINS IN GLOMERULAR DISEASE

Many pharmacological agents have been reported to inhibit complement activation. However, none of these agents are suitable in the clinical context. Heparin, perhaps the most studied of these, is a rather weak inhibitor. Cobra venom factor is widely used in experimental animals, but toxic side effects including fatal anaphylaxis preclude its use in humans. Many other complement blockers function as nonspecific protease inhibitors and, therefore, could affect other important serum proteases.

The lack of a good pharmaceutical inhibitor of complement led researchers to seek alternatives. One possible approach is to utilize a blocking antibody against complement component that inhibits the complement cascade^90,91. Monoclonal antibody against C5 is currently in phase I trials for the prevention of inflammation during cardiopulmonary bypass. However, recent progress in molecular biological techniques has made completely new approaches feasible. These new techniques include systemic administration of soluble recombinant protein Table 3 and local overexpression of complement regulatory proteins at the cellular level.

Table 3 - Solubilized forms of complement regulatory proteins as a therapeutic application.

Full table (45K)

The first report that applied reagents produced by molecular techniques to treat immunological glomerular diseases through complement modulation in vivo was published by Couser and colleagues in 1995⁹². In this insightful study, they utilized a soluble recombinant CR1 (sCR1) lacking the transmembrane and cytoplasmic domains. Intraperitoneal administration of 60 mg/kg per day of sCR1 significantly reduced mesangiolysis, platelet and macrophage infiltration, and urine protein excretion in the ATS model of mesangial proliferative glomerulonephritis. sCR1 treatment also resulted in significant reduction of glomerular injury, associated with a decrease in proteinuria in both the passive Heymann nephritis model of membranous nephropathy and the concanavalin A/anti-concanavalin A model of glomerulonephritis mediated by subendothelial formation of immune complexes. Therapeutic efficacy of sCR1 has also been demonstrated in several other forms of tissue injury, including tubulointerstitial injury due to leakage of complement components in massive proteinuria^93,94, rejection of kidney allografts⁹⁵, and complement activation during hemodialysis^96,97. sCR1 is now undergoing human clinical testing, and is being evaluated in a phase IIa trial for adult respiratory distress syndrome and a phase I/II trial of reperfusion injury following lung transplantation.

Recombinant soluble MCP has been shown to be effective by Christiansen and colleagues in hyperacute graft rejection in a xenograft model⁹⁸ and in the reverse passive Arthus reaction model⁹⁹. There is no report of administration of recombinant soluble MCP in kidney disease to my knowledge.

A novel secreted form of DAF has been generated by a deletion of the signal for the GPI anchor by Moran et al¹⁰⁰. While this form of DAF reduced the severity of a reversed Arthus reaction, it was a less potent inhibitor of complement mediated hemolysis than GPI-linked DAF.

Truncated soluble CD59 has been prepared using recombinant baculovirus-infected insect cells by Sugita and his colleagues. Recombinant soluble CD59 inhibited reactive hemolysis, although its activity was much less than that of purified erythrocyte CD59¹⁰¹. Soluble CD59 has not been tested in vivo.

Recently Quigg's group succeeded in producing a functional soluble recombinant Crry utilizing a yeast expression system¹⁰². The recombinant protein was highly active against both the classical and alternative pathways of complement. Quigg and Holers also developed a Crry-Ig chimera, which showed a significant protective effect in the nephrotoxic serum nephritis model of mice¹⁰³.

Although sCR1 was effective in glomerulonephritis models in rats, it is not ideal. It is a very large molecule (200 kD) that must be given systemically and has a relatively short half-life in the circulation. Soluble recombinant forms of DAF and MCP can share many of these problems, although this remains to be tested. Current research is thus focused on the development of more active forms of the inhibitors utilizing data obtained by more detailed analysis on the function-structure relationship of various complement regulatory proteins. Removal of the single N-linked glycosylation site of CD59 resulted in an enhancement of complement inhibitory activity¹⁰⁴. The complement regulating activity of CR1 could be increased by changing a few amino acids within SCRs¹⁰⁵. A soluble chimeric form of DAF and MCP with eight SCRs in total was shown to inactivate both classical and alternative C3/C5 convertases via two different mechanisms: factor I-mediated proteolysis of C3b and enhancement of convertase decay. This protein, named CAB-2, was more competent as a complement inhibitor than the soluble forms of either DAF or MCP¹⁰⁶. These studies will guide the engineering of new inhibitors containing just the active site with minimal framework residues to provide a small, stable, and active inhibitor.

Another fascinating and more challenging way to modulate complement activation at a molecular level is to perform in vivo gene transfer of complement regulatory proteins. As a first step in exploring this technique, in studies in Dr. Couser's laboratory, we transfected cultured glomerular cells with expression vectors containing complement regulatory protein cDNA^107,108. Our stably transfected mesangial cell lines overexpressing CD59-FLAG or Crry-c-myc showed remarkable resistance to both lytic complement attack and the sublytical effects of C5b-9, which supported the feasibility of this kind of approach. To date, no successful studies of in vivo gene transfer of complement regulatory proteins have been reported.

We can develop another potential novel strategy for therapeutic intervention utilizing a characteristic feature of GPI-linked molecules. GPI-linked proteins can detach from the host membrane and reintegrate into another^109,110. GPI-mediated transfer of complement regulatory proteins such as DAF and CD59 may provide another possible way to treat complement mediated diseases and spare us any risks of perturbing gene expression in vivo, which always is a concern associated with gene therapy.

Complement regulatory proteins can be utilized in a completely different way. In hyperacute xenograft rejection, fixation of complement is known to be crucial. To abrogate the hyperacute rejection, transgenic animals expressing human complement regulatory proteins have been developed¹¹¹. Since the demand for organ transplants is greater than the supply of human donor organs, xenotransplantation may become an alternative to allograft transplantation. Those who suffer from chronic renal failure due to glomerulonephritis (and other diseases) may benefit from transgenic allogenic organs overexpressing human complement regulatory proteins¹¹².

SUMMARY AND CONCLUSION

Uncontrolled complement activation either in extent or location is detrimental, and host cells have developed a complex system of proteins that regulate potentially harmful complement activation and prevent tissue injury in vivo, the so-called complement regulatory proteins. Three membrane-bound complement regulatory proteins, DAF, MCP, and CR1, control activation of the complement cascade at the C3/C5 convertase level, while CD59 regulates C5b-9 formation. In the glomerulus, CR1 is localized exclusively in podocytes, while DAF, MCP, and CD59 are ubiquitously expressed in glomerular epithelial, endothelial, and mesangial cells. Expression levels of these proteins are altered by complement attack and in various diseases. Recent studies utilizing cultured glomerular cells and animal models of glomerulonephritis suggest that complement regulatory proteins play an important protective role against immune-mediated glomerular injury. Recent technological advances have made manipulation of complement regulatory proteins a feasible and promising therapeutic approach for the future.

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Acknowledgments

The author is a recipient of an award from the Sankyo Foundation of Life Science. The author is very grateful to Dr. William G. Couser (University of Washington, Seattle, USA) for his mentorship in several studies of complement regulatory proteins in glomerular disease reported here, and his advice and comments on this manuscript. The author is also grateful to Drs. Kiyoshi Kurokawa (Tokai University, Isehara, Japan), Richard J. Johnson (University of Washington, Seattle), Stuart J. Shankland (University of Washington, Seattle), Seiichi Matsuo (University of Nagoya, Nagoya, Japan), Toshiro Fujita (University of Tokyo, Tokyo), and Toshio Miyata (Tokai University) for their suggestions in the writing of this manuscript. The author apologizes if he did not cite the work of any investigator.