Membrane complement regulatory proteins

Clinical Immunology 118 (2006) 127 – 136 www.elsevier.com/locate/yclim

Short Analytical Review

Membrane complement regulatory proteins David D. Kim, Wen-Chao Song * Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Rm 1254 BRBII/III, 421 Curie Blvd, Philadelphia, PA 19104, USA Received 12 October 2005; accepted with revision 28 October 2005 Available online 9 December 2005

Abstract A number of proteins anchored on the cell surface function to protect host tissues from bystander injury when complement is activated. In humans, they include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and CD59. Although disease conditions directly attributable to abnormal function of these proteins are relatively rare, it has become evident from recent studies using animal models that membrane complement regulatory proteins are important modulators of tissue injury in many autoimmune and inflammatory disease settings. Evidence is also emerging to support a role of these proteins in regulating cellular immunity. In this article, we highlight recent advances on the in vivo biology of membrane complement regulatory proteins and discuss their relevance in human disease pathogenesis and therapeutics. D 2005 Elsevier Inc. All rights reserved. Keywords: CD55; CD46; CD59; Crry; MCP; DAF; CR1; Membrane complement regulators

Introduction Complement is a form of the innate immune system that plays an important role in defending the host against invading microorganisms. It is composed of over 30 different serum and membrane proteins. Complement can be activated via the classical pathway (CP, antibody-dependent), the lectin pathway (LP, mannose-binding lectin (MBL)-mediated) or the alternative pathway (AP, spontaneous tick-over) [1 –3] (Fig. 1). All three activation pathways lead to the generation of proteolytic enzyme complexes known as C3 convertases, which cleave the C3 protein into C3a and C3b [1– 3] (Fig. 1). C3b participates in the self-amplification loop of complement activation via the alternative pathway (Fig. 1). It also cross-links with C3 convertases to form C5 convertases, which go on to cleave the C5 protein into C5a and C5b [1 – 3] (Fig. 1). Subsequently, C5b aggregates with C6 and C7 to form a membrane-inserting C5b-7 complex. Recruitment of C8 and multiple units of C9 to the membrane-bound C5b-7 completes the formation of the membrane-attack complex (MAC, C5b-9) [1 – 3] (Fig. 1). Activated complement elicits potent biological activities by * Corresponding author. Fax: +1 215 746 8941. E-mail address: [email protected] (W.-C. Song). 1521-6616/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2005.10.014

promoting inflammation, direct lysis of microorganisms or target cells and opsonization of pathogens or immune complexes with complement activation products [1– 3]. To prevent unintended injury by activated complement, host tissues have developed intricate and elaborate mechanisms to inhibit complement activation. A critical component of these regulatory mechanisms is a group of cell surface anchored regulatory proteins. Structure and function of membrane complement regulatory proteins There are several membrane-associated complement regulatory proteins in humans [2,4,5]. These are decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor type 1 (CR1, CD35) and CD59. These proteins differ in their mechanism of action and in the way in which they attach to the cell surface (Fig. 2). DAF inhibits the activation of C3 and C5 by preventing the formation of new and accelerating the decay of preformed C3 and C5 convertases [6] (Fig. 1). MCP regulates C3 activation by functioning as a cofactor protein for factor I-mediated cleavage of C3b [7] (Fig. 1). CR1 has both DAF and MCP activities (Fig. 1). Additionally, CR1 is a major immune adherence receptor and

128

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

Fig. 1. Complement activation cascade. The classical pathway (CP) and lectin pathway (LP) are initiated by PAMPs (pathogen-associated molecular patterns) such as foreign antigens and mannose, respectively. The C1 complex of CP consists of C1q, C1r and C1s. The MBL (mannose-binding lectin) complex consists of MBL, MASP (MBL-associated serine protease) 1, 2 and 3. The alternative pathway is activated by spontaneous hydrolysis of C3. DAF (decay-accelerating factor), MCP (membrane cofactor protein), Crry (complement-receptor 1-related gene/protein y), and CR1 (complement receptor 1) are inhibitors of C3 and C5 convertases and their sites of action are indicated by a star symbol. CD59 prevents the binding of C9 to C8 and acts as an inhibitor of MAC (the membrane attack complex) formation.

plays a role in immune complex processing and clearance [8]. Finally, CD59 prevents the formation of the MAC at the terminal step of the complement activation cascade [5] (Fig. 1). DAF and CD59 attach to the cell surface via a glycosylphosphatidylinositol anchor whereas MCP and CR1 associate with the plasma membrane via their C-terminal transmembrane domains [5] (Fig. 2). Structurally, DAF, MCP and CR1 belong to the RCA (regulators of complement activation) family of genes and contain a variable number of short consensus repeat (SCR) domains [5] (Fig. 2). CD59 is a much smaller protein with no sequence or structural resemblance to the RCA family of proteins [5] (Fig. 2). Corresponding orthologs of DAF, MCP, CR1 and CD59 have also been identified in a number of animal species including the mouse which is the species of choice for developing mutant strains to explore the in vivo functions of these proteins [5]. However, there are several noticeable

differences between human and mouse in the composition and expression patterns of membrane complement regulatory proteins [5]. For example, both the DAF and CD59 genes are duplicated in the mouse (daf-1, daf-2, cd59a and cd59b) [9– 12]. Daf-2 and cd59b are expressed only in the mouse testis whereas daf-1 and cd59a are expressed broadly [9 – 12]. Human MCP is ubiquitously expressed except on erythrocytes whereas mouse MCP expression is restricted to the testis [7,13 – 16]. In the mouse, a unique transmembrane protein known as Crry (complement-receptor 1-related gene/protein y) which possesses both MCP and DAF activities has also been identified [17 – 19]. Since Crry has MCP activity and, like MCP in humans, is ubiquitously expressed in the mouse, it is considered a functional homologue of human MCP in this species [5,18,20]. Human CR1 is an efficient complement inhibitor and recombinant CR1 has been investigated as a therapeutic agent in a number of inflammatory disease models

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

Fig. 2. Domain structures and membrane attachment characteristics of human DAF, MCP, CR1, CD59 and mouse Crry. Human DAF and MCP contain four short consensus repeats (SCRs). Human CR1 contains 30 SCRs and mouse Crry contains five SCRs. Each SCR domain consists of approximately 60 amino acids with 4 conserved cystein residues which form intradomain disulfide bonds. No SCR domains are present in CD59. Instead, the extracellular domain of CD59 contains over 70 amino acids with 5 disulfide bonds linking the cystein residues. DAF and CD59 attach to the cell membrane via a glycosylphosphatidylinositol (GPI)-anchor while MCP, CR1 and Crry insert into the cell membrane through transmembrane domains. DAF and MCP have Ser/Thr-rich regions between their SCR domains and the GPI-anchor or the transmembrane domain.

[21 –24]. Murine CR1 and CR2 (CD21) are encoded by a single Cr1/2 gene through alternative splicing [25]. There is a paucity of data regarding the functional relevance of murine CR1 in complement regulation but compared with human CR1, its tissue distribution is more limited and it does not appear to function as an immune adherence receptor [25,26]. The murine Cr1/2 locus has been studied mostly in the context of CR2 function in B cell biology [27]. Hematological disorders The pathological consequence of membrane complement regulator deficiency on host tissues was first recognized in the hematological disorder paroxysmal nocturnal hemoglobinuria (PNH) [28 – 31]. PNH patients suffer from complementmediated intravascular hemolysis as a result of DAF and CD59 deficiency on their affected blood cells [28 – 31]. Increased platelet sensitivity to complement-induced activation also occurs and accounts for the elevated risk of thrombosis and stroke in these patients [32]. The cause of DAF and CD59

129

deficiency on affected blood cells of PNH patients is somatic mutations, occurring in hematopoetic stem cells, in the phosphatidylinositol glycan class A (PIG-A) gene which is essential for GPI anchor biosynthesis [33]. Thus, PNH patients are not globally deficient in DAF and CD59 and the disease does not represent a setting wherein the consequence of complete DAF and CD59 deficiency could be assessed. The relative role of DAF and CD59 in preventing a PNH phenotype has not been clearly defined. A number of individuals with selective, germline-encoded mutations of the DAF gene (Inab phenotype) [34,35], and at least one individual with selective mutation of the CD59 gene [36], have been described in the literature. The CD59-deficient but not the DAF-deficient individuals developed a PNH-like disease [34 – 37]. These observations have been taken as anecdotal evidence for the conclusion that CD59 plays a more important role than DAF in protecting human erythrocytes from complement attack. Targeted deletion in the mouse of the Daf-1 and the cd59a gene (the murine ortholog of human DAF and CD59, respectively) showed that neither Daf-1 nor cd59a single gene deficiency, nor Daf-1/CD59a double gene deficiency was sufficient to render murine erythrocytes sensitive to complement-mediated intravascular hemolysis [38,39]. Although one study of a CD59a knockout mouse described a mild form of intravascular hemolysis in a gender (male mice)-specific manner [40], such a phenotype was not observed in a second, independently generated line of CD59a-deficient mice [38]. It is unlikely that the lack of a PNH-like phenotype in the mutant mice could be explained by compensation from Daf-2 and/or CD59b, as both genes are expressed in the mouse testis only [5]. Though not susceptible to alternative pathway complement attack, erythrocytes from CD59a knockout mice were more sensitive to classical pathway complement-mediated lysis [38]. Furthermore, Daf-1 deficiency has a synergistic effect with CD59a deficiency in this regard [38]. This raised the possibility that DAF and CD59 may play a critical role in preventing autoimmune hemolytic anemia wherein complement, as well as the Fc receptor (FcR) pathway, is known to be operative [41]. Further studies revealed that protection of murine erythrocytes from alternative pathway complement attack is afforded by Crry, the third membrane complement regulator present on murine erythrocytes [38,42]. In vivo tracking experiments using labeled mouse erythrocytes showed that cells deficient in Daf-1 and/or CD59a had normal half-lives but erythrocytes deficient in Crry were eliminated from the circulation within 24 h of introduction by alternative pathway complement-mediated extravascular hemolysis [38,42]. Several questions arose from these observations regarding the relative functions of membrane complement regulators on human and murine erythrocytes. Why DAF and CD59 apparently play a less critical role on murine erythrocytes than on human erythrocytes in preventing spontaneous complement attack? One obvious possibility is that the rodent-specific Crry is both expressed at a high level and possesses potent DAF and MCP activities. The other question was whether human erythrocytes were also susceptible to alternative pathway complement-

130

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

mediated extravascular hemolysis and what prevents it from happening. The fact that Inab individuals with DAF gene mutations have normal erythrocyte function [34,43] suggests that DAF does not play such a role on human erythrocytes. Since MCP is not present on human erythrocytes, it is possible that CR1, which is present on human erythrocytes and has both MCP and DAF activities, might play a role on human erythrocytes similar to Crry on murine cells. Arguing against such a hypothesis is the limited number and unusual clustered topology of CR1 on human erythrocytes [8]. Finally, although it has been shown that Crry is more potent on a molar basis than murine DAF in inhibiting alternative pathway complement activation [44], it remains to be established whether it is the MCP activity of Crry that makes it indispensable on murine erythrocytes or that the predominant role of Crry over DAF in regulating alternative pathway complement reflects different levels of expression of the two regulators. Vascular diseases Apart from blood cells, a second type of cells that are constantly in close contact with plasma complement are endothelial cells (EC). Not surprisingly, ECs are well endowed with membrane complement regulatory proteins [5,45,46]. The critical role of these proteins on EC is demonstrated in the setting of xenotransplantation where complement-mediated hyperacute rejection occurs [47 – 51]. After organ transplantation from a discordant species (e.g. pig) to human or a primate recipient, natural antibodies in the recipient with specificity to gal-(alpha 1– 3)-gal epitopes present on the endothelial cells of the donor organ will trigger the classical pathway of complement, producing severe endothelial cell injury with loss of natural anticoagulant surface which results in generalized intravascular coagulation [48,49]. This sequence of events leads to hyperacute rejection of the transplanted organs within minutes to hours [49]. One reason for complement activation to occur in this setting is thought to be inadequate function of membrane complement regulatory proteins on the donor EC [47,51]. High levels of natural antibodies may trigger the classical pathway of complement to such a degree that it overwhelms the activity of the regulatory proteins. Additionally, the activity of membrane complement regulators is considered to be homologously restricted, i.e. they work less efficiently on complement from a different species. To circumvent hyperacute rejection, transgenic pigs over-expressing human MCP, DAF or CD59 on their endothelial cells have been developed [51 – 53]. Kidneys and hearts from such transgenic pigs have been demonstrated to be much more resistant to human complement-mediated endothelial injury and the transgenic organs had substantially improved survival time after transplantation to primate recipients [52,54 –56]. In settings of acute or chronic inflammation, membrane complement regulatory proteins may be up-regulated to offer extra protection of the vascular wall from complement injury. A number of inflammatory cytokines have been shown to induce DAF expression on cultured endothelial cells [57 –59].

Recently, both statins and C-reactive protein (CRP), a marker of chronic inflammation and strong predictor of vascular diseases, have been shown to induce endothelial DAF, CD59 and MCP [60 –65]. Statins are a class of cholesterol-lowering drugs which are also known to have anti-inflammatory effects in vivo [66]. By acting as inducers of membrane complement regulatory proteins on endothelial cells, statins could increase the resistance of these cells to anaphylatoxin-mediated inflammatory injury and/or C5b-9-induced activation [67]. This may constitute a mechanism by which statins exert their antiinflammatory effect in vivo. CRP is a serum protein and its level is correlated with chronic inflammation and increased risk of coronary heart diseases [61]. However, whether elevated CRP levels contribute positively or negatively to atherogenesis is not fully understood [61]. Although CRP can activate the complement via the classical pathway [60 – 63] and thus may be considered pro-inflammatory, a recent study showed that CRP, like the statins, could also induce the expression of DAF, CD59 and MCP on cultured human coronary artery and saphenous vein endothelial cells [65]. On the other hand, down-regulation or impaired function of membrane complement regulatory proteins on endothelial cells may exacerbate vascular injury and accelerate atherosclerosis in individuals predisposed to vascular diseases. An example in this regard is the postulated role of endothelial CD59 inactivation in the vascular complications of diabetic patients [68,69]. Human CD59 has a glycation motif in its protein sequence and it has been demonstrated with purified protein that CD59 is susceptible to chemical modification after prolonged incubation with glucose in test tubes [69]. Furthermore, there is evidence to suggest that blood sugar-catalyzed glycation and inactivation of human CD59 occur on intact cells in vivo as well [68,69]. With the use of specific antibodies, glycated CD59 protein was detected in the urine samples of diabetic patients but not in that of normal controls [69,70] and erythrocytes from poorly controlled type 1 diabetic (hyperglycemic) patients were more susceptible to complement lysis than that of normoglycemic patients despite similar levels of CD59 expression [70]. These observations support the hypothesis that endothelial and erythrocyte CD59 inactivation in hyperglycemic diabetic patients contributes to the vascular complications (atherosclerosis, anemia) of the diabetes syndrome [68 – 70]. However, this hypothesis remains to be tested in animal models of vascular disease using individual or combined membrane complement regulator-deficient mice. Autoimmune and inflammatory diseases The production of autoantibodies is a hallmark of many autoimmune diseases [71,72]. The autoantibodies may bind cell surface antigens or form immune complexes after encountering circulating antigens. If not properly disposed, immune complexes may become trapped in end organs such as the kidney glomeruli and subsequently activate complement via the classical pathway to cause inflammatory injury [72]. Although the role of complement as an effector pathway in end organ injury of autoimmunity is well appreciated, relatively

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

little is known about the degree to which membrane complement regulatory proteins modulate disease severity in these settings. This issue has been addressed recently in a number of disease models with the use of DAF and/or CD59 knockout mice. Miwa et al. demonstrated that deletion of the Daf-1 gene in MRL/lpr mice significantly exacerbated the autoimmune disease phenotype [73]. The MRL/lpr mouse is a widely used murine model of human systemic lupus erythematosus (SLE) [74,75]. Compared to Daf-1 gene-sufficient littermate controls, Daf-1 gene-deficient female MRL/lpr mice developed more pronounced lymphadenopathy and splenomegaly, higher serum antichromatin autoantibody levels and aggravated dermatitis [73]. Consistent with the phenotype of aggravated dermatitis in Daf-1-deficient MRL/lpr mice, Northern and Western blots and immunofluorescence studies showed Daf-1 to be expressed abundantly in the mouse skin [73], suggesting that it may play a particularly important role in this tissue. Increased lymphadenopathy, splenomegaly and serum antichromatin autoantibody titers in the Daf-1-deficient MRL/lpr mice also suggested a potential role of DAF in suppressing cellular immunity, at least in the setting of predisposed autoimmunity [73]. Both Daf-1 knockout mice and CD59a knockout mice have been found to develop more severe disease in experimental autoimmune encephalomyelitis (EAE), a disease model for human multiple sclerosis [76,77]. In the model of EAE disease induced by myelin oligodendrocyte peptide (MOG38-50), Daf-1 knockout mice had markedly increased daily clinical scores and higher overall mortality rate compared with wild-type controls [77]. Histological examination of the spinal cords revealed more pronounced demyelination and a greater number of infiltrated inflammatory cells in Daf-1 knockout mice [77]. Notably, C3 deficiency rescued the EAE disease phenotype of Daf-1 mice [77]. Thus, Daf-1/C3 double knockout mice developed EAE that was similar to wild-type mice in disease score and end point mortality and had minimal spinal cords demyelination [77]. The latter result suggested that the protective role of DAF in MOG38-50-induced EAE was complement-dependent. In a separate study of a model of EAE induced by whole recombinant myelin oligodendrocyte glycoprotein, CD59a knockout mice were also shown to have increased disease incidence and severity [76]. The extent of inflammation, demyelination and axonal injury in spinal cord cross-sections were enhanced in CD59a-deficient mice compared with control mice [76]. Areas of myelin loss and axonal damage in CD59adeficient mice were associated with deposits of MAC [76]. While CD59a clearly acted as a MAC inhibitor at the end organ level in the EAE model employed in this study, the mechanism of action of Daf-1 in the MOG38-50 peptide-induced EAE may be more complex. The MOG peptide-induced EAE model is thought to be principally a T cell-mediated disease and Daf-1, acting as a complement inhibitor, may have attenuated disease development indirectly by suppressing T cell immunity [77,78], rather than by limiting complement-mediated tissue injury at the end organ level. The protective role of DAF and CD59 was revealed in two additional inflammatory disease models, nephrotoxic serum

131

nephritis and renal ischemia –reperfusion injury. In nephrotoxic serum nephritis, injection of a heterologous serum containing murine glomerular basement membrane (GBM)-specific antibodies activates the classical pathway of complement in the glomeruli, causing acute complement-mediated inflammation and glomerular injury. Disease severity can be measured by the level of proteinuria and histological scoring of the pathological changes in the glomeruli. The nephrotoxic serum reaction can be amplified if the mice are pre-immunized with IgG of the species from which the anti-GBM serum is produced. In such a case, the heterologous anti-GBM IgGs also serve as planted antigens to induce a homologous phase of immune reaction [79]. Using this model, Daf-1 knockout mice were demonstrated to develop more severe glomerulonephritis than similarly treated wild-type mice [80]. Exacerbated glomerulonephritis in the Daf-1 mutant mice was reflected by increased proteinuria, worsened glomerular injury score and more abundant inflammatory cell infiltrates in the glomeruli [80]. It was also associated with increased C3 deposition in the glomeruli [80], suggesting that deficiency of Daf-1 led to increased complement activation in the glomeruli. Although the mechanism remains to be fully elucidated, it is now well accepted that complement activation occurs in a number of ischemia –reperfusion (IR) injury settings and is responsible, at least partially, for initiating and/or propagating the inflammatory response associated with IR [81,82]. It is thought that tissue ischemia and reperfusion expose phospholipids and mitochondrial proteins that can serve as neoantigens to activate complement, either directly by binding to C1q or mannose-binding lectin or indirectly by binding to natural antibodies or C-reactive protein, which then activate the classical pathway [60,72,83 – 89]. In one model of renal ischemia – reperfusion injury (IRI), renal pedicles of the mice were bilaterally clamped for 22 min and reperfused for 24 h before renal assessment [90]. In this model, compared to WT controls, Daf-1 knockout mice sustained more severe renal injury as indicated by elevated blood urea nitrogen levels, more severe tubular injury and increased neutrophil infiltration [90]. Although CD59a knockout mice were no more susceptible to renal IRI than wild-type mice in this model, CD59a deficiency potentiated IRI in the Daf-1 knockout mice such that renal IRI in Daf-1/CD59a double knockout mice was significantly more severe than that in Daf-1 knockout mice [90]. The relevance of CD59 in renal IRI was also demonstrated in a different model where the mice were reperfused longer after ischemia [91]. In this study, impaired renal function was observed in mice that were deficient in CD59a alone [91]. Given the redundant activity and overlapping expression patterns in the kidney between Daf-1 and Crry, it is somewhat surprising that Daf-1 deficiency had a clear phenotype in the anti-GBM nephritis and renal IRI models. In both models, complement-mediated endothelial injury and dysfunction were likely to be at the root of the observed tissue injury. As discussed above, endothelial DAF expression is known to be up-regulated by inflammatory cytokines [57 – 59]. Such a property is not shared by other human membrane complement regulators such as CD59 and MCP [57 – 59]. Whether Crry on

132

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

murine endothelial cells is subjected to induction during inflammation is not known. The regulated expression of DAF on endothelial cells may enable it to play a more critical role under inflammatory conditions and could explain why Crry was not able to completely compensate for the lack of Daf-1 in these two disease models. Since MCP expression in the mouse is limited to the testis, the role of MCP in settings of inflammatory injury cannot be studied in a MCP knockout mouse. Of interest, recent studies have established that MCP mutation is a predisposing factor in humans for the development of hemolytic uremic syndrome (HUS) [92,93]. Sequencing of MCP coding exons in affected individuals from 30 families detected heterozygous or homozygous MCP mutations in 3 families [92]. These mutations either reduce the C3b-binding activity of MCP or prevent its trafficking from inside the cells to the cell surface [92,93]. Unlike patients with factor H mutations, HUS patients with MCP mutations experienced no recurrence after kidney transplantation, suggesting that MCP defect in the kidney tissues was the main pathological cause. Two observations of these familial cases are notable. First, not all individuals with heterozygous MCP mutations developed HUS. Second, while heterozygous MCP mutations were sufficient to cause HUS in two families, only members with homozygous mutation in the third family developed HUS [92,93]. These observations indicated that MCP mutations predispose rather than cause HUS. It was hypothesized that the development of a thrombotic microangiopathy in association with MCP mutations requires an endothelial injury that, instead of resolving, is maintained through excessive activation of the complement system [92,93]. Reproductive processes Membrane complement regulatory proteins are highly expressed in the reproductive systems both in animals and man [5]. Human DAF, MCP and CD59 are expressed on sperm and in the female reproductive tract [45,94 – 96]. In the mouse, Daf-1 is expressed in the uterus where its expression was selectively up-regulated by estrogen [10]. Crry, Daf-1 and CD59a are highly, and MCP, Daf-2 and CD59b are exclusively, expressed in the mouse testis [9,12,16,97,98]. These expression characteristics have fueled the speculation that membrane complement regulatory proteins play an essential role in mammalian reproduction. Such a prediction, however, has not been borne out by genetic studies. Individuals with germline-encoded CD59 or DAF mutations (Inab phenotype) were not known to be associated with infertility [35,37, 43,99,100]. In the mouse, single or double Daf-1 and CD59a gene knockout did not impair their reproductive function [38 – 40]. Although one study with CD59b knockout mice claimed a phenotype of declining male infertility [101], part of the reported results in the same study on erythrocyte CD59b expression and function was contradicted by another study [102] and the sub-fertility phenotype claimed thus awaits independent confirmation from other investigators. The possible function of MCP on mammalian sperm has attracted particular interest but the issue remains enigmatic. On

human and mouse sperm, MCP is localized to the inner acrosomal membrane [103,104] and this has led to the hypothesis that it may be involved in acrosomal reaction during sperm – egg fusion, either as a complement regulator or a cell adhesion molecule [103,104]. Limitation of complement activation by MCP and other regulators on sperm after acrosomal reaction may be necessary to prevent anaphylatoxin-mediated inflammatory injury or C5b-9-induced lysis. However, a recent study of MCP function and complement activation during human sperm acrosomal reaction suggested that the role of MCP as a complement regulator in this process may be redundant [104]. It was observed that upon exposure of human spermatozoa to autologous serum or follicular fluid, acrosome-reacted spermatozoa activated the complement cascade efficiently through C3 but not beyond [104]. Blockade of MCP activity with mAb did not enhance or diminish C3 fragment deposition or C5b-9 deposition on the sperm [104]. Furthermore, C3b deposited on human spermatozoa is cleaved to C3bi by factor H and not MCP. It was postulated that complement activation through the C3 stage may serve to opsonize the sperm to facilitate the fusion of sperm to oocytes which express complement receptors 1 and 2 [104]. Such targeted and restricted form of complement activation on host cells may represent a common strategy to handle modified self [104]. The possibility that MCP may directly mediate the binding of sperm to eggs is supported by the observation that MCP associates with CD9, a tetraspan membrane protein on macrophages and other cell types and whose targeted disruption in the mouse resulted in infertility due to impaired sperm egg interaction [105]. In one clinical investigation, Nomura et al. found three patients with no MCP on their spermatozoa when screening over 500 idiopathic male infertile patients [106]. However, targeted disruption of the mouse MCP gene had no impact on infertility [107]. Paradoxically, MCPdeficient mouse sperm had accelerated acrosomal reaction compared with wild-type mouse sperm, suggesting that MCP may influence membrane fluidity of the sperm [104,107]. The most striking finding related to membrane complement regulators in reproduction came from the experiment of Crry gene knockout [108]. Targeted deletion of the mouse Crry gene revealed an indispensable role of this protein in fetal survival [108]. Crry-deficient embryos could not develop passing 9.5 dpc but this phenotype could be rescued by C3 deficiency, suggesting that complement-mediated attack was the cause of fetal demise [108]. In a subsequent study, it was established that Crry-deficient embryos were destroyed by the complement alternative pathway and the effector mechanisms provided by the maternal C3, with minimal contribution from other complement activation pathways and of the effector mechanisms provided by other complement components [109]. Interestingly, immunohistochemical studies revealed that DAF is not expressed on developing mouse embryos [109,110]. The lack of compensation from DAF and MCP may explain why Crry-deficient mouse embryos are susceptible to complement attack. Whether membrane complement regulatory proteins also play a crucial role on developing

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

human fetuses is not known. The fact that complete DAFdeficient individuals are viable [34,99] would suggest that DAF is not indispensable for human embryo survival. It is possible that DAF, MCP and CR1 collectively provide such protection and single deficiency of these genes is not sufficient to cause a phenotype comparable to that observed in Crry knockout mice. Therapeutic applications The effectiveness of membrane regulators in protecting tissues from complement injury has provided an impetus to explore their therapeutic applications in inflammatory disorders. Several strategies have been developed and tested experimentally in rodent. By removing the transmembrane domains or GPI anchors, soluble recombinant regulatory proteins have been engineered which can be given systemically [99,111 –117]. For example, systemic administration of recombinant CR1 was shown to ameliorate tissue injury in a rat model of myocardial IRI [114,115]. To increase the plasma half-life, DAF-Ig and Crry-Ig fusion proteins have been developed [117,118]. Administration of Crry-Ig in the range of 30 to 100 mg/kg has been found to protect mice from antibody-induced glomerulonephritis [113], attenuate intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice [112] and prevent antiphospholipid antibodyinduced fetal loss in a murine model of lupus pregnancy failure [111]. In contrast to recombinant C3 inhibitors, recombinant soluble CD59 had limited activity as a MAC inhibitor when given systemically [118,119]. However, the in vivo activity of recombinant CD59 was drastically increased when a membrane-targeted form was used. In this strategy, the bacterially expressed protein was coupled through its carboxyl terminus to a short, synthetic address tag that confers membrane binding activity [117]. This form of recombinant CD59 showed markedly increased complement-inhibitory activity when assessed in vitro in hemolysis assays and in vivo in a rat model of rheumatoid arthritis [117]. A disadvantage of systemic use of recombinant soluble complement regulators is the suppression of the normal physiological functions of complement such as immune complex handling and host defense from infection. To circumvent this problem, two strategies have been used to produce recombinant regulator fusion proteins to target their homing to specific sites of action. In one strategy, Crry and CD59 were linked to a scFv-targeting moiety derived from K9/9 mAb that binds in vivo to an unidentified Ag on rat glomerular and proximal tubular epithelial cells [120]. This enabled recombinant Crry and CD59 to be targeted to the tubular epithelium of the rat [120]. In a rat model of puromycin-induced nephrosis, Ag-targeted Crry or CD59 protected the animals from tubulointerstitial injury and renal dysfunction [120]. In a second strategy, recombinant Crry was targeted to the site of complement activation by using the iC3b/C3dg-binding fragment of complement receptor 2 (CR2) as a fusion partner [121]. The presence of CR2 fragment allows the fusion protein to seek and bind only to cells or

133

tissues which have sustained C3 deposition at sites of inflammation. The CR2-Crry fusion protein required a 10fold lower dose than its systemic counterpart, Crry-Ig, to prevent equivalent degree of local and systemic injury in a murine model of intestinal ischemia and reperfusion injury [121]. CR2-Crry had significantly shorter plasma half-life and, unlike Crry-Ig, did not depress serum complement activity [121]. Notably, the minimum effective dose of Crry-Ig rendered mice susceptible to infection in a model of acute peritonitis whereas CR2-Crry produced no such effect [121]. Conclusion There are multiple forms of membrane complement regulatory proteins. Each is defined by its way of membrane attachment, mechanism of action, site of inhibition in the complement cascade and tissue distribution pattern. The complexity, and in some cases redundancy, in these proteins suggests that they are evolved to play a critical role in protecting the host from complement injury. Recent transgenic animal studies have provided much insight into the physiologic role of these proteins and their relevance in human disease pathogenesis and therapeutics. While dysfunction in one or two of these regulators may not always be sufficient to cause tissue injury in normal individuals, membrane complement regulatory proteins are clearly disease modifying genes in many inflammatory disease settings. Further studies of transgenic mice with targeted deletion of these proteins will shed new light on the role of complement in other models of tissue and vascular injury and facilitate the development of novel anticomplement therapies. Acknowledgments Work in the author’s laboratory has been supported by National Institutes of Health grants (AI-44970, AI-49344, AI63288) and a grant from the National Multiple Sclerosis Society (RG7246). References [1] W.C. Song, M.R. Sarrias, J.D. Lambris, Complement and innate immunity, Immunopharmacology 49 (2000) 187. [2] T.E. Mollnes, W.C. Song, J.D. Lambris, Complement in inflammatory tissue damage and disease, Trends Immunol. 23 (2002) 61. [3] M.J. Walport, Complement. First of two parts, N. Engl. J. Med. 344 (2001) 1058. [4] D. Hourcade, V.M. Holers, J.P. Atkinson, The regulators of complement activation (RCA) gene cluster, Adv. Immunol. 45 (1989) 381. [5] T. Miwa, W.C. Song, Membrane complement regulatory proteins: insight from animal studies and relevance to human diseases, Int. Immunopharmacol. 1 (2001) 445. [6] D.M. Lublin, J.P. Atkinson, Decay-accelerating factor: biochemistry, molecular biology, and function, Annu. Rev. Immunol. 7 (1989) 35. [7] M.K. Liszewski, T.W. Post, J.P. Atkinson, Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster, Annu. Rev. Immunol. 9 (1991) 431. [8] J.M. Ahearn, D.T. Fearon, Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21), Adv. Immunol. 46 (1989) 183.

134

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136

[9] A.P. Spicer, M.F. Seldin, S.J. Gendler, Molecular cloning and chromosomal localization of the mouse decay-accelerating factor genes. Duplicated genes encode glycosylphosphatidylinositol-anchored and transmembrane forms, J. Immunol. 155 (1995) 3079. [10] W.C. Song, C. Deng, K. Raszmann, R. Moore, R. Newbold, J.A. McLachlan, M. Negishi, Mouse decay-accelerating factor: selective and tissue-specific induction by estrogen of the gene encoding the glycosylphosphatidylinositol-anchored form, J. Immunol. 157 (1996) 4166. [11] M.B. Powell, K.J. Marchbank, N.K. Rushmere, C.W. van den Berg, B.P. Morgan, Molecular cloning, chromosomal localization, expression, and functional characterization of the mouse analogue of human CD59, J. Immunol. 158 (1997) 1692. [12] Y.M. Qian, X. Qin, T. Miwa, X. Sun, J.A. Halperin, W.C. Song, Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59, J. Immunol. 165 (2000) 2528. [13] J.L. Cole, G.A. Housley Jr., T.R. Dykman, R.P. MacDermott, J.P. Atkinson, Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines, Proc. Natl. Acad. Sci. U. S. A. 82 (1985) 859. [14] M.W. Nickells, J.P. Atkinson, Characterization of CR1- and membrane cofactor protein-like proteins of two primates, J. Immunol. 144 (1990) 4262. [15] R.W. Johnstone, B.E. Loveland, I.F. McKenzie, Identification and quantification of complement regulator CD46 on normal human tissues, Immunology 79 (1993) 341. [16] T. Miwa, M. Nonaka, N. Okada, S. Wakana, T. Shiroishi, H. Okada, Molecular cloning of rat and mouse membrane cofactor protein (MCP, CD46): preferential expression in testis and close linkage between the mouse Mcp and Cr2 genes on distal chromosome 1, Immunogenetics 48 (1998) 363. [17] V.M. Holers, T. Kinoshita, H. Molina, The evolution of mouse and human complement C3-binding proteins: divergence of form but conservation of function, Immunol. Today 13 (1992) 231. [18] B. Li, C. Sallee, M. Dehoff, S. Foley, H. Molina, V.M. Holers, Mouse Crry/p65. Characterization of monoclonal antibodies and the tissue distribution of a functional homologue of human MCP and DAF, J. Immunol. 151 (1993) 4295. [19] M.S. Paul, M. Aegerter, S.E. O’Brien, C.B. Kurtz, J.H. Weis, The murine complement receptor gene family. Analysis of mCRY gene products and their homology to human CR1, J. Immunol. 142 (1989) 582. [20] W.C. Song, Membrane complement regulatory proteins in autoimmune and inflammatory tissue injury, Curr. Dir. Autoimmun. 7 (2004) 181. [21] R.M. Goodfellow, A.S. Williams, J.L. Levin, B.D. Williams, B.P. Morgan, Soluble complement receptor one (sCR1) inhibits the development and progression of rat collagen-induced arthritis, Clin. Exp. Immunol. 119 (2000) 210. [22] M. Mizuno, K. Nishikawa, B.P. Morgan, S. Matsuo, Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59, Clin. Exp. Immunol. 119 (2000) 368. [23] J. Hamacher, S. Sadallah, J.A. Schifferli, J. Villard, L.P. Nicod, Soluble complement receptor type 1 (CD35) in bronchoalveolar lavage of inflammatory lung diseases, Eur. Respir. J. 11 (1998) 112. [24] M.S. Mulligan, R.L. Warner, C.W. Rittershaus, L.J. Thomas, U.S. Ryan, K.E. Foreman, L.D. Crouch, G.O. Till, P.A. Ward, Endothelial targeting and enhanced antiinflammatory effects of complement inhibitors possessing sialyl Lewisx moieties, J. Immunol. 162 (1999) 4952. [25] H. Molina, T. Kinoshita, K. Inoue, J.C. Carel, V.M. Holers, A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2, J. Immunol. 145 (1990) 2974. [26] T. Kinoshita, J. Takeda, K. Hong, H. Kozono, H. Sakai, K. Inoue, Monoclonal antibodies to mouse complement receptor type 1 (CR1). Their use in a distribution study showing that mouse erythrocytes and platelets are CR1-negative, J. Immunol. 140 (1988) 3066. [27] V.M. Holers, S.A. Boackle, Complement receptor 2 and autoimmunity, Curr. Dir. Autoimmun. 7 (2004) 33.

[28] A. Nicholson-Weller, J.P. March, S.I. Rosenfeld, K.F. Austen, Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor, Proc. Natl. Acad. Sci. U. S. A. 80 (1983) 5066. [29] M.K. Pangburn, R.D. Schreiber, H.J. Muller-Eberhard, Deficiency of an erythrocyte membrane protein with complement regulatory activity in paroxysmal nocturnal hemoglobinuria, Proc. Natl. Acad. Sci. U. S. A. 80 (1983) 5430. [30] M.K. Pangburn, R.D. Schreiber, J.S. Trombold, H.J. Muller-Eberhard, Paroxysmal nocturnal hemoglobinuria: deficiency in factor H-like functions of the abnormal erythrocytes, J. Exp. Med. 157 (1983) 1971. [31] W.F. Rosse, C.J. Parker, Paroxysmal nocturnal haemoglobinuria, Clin. Haematol. 14 (1985) 105. [32] C. Parker, M. Omine, S. Richards, J.I. Nishimura, M. Bessler, R. Ware, P. Hillmen, L. Luzzatto, N. Young, T. Kinoshita, W. Rosse, G. Socie, Diagnosis and management of paroxysmal nocturnal hemoglobinuria, Blood (2005) 3699 – 3709. [33] T. Miyata, N. Yamada, Y. Iida, J. Nishimura, J. Takeda, T. Kitani, T. Kinoshita, Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria, N. Engl. J. Med. 330 (1994) 249. [34] M.J. Telen, A.M. Green, The Inab phenotype: characterization of the membrane protein and complement regulatory defect, Blood 74 (1989) 437. [35] D.M. Lublin, G. Mallinson, J. Poole, M.E. Reid, E.S. Thompson, B.R. Ferdman, M.J. Telen, D.J. Anstee, M.J. Tanner, Molecular basis of reduced or absent expression of decay-accelerating factor in Cromer blood group phenotypes, Blood 84 (1994) 1276. [36] M. Yamashina, E. Ueda, T. Kinoshita, T. Takami, A. Ojima, H. Ono, H. Tanaka, N. Kondo, T. Orii, N. Okada, et al., Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria, N. Engl. J. Med. 323 (1990) 1184. [37] T. Shichishima, Y. Saitoh, T. Terasawa, H. Noji, T. Kai, Y. Maruyama, Complement sensitivity of erythrocytes in a patient with inherited complete deficiency of CD59 or with the Inab phenotype, Br. J. Haematol. 104 (1999) 303. [38] T. Miwa, L. Zhou, B. Hilliard, H. Molina, W.C. Song, Crry, but not CD59 and DAF, is indispensable for murine erythrocyte protection in vivo from spontaneous complement attack, Blood 99 (2002) 3707. [39] X. Sun, C.D. Funk, C. Deng, A. Sahu, J.D. Lambris, W.C. Song, Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 628. [40] D.S. Holt, M. Botto, A.E. Bygrave, S.M. Hanna, M.J. Walport, B.P. Morgan, Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria, Blood 98 (2001) 442. [41] L. Fossati-Jimack, L. Reininger, Y. Chicheportiche, R. Clynes, J.V. Ravetch, T. Honjo, S. Izui, High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia, J. Exp. Med. 190 (1999) 1689. [42] H. Molina, T. Miwa, L. Zhou, B. Hilliard, D. Mastellos, M.A. Maldonado, J.D. Lambris, W.C. Song, Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor, Blood 100 (2002) 4544. [43] M.J. Telen, S.E. Hall, A.M. Green, J.J. Moulds, W.F. Rosse, Identification of human erythrocyte blood group antigens on decay-accelerating factor (DAF) and an erythrocyte phenotype negative for DAF, J. Exp. Med. 167 (1988) 1993. [44] M.H.J. Kraus, D.G.J. Holers, VM, A direct comparison of complement inhibitory capacities of the GPI- and transmembrane forms of mouse DAF to mouse Crry and human rsCR1, Immunopharmacology 49 (2000) 64. [45] R.C. Riley-Vargas, D.B. Gill, C. Kemper, M.K. Liszewski, J.P. Atkinson, CD46: expanding beyond complement regulation, Trends Immunol. 25 (2004) 496. [46] M.R. Daha, The possible role of membrane complement regulators in vasculitis, Behring Inst. Mitt. (1993) 184.

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136 [47] T.M. Diaz, R. Manez, I. Moscoso, D. Lopez, I. Santamarina, E. Lopez, A. Centeno, N. Domenech, The serum level of xenoantibodies, and hDAF or alphaGAL expression on pig cells, modulate in vitro the protection given by hDAF to primate complement-mediated damage, Transplant Proc. 37 (2005) 510. [48] Z.E. Holzknecht, S. Coombes, B.A. Blocher, C.L. Lau, R.D. Davis, J.L. Platt, Identification of antigens on porcine pulmonary microvascular endothelial cells recognized by human xenoreactive natural antibodies, Lab. Invest. 79 (1999) 763. [49] S. Saadi, J.L. Platt, Immunology of xenotransplantation, Life Sci. 62 (1998) 365. [50] Y. Banz, T. Cung, E.Y. Korchagina, N.V. Bovin, A. Haeberli, R. Rieben, Endothelial cell protection and complement inhibition in xenotransplantation: a novel in vitro model using whole blood, Xenotransplantation 12 (2005) 434. [51] W. Fecke, J. Long, A. Richards, R. Harrison, Protection of hDAFtransgenic porcine endothelial cells against activation by human complement: role of the membrane attack complex, Xenotransplantation 9 (2002) 97. [52] B.E. Loveland, J. Milland, P. Kyriakou, B.R. Thorley, D. Christiansen, M.B. Lanteri, M. Regensburg, M. Duffield, A.J. French, L. Williams, L. Baker, M.R. Brandon, P.X. Xing, D. Kahn, I.F. McKenzie, Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons, Xenotransplantation 11 (2004) 171. [53] S. Menoret, M. Plat, G. Blancho, F. Martinat-Botte, P. Bernard, G. Karam, L. Tesson, K. Renaudin, P. Guillouet, B. Weill, C. Chereau, L.M. Houdebine, J.P. Soulillou, M. Terqui, I. Anegon, Characterization of human CD55 and CD59 transgenic pigs and kidney xenotransplantation in the pig-to-baboon combination, Transplantation 77 (2004) 1468. [54] M. Schmoeckel, F.N. Bhatti, A. Zaidi, E. Cozzi, G. Pino-Chavez, J.J. Dunning, J. Wallwork, D.J. White, Xenotransplantation of pig organs transgenic for human DAF: an update, Transplant Proc. 29 (1997) 3157. [55] M. Schmoeckel, G. Nollert, M. Shahmohammadi, J. Muller-Hocker, V.K. Young, W. Kasper-Konig, D.J. White, C. Hammer, B. Reichart, Transgenic human decay accelerating factor makes normal pigs function as a concordant species, J. Heart Lung Transplant 16 (1997) 758. [56] W.L. Fodor, B.L. Williams, L.A. Matis, J.A. Madri, S.A. Rollins, J.W. Knight, W. Velander, S.P. Squinto, Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 11153. [57] S.R. Ahmad, E.A. Lidington, R. Ohta, N. Okada, M.G. Robson, K.A. Davies, M. Leitges, C.L. Harris, D.O. Haskard, J.C. Mason, Decayaccelerating factor induction by tumour necrosis factor-alpha, through a phosphatidylinositol-3 kinase and protein kinase C-dependent pathway, protects murine vascular endothelial cells against complement deposition, Immunology 110 (2003) 258. [58] J.C. Mason, E.A. Lidington, H. Yarwood, D.M. Lublin, D.O. Haskard, Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis, Arthritis Rheum. 44 (2001) 138. [59] J.C. Mason, H. Yarwood, K. Sugars, B.P. Morgan, K.A. Davies, D.O. Haskard, Induction of decay-accelerating factor by cytokines or the membrane-attack complex protects vascular endothelial cells against complement deposition, Blood 94 (1999) 1673. [60] M. Griselli, J. Herbert, W.L. Hutchinson, K.M. Taylor, M. Sohail, T. Krausz, M.B. Pepys, C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction, J. Exp. Med. 190 (1999) 1733. [61] E.T. Yeh, J.T. Willerson, Coming of age of C-reactive protein: using inflammation markers in cardiology, Circulation 107 (2003) 370. [62] S. Bhakdi, M. Torzewski, M. Klouche, M. Hemmes, Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation, Arterioscler., Thromb., Vasc. Biol. 19 (1999) 2348. [63] G.J. Wolbink, M.C. Brouwer, S. Buysmann, I.J. ten Berge, C.E. Hack, CRP-mediated activation of complement in vivo: assessment by

[64] [65]

[66] [67]

[68]

[69]

[70]

[71] [72] [73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82] [83]

[84]

[85]

135

measuring circulating complement-C-reactive protein complexes, J. Immunol. 157 (1996) 473. F. Niculescu, H. Rus, Complement activation and atherosclerosis, Mol. Immunol. 36 (1999) 949. S.H. Li, P.E. Szmitko, R.D. Weisel, C.H. Wang, P.W. Fedak, R.K. Li, D.A. Mickle, S. Verma, C-reactive protein upregulates complementinhibitory factors in endothelial cells, Circulation 109 (2004) 833. G. Weitz-Schmidt, Statins as anti-inflammatory agents, Trends Pharmacol. Sci. 23 (2002) 482. J.C. Mason, Z. Ahmed, R. Mankoff, E.A. Lidington, S. Ahmad, V. Bhatia, A. Kinderlerer, A.M. Randi, D.O. Haskard, Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury, Circ. Res. 91 (2002) 696. X. Qin, A. Goldfine, N. Krumrei, L. Grubissich, J. Acosta, M. Chorev, A.P. Hays, J.A. Halperin, Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes, Diabetes 53 (2004) 2653. J. Acosta, J. Hettinga, R. Fluckiger, N. Krumrei, A. Goldfine, L. Angarita, J. Halperin, Molecular basis for a link between complement and the vascular complications of diabetes, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 5450. C.S. Davies, C.L. Harris, B.P. Morgan, Glycation of CD59 impairs complement regulation on erythrocytes from diabetic subjects, Immunology 114 (2005) 280. J.W. Semple, J. Freedman, Autoimmune pathogenesis and autoimmune hemolytic anemia, Semin. Hematol. 42 (2005) 122. M.J. Walport, Complement. Second of two parts, N. Engl. J. Med. 344 (2001) 1140. T. Miwa, M.A. Maldonado, L. Zhou, X. Sun, H.Y. Luo, D. Cai, V.P. Werth, M.P. Madaio, R.A. Eisenberg, W.C. Song, Deletion of decayaccelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice, Am. J. Pathol. 161 (2002) 1077. P.L. Cohen, R.A. Eisenberg, Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease, Annu. Rev. Immunol. 9 (1991) 243. P.L. Cohen, R.A. Eisenberg, The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane, Immunol. Today 13 (1992) 427. R.J. Mead, J.W. Neal, M.R. Griffiths, C. Linington, M. Botto, H. Lassmann, B.P. Morgan, Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis, Lab. Invest. 84 (2004) 21. J. Liu, T. Miwa, B. Hilliard, Y. Chen, J.D. Lambris, A.D. Wells, W.C. Song, The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo, J. Exp. Med. 201 (2005) 567. P.S. Heeger, P.N. Lalli, F. Lin, A. Valujskikh, J. Liu, N. Muqim, Y. Xu, M.E. Medof, Decay-accelerating factor modulates induction of T cell immunity, J. Exp. Med. 201 (2005) 1523. G. Schrijver, M.J. Bogman, K.J. Assmann, R.M. de Waal, H.C. Robben, H. van Gasteren, R.A. Koene, Anti-GBM nephritis in the mouse: role of granulocytes in the heterologous phase, Kidney Int. 38 (1990) 86. H. Sogabe, M. Nangaku, Y. Ishibashi, T. Wada, T. Fujita, X. Sun, T. Miwa, M.P. Madaio, W.C. Song, Increased susceptibility of decayaccelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis, J. Immunol. 167 (2001) 2791. T.V. Arumugam, I.A. Shiels, T.M. Woodruff, D.N. Granger, S.M. Taylor, The role of the complement system in ischemia – reperfusion injury, Shock 21 (2004) 401. Y.H. Lien, L.W. Lai, A.L. Silva, Pathogenesis of renal ischemia/reperfusion injury: lessons from knockout mice, Life Sci. 74 (2003) 543. R.D. Rossen, L.H. Michael, H.K. Hawkins, K. Youker, W.J. Dreyer, R.E. Baughn, M.L. Entman, Cardiolipin – protein complexes and initiation of complement activation after coronary artery occlusion, Circ. Res. 75 (1994) 546. M.L. Entman, L. Michael, R.D. Rossen, W.J. Dreyer, D.C. Anderson, A.A. Taylor, C.W. Smith, Inflammation in the course of early myocardial ischemia, FASEB J. 5 (1991) 2529. C.D. Collard, M.C. Montalto, W.R. Reenstra, J.A. Buras, G.L. Stahl,

136

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95] [96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

D.D. Kim, W.-C. Song / Clinical Immunology 118 (2006) 127 – 136 Endothelial oxidative stress activates the lectin complement pathway: role of cytokeratin 1, Am. J. Pathol. 159 (2001) 1045. W.G. Austen Jr., L. Kobzik, M.C. Carroll, H.B. Hechtman, F.D. Moore Jr., The role of complement and natural antibody in intestinal ischemia – reperfusion injury, Int. J. Immunopathol. Pharmacol. 16 (2003) 1. R.K. Chan, S.I. Ibrahim, N. Verna, M. Carroll, F.D. Moore Jr., H.B. Hechtman, Ischaemia – reperfusion is an event triggered by immune complexes and complement, Br. J. Surg. 90 (2003) 1470. S.D. Fleming, R.P. Egan, C. Chai, G. Girardi, V.M. Holers, J. Salmon, M. Monestier, G.C. Tsokos, Anti-phospholipid antibodies restore mesenteric ischemia/reperfusion-induced injury in complement receptor 2/complement receptor 1-deficient mice, J. Immunol. 173 (2004) 7055. S.D. Fleming, T. Shea-Donohue, J.M. Guthridge, L. Kulik, T.J. Waldschmidt, M.G. Gipson, G.C. Tsokos, V.M. Holers, Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire, J. Immunol. 169 (2002) 2126. K. Yamada, T. Miwa, J. Liu, M. Nangaku, W.C. Song, Critical protection from renal ischemia reperfusion injury by CD55 and CD59, J. Immunol. 172 (2004) 3869. D. Turnberg, M. Botto, M. Lewis, W. Zhou, S.H. Sacks, B.P. Morgan, M.J. Walport, H.T. Cook, CD59a deficiency exacerbates ischemia – reperfusion injury in mice, Am. J. Pathol. 165 (2004) 825. A. Richards, E.J. Kemp, M.K. Liszewski, J.A. Goodship, A.K. Lampe, R. Decorte, M.H. Muslumanoglu, S. Kavukcu, G. Filler, Y. Pirson, L.S. Wen, J.P. Atkinson, T.H. Goodship, Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 12966. M. Noris, S. Brioschi, J. Caprioli, M. Todeschini, E. Bresin, F. Porrati, S. Gamba, G. Remuzzi, Familial haemolytic uraemic syndrome and an MCP mutation, Lancet 362 (2003) 1542. I.A. Rooney, A. Davies, B.P. Morgan, Membrane attack complex (MAC)mediated damage to spermatozoa: protection of the cells by the presence on their membranes of MAC inhibitory proteins, Immunology 75 (1992) 499. O.A. Vanderpuye, C.A. Labarrere, J.A. McIntyre, The complement system in human reproduction, Am. J. Reprod Immunol. 27 (1992) 145. T.J. Oglesby, J.E. Longwith, P.C. Huettner, Human complement regulator expression by the normal female reproductive tract, Anat. Rec. 246 (1996) 78. C.L. Harris, N.K. Rushmere, B.P. Morgan, Molecular and functional analysis of mouse decay accelerating factor (CD55), Biochem. J. 341 (Pt. 3) (1999) 821. D.S. Holt, M.B. Powell, N.K. Rushmere, B.P. Morgan, Genomic structure and chromosome location of the gene encoding mouse CD59, Cytogenet. Cell Genet. 89 (2000) 264. L. Wang, M. Uchikawa, H. Tsuneyama, K. Tokunaga, K. Tadokoro, T. Juji, Molecular cloning and characterization of decay-accelerating factor deficiency in Cromer blood group Inab phenotype, Blood 91 (1998) 680. T. Matthes, E. Tullen, J. Poole, J. Banks, M. Nagy, M.J. Stelling, F. Boehlen, M. Michel, P. Beris, H. Hustinx, V. Crew, G. Daniels, Acquired and transient RBC CD55 deficiency (Inab phenotype) and anti-IFC, Transfusion 42 (2002) 1448. X. Qin, N. Krumrei, L. Grubissich, M. Dobarro, H. Aktas, G. Perez, J.A. Halperin, Deficiency of the mouse complement regulatory protein mCd59b results in spontaneous hemolytic anemia with platelet activation and progressive male infertility, Immunity 18 (2003) 217. S. Baalasubramanian, C.L. Harris, R.M. Donev, M. Mizuno, N. Omidvar, W.C. Song, B.P. Morgan, CD59a is the primary regulator of membrane attack complex assembly in the mouse, J. Immunol. 173 (2004) 3684. K.L. Simpson, C.H. Holmes, Differential expression of complement regulatory proteins decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59 during human spermatogenesis, Immunology 81 (1994) 452. R.C. Riley-Vargas, S. Lanzendorf, J.P. Atkinson, Targeted and restricted complement activation on acrosome-reacted spermatozoa, J. Clin. Invest. 115 (2005) 1241. M. Kurita-Taniguchi, K. Hazeki, N. Murabayashi, A. Fukui, S. Tsuji, M. Matsumoto, K. Toyoshima, T. Seya, Molecular assembly of CD46 with

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

CD9, alpha3-beta1 integrin and protein tyrosine phosphatase SHP-1 in human macrophages through differentiation by GM-CSF, Mol. Immunol. 38 (2002) 689. M. Nomura, M. Kitamura, K. Matsumiya, A. Tsujimura, A. Okuyama, M. Matsumoto, K. Toyoshima, T. Seya, Genomic analysis of idiopathic infertile patients with sperm-specific depletion of CD46, Exp. Clin. Immunogenet. 18 (2001) 42. N. Inoue, M. Ikawa, T. Nakanishi, M. Matsumoto, M. Nomura, T. Seya, M. Okabe, Disruption of mouse CD46 causes an accelerated spontaneous acrosome reaction in sperm, Mol. Cell. Biol. 23 (2003) 2614. C. Xu, D. Mao, V.M. Holers, B. Palanca, A.M. Cheng, H. Molina, A critical role for murine complement regulator crry in fetomaternal tolerance, Science 287 (2000) 498. D. Mao, X. Wu, C. Deppong, L.D. Friend, G. Dolecki, D.M. Nelson, H. Molina, Negligible role of antibodies and C5 in pregnancy loss associated exclusively with C3-dependent mechanisms through complement alternative pathway, Immunity 19 (2003) 813. T. Miwa, X. Sun, R. Ohta, N. Okada, C.L. Harris, B.P. Morgan, W.C. Song, Characterization of glycosylphosphatidylinositol-anchored decay accelerating factor (GPI-DAF) and transmembrane DAF gene expression in wild-type and GPI-DAF gene knockout mice using polyclonal and monoclonal antibodies with dual or single specificity, Immunology 104 (2001) 207. V.M. Holers, G. Girardi, L. Mo, J.M. Guthridge, H. Molina, S.S. Pierangeli, R. Espinola, L.E. Xiaowei, D. Mao, C.G. Vialpando, J.E. Salmon, Complement C3 activation is required for antiphospholipid antibody-induced fetal loss, J. Exp. Med. 195 (2002) 211. S. Rehrig, S.D. Fleming, J. Anderson, J.M. Guthridge, J. Rakstang, C.E. McQueen, V.M. Holers, G.C. Tsokos, T. Shea-Donohue, Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice, J. Immunol. 167 (2001) 5921. R.J. Quigg, Y. Kozono, D. Berthiaume, A. Lim, D.J. Salant, A. Weinfeld, P. Griffin, E. Kremmer, V.M. Holers, Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor, J. Immunol. 160 (1998) 4553. H.F. Weisman, T. Bartow, M.K. Leppo, H.C. Marsh Jr., G.R. Carson, M.F. Concino, M.P. Boyle, K.H. Roux, M.L. Weisfeldt, D.T. Fearon, Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis, Science 249 (1990) 146. H.F. Weisman, T. Bartow, M.K. Leppo, M.P. Boyle, H.C. Marsh Jr., G.R. Carson, K.H. Roux, M.L. Weisfeldt, D.T. Fearon, Recombinant soluble CR1 suppressed complement activation, inflammation, and necrosis associated with reperfusion of ischemic myocardium, Trans. Assoc. Am. Physicians 103 (1990) 64. Y. Sugita, K. Ito, K. Shiozuka, H. Suzuki, H. Gushima, M. Tomita, Y. Masuho, Recombinant soluble CD59 inhibits reactive haemolysis with complement, Immunology 82 (1994) 34. D.A. Fraser, C.L. Harris, A.S. Williams, M. Mizuno, S. Gallagher, R.A. Smith, B.P. Morgan, Generation of a recombinant, membrane-targeted form of the complement regulator CD59: activity in vitro and in vivo, J. Biol. Chem. 278 (2003) 48921. C.L. Harris, A.S. Williams, S.M. Linton, B.P. Morgan, Coupling complement regulators to immunoglobulin domains generates effective anti-complement reagents with extended half-life in vivo, Clin. Exp. Immunol. 129 (2002) 198. H.F. Zhang, J. Yu, E. Bajwa, S.L. Morrison, S. Tomlinson, Targeting of functional antibody-CD59 fusion proteins to a cell surface, J. Clin. Invest. 103 (1999) 55. C. He, M. Imai, H. Song, R.J. Quigg, S. Tomlinson, Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for C5b-9, J. Immunol. 174 (2005) 5750. C. Atkinson, H. Song, B. Lu, F. Qiao, T.A. Burns, V.M. Holers, G.C. Tsokos, S. Tomlinson, Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection, J. Clin. Invest. 115 (2005) 2444.