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Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
Correspondence to DR. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8648; Fax: 81-3-5800-8806; E-mail: mnangaku-tky{at}umin.ac.jp
In this issue of JASN, Turnberg et al. (1) report that the manifestations of disease in an immune complex-mediated glomerulonephritis model are exacerbated in Cd59a knockout mice. Exacerbation was associated with an increase in C9 deposition in glomeruli, suggesting that the deficiency of Cd59a allowed greater C5b-9 deposition, which in turn led to more severe renal disease.
These findings are potentially of great importance. Complement activation plays a critical role in tissue injury, including various forms of glomerulonephritis (2,3) and tubulointerstitial injury (4,5). Against this, the host is endowed with rigorous regulatory mechanisms (6). The balance between acceleration and inhibition of complement activation is critical to whether complement activation leads to host defense or tissue injury of host organs. It therefore comes as no surprise that functional abnormality or deficiency of complement regulatory proteins in humans results in disorders characterized by excessive complement activation.
In humans and animals, genetic abnormalities of factor H, a soluble complement regulatory protein, induce membranoproliferative glomerulonephritis or hemolytic uremic syndrome (7,8). Deficiency of CD59, an important regulator of complement activation, which serves as the one and only membrane-bound inhibitor of C5b-9 formation, also results in a well-known hematologic disease, paroxysmal nocturnal hemoglobinuria (PNH). Deficiency of CD59 in combination with a lack of decay accelerating factor (DAF), a membrane-bound complement inhibitor at the C3/C5 convertase step, on erythrocytes is the cause of complement-mediated hemolysis in patients with PNH.
Is CD59 the most relevant complement regulatory protein to the pathogenesis of PNH? An isolated deficiency of DAF has been described in four human families that had an unusual blood group phenotype termed Inab (9,10). Despite the total absence of DAF on all circulating cells, none of the propositi had symptoms suggestive of PNH (11). In contrast, a man who had a global deficiency of CD59 due to a single nucleotide deletion in the CD59 gene expressed a severe PNH-like phenotype (12,13). Given that his is the only known case of selective CD59 deficiency, however, the evidence supporting a critical role of CD59 in vivo remains flimsy.
Using a neutralizing antibody, Matsuo and colleagues (14,15) performed various studies to elucidate the biologic role of CD59 in the kidney in rodents. Neutralization of renal CD59 function alone did not induce complement-mediated injury in healthy rats. However, any interpretation of experiments in rats and mice is confounded by the presence of Crry, a rodent-specific analog of DAF and membrane cofactor protein (MCP) that inhibits early complement activation; therefore, these data do not necessarily exclude a crucial role of complement activation regulation at the C5b-9 formation level.
In contrast, the suppression of CD59 significantly enhanced complement activation and exacerbated tissue injury in animals given a neutralizing antibody against a complement regulatory protein at the C3/C5 convertase level (16). Neutralization of CD59 has been shown to exacerbate disease manifestations in two different models of immune-mediated glomerular endothelial injury in rats (17,18). Passive Heymann nephritis, a model of membranous nephropathy in rats, is mediated by C5b-9 formation on podocytes, which is induced by administration of heterologous anti-Fx1A antibodies. Fx1A is a crude fraction of rat proximal tubule brush-border antigens, and Quigg and colleagues (19) showed that antibodies neutralizing complement regulatory proteins including CD59 in the rat glomerulus are required to induce complement activation and proteinuria. All these studies suggest that CD59 is essential when the upstream inhibitors of the complement cascade are overwhelmed by either excessive activation or loss of inhibitory function.
The study by Turnberg et al. (1) confirms and extends previous studies, demonstrating a protective role of Cd59a in immune renal injury utilizing genetically engineered mice. Mouse molecular genetics have enabled quite sophisticated study of the biologic role of various molecules, including complement components and complement regulatory proteins (20). Two groups, including ours, recently demonstrated exacerbation of the anti–glomerular basement membrane nephritis model by independent targeting of the DAF gene (21,22). Quigg and colleagues (23–25) also showed that overexpression of soluble Crry in transgenic mice protects the kidney against immune injury.
Cd59a knockout mice are phenotypically normal and do not develop spontaneous hemolytic anemia, despite the increased sensitivity of their erythrocytes to induced complement lysis (26,27). In the Turnberg et al. study (1), however, deficiency of Cd59a led to an increase in complement activation in association with more severe manifestations of nephrotoxic serum nephritis. This finding establishes a critical role of Cd59a in autoimmune kidney injury in vivo.
Is CD59 important only in immunologic disease? Acosta et al. (28) recently showed that CD59 is inhibited by glycation, the non-enzymatic attachment of glucose to amino acids in proteins, which occurs in diabetes mellitus as a consequence of hyperglycemia. Malfunction of CD59 may be important in the pathogenesis of non-immunologic tissue injury such as diabetic complications, including atherosclerosis and nephropathy.
Several questions remain. Two groups have independently developed Cd59a knockout mice. The Cd59a-deficient mice established by Morgan’s group, which was employed in this study, show spontaneous intravascular hemolysis (27). In contrast, Song’s gene-targeted animals show none of these signs, including differences in reticulocyte count or changes in plasma and urine hemoglobin level (26). Cd59b is expressed predominantly in the testes, and this is the rationale why Turnberg and colleagues used Cd59a knockout mice to study the functional role of CD59 in the kidney. However, mice with a targeted deletion of the Cd59b gene develop severe hemolytic anemia in addition to male infertility (29). It is likely that the relative roles of the different complement regulatory proteins, such as Cd59a, Cd59b, and DAF, in protecting self cells from complement attack vary depending on the tissue or site of complement attack as well as on the mechanism and degree of activation.
Why are studies on complement regulatory proteins of interest to clinical nephrologists? Recent progress in molecular biologic techniques has made feasible a variety of new approaches utilizing recombinant complement inhibitors. The first application of reagents produced by molecular techniques to the treatment of renal disease arising from perturbed complement activation in vivo was reported by Couser et al. nearly 10 yr ago (30). They demonstrated the efficacy of soluble complement receptor 1 (sCR1) in a variety of glomerulonephritis models in rats. Soluble Crry-IgG chimeric protein was also effective in models of immunologic glomerular diseases (31). Although soluble DAF was effective in vitro, its efficacy was marginal in vivo (32). While DAF-IgG chimera was less effective in vitro, probably due to steric constraints, DAF-Ig had a much extended half-life in the circulation compared with soluble DAF and was concomitantly more effective in vivo (33). Construction of chimeric complement regulatory proteins with a longer half-life in vivo may open the door to novel therapeutic approaches.
Recombinant soluble CD59 has also been found more effective in vitro than in vivo. Recent studies demonstrated that fusion of CD59 with IgG or CR2 targets these complement inhibitors to sites of disease and improves their efficacy (34,35).
The potential of using complement regulators to modify renal disease exists not just for acute immune injury. Our studies on C6-deficient rats demonstrated that amelioration of inappropriate complement activation also retards progression of chronic proteinuric renal disease (36,37). This field holds exciting promise and should lead to the development of novel therapeutic approaches not only in immunologic kidney disease but possibly also in chronic non-immunologic renal injury.
References
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