EDITORIALS J Am Soc Nephrol 14: 2411–2413, 2003 Complement Regulatory Proteins: Are They Important in Disease? MASAOMI NANGAKU Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. In this issue of JASN, Turnberg et al. (1) report that the deletion in the CD59 gene expressed a severe PNH-like phe- manifestations of disease in an immune complex-mediated notype (12,13). Given that his is the only known case of glomerulonephritis model are exacerbated in Cd59a knockout selective CD59 deficiency, however, the evidence supporting a mice. Exacerbation was associated with an increase in C9 critical role of CD59 in vivo remains flimsy. deposition in glomeruli, suggesting that the deficiency of Using a neutralizing antibody, Matsuo and colleagues Cd59a allowed greater C5b-9 deposition, which in turn led to (14,15) performed various studies to elucidate the biologic role more severe renal disease. of CD59 in the kidney in rodents. Neutralization of renal CD59 These findings are potentially of great importance. Comple- function alone did not induce complement-mediated injury in ment activation plays a critical role in tissue injury, including healthy rats. However, any interpretation of experiments in rats various forms of glomerulonephritis (2,3) and tubulointerstitial and mice is confounded by the presence of Crry, a rodent- injury (4,5). Against this, the host is endowed with rigorous specific analog of DAF and membrane cofactor protein (MCP) regulatory mechanisms (6). The balance between acceleration that inhibits early complement activation; therefore, these data and inhibition of complement activation is critical to whether do not necessarily exclude a crucial role of complement acti- complement activation leads to host defense or tissue injury of vation regulation at the C5b-9 formation level. host organs. It therefore comes as no surprise that functional In contrast, the suppression of CD59 significantly enhanced abnormality or deficiency of complement regulatory proteins complement activation and exacerbated tissue injury in animals in humans results in disorders characterized by excessive com- given a neutralizing antibody against a complement regulatory plement activation. protein at the C3/C5 convertase level (16). Neutralization of In humans and animals, genetic abnormalities of factor H, a CD59 has been shown to exacerbate disease manifestations in soluble complement regulatory protein, induce membranopro- two different models of immune-mediated glomerular endo- liferative glomerulonephritis or hemolytic uremic syndrome thelial injury in rats (17,18). Passive Heymann nephritis, a (7,8). Deficiency of CD59, an important regulator of comple- model of membranous nephropathy in rats, is mediated by ment activation, which serves as the one and only membrane- C5b-9 formation on podocytes, which is induced by adminis- bound inhibitor of C5b-9 formation, also results in a well- tration of heterologous anti-Fx1A antibodies. Fx1A is a crude known hematologic disease, paroxysmal nocturnal fraction of rat proximal tubule brush-border antigens, and hemoglobinuria (PNH). Deficiency of CD59 in combination Quigg and colleagues (19) showed that antibodies neutralizing with a lack of decay accelerating factor (DAF), a membrane- complement regulatory proteins including CD59 in the rat bound complement inhibitor at the C3/C5 convertase step, on glomerulus are required to induce complement activation and erythrocytes is the cause of complement-mediated hemolysis in proteinuria. All these studies suggest that CD59 is essential patients with PNH. when the upstream inhibitors of the complement cascade are Is CD59 the most relevant complement regulatory protein to overwhelmed by either excessive activation or loss of inhibi- the pathogenesis of PNH? An isolated deficiency of DAF has tory function. been described in four human families that had an unusual The study by Turnberg et al. (1) confirms and extends blood group phenotype termed Inab (9,10). Despite the total previous studies, demonstrating a protective role of Cd59a in absence of DAF on all circulating cells, none of the propositi immune renal injury utilizing genetically engineered mice. had symptoms suggestive of PNH (11). In contrast, a man who Mouse molecular genetics have enabled quite sophisticated had a global deficiency of CD59 due to a single nucleotide study of the biologic role of various molecules, including complement components and complement regulatory proteins (20). Two groups, including ours, recently demonstrated exac- Correspondence to DR. Masaomi Nangaku, Division of Nephrology and Endo- erbation of the anti–glomerular basement membrane nephritis crinology, 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: model by independent targeting of the DAF gene (21,22). [email protected] Quigg and colleagues (23–25) also showed that overexpression 1046-6673/1409-2411 of soluble Crry in transgenic mice protects the kidney against Journal of the American Society of Nephrology immune injury. Copyright © 2003 by the American Society of Nephrology Cd59a knockout mice are phenotypically normal and do not DOI: 10.1097/01.ASN.0000088010.15313.A1 develop spontaneous hemolytic anemia, despite the increased 2412 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2411–2413, 2003 sensitivity of their erythrocytes to induced complement lysis inappropriate complement activation also retards progression of (26,27). In the Turnberg et al. study (1), however, deficiency of chronic proteinuric renal disease (36,37). This field holds exciting Cd59a led to an increase in complement activation in associ- promise and should lead to the development of novel therapeutic ation with more severe manifestations of nephrotoxic serum approaches not only in immunologic kidney disease but possibly nephritis. This finding establishes a critical role of Cd59a in also in chronic non-immunologic renal injury. autoimmune kidney injury in vivo. Is CD59 important only in immunologic disease? Acosta et References al. (28) recently showed that CD59 is inhibited by glycation, 1. Turnberg D, Botto M, Warren J, Morgan BP, Walport MJ, Cook the non-enzymatic attachment of glucose to amino acids in HT CD59a deficiency exacerbates accelerated nephrotoxic ne- proteins, which occurs in diabetes mellitus as a consequence of phritis in mice. J Am Soc Nephrol 14: 2271–2279, 2003 hyperglycemia. Malfunction of CD59 may be important in the 2. Couser WG: Pathogenesis of glomerular damage in glomerulo- pathogenesis of non-immunologic tissue injury such as diabetic nephritis. Nephrol Dial Transplant 13[Suppl 1]: 10–15, 1998 complications, including atherosclerosis and nephropathy. 3. Couser WG: Pathogenesis of glomerulonephritis. Kidney Int Several questions remain. Two groups have independently 42[Suppl]: S19–26, 1993 developed Cd59a knockout mice. The Cd59a-deficient mice 4. Nangaku M: Final common pathways of progression of renal established by Morgan’s group, which was employed in this diseases. Clin Exp Nephrol 6: 182–189, 2002 study, show spontaneous intravascular hemolysis (27). In con- 5. Nangaku M: Mechanisms of tubulointerstitial injury in the kid- trast, Song’s gene-targeted animals show none of these signs, ney. Intern Med 2003, in press 6. Nangaku M: Complement regulatory proteins in glomerulone- including differences in reticulocyte count or changes in phritis. Kidney Int 54, 1419–1428, 1998 plasma and urine hemoglobin level (26). Cd59b is expressed 7. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Wal- predominantly in the testes, and this is the rationale why port MJ, Botto M: Uncontrolled C3 activation causes membrano- Turnberg and colleagues used Cd59a knockout mice to study proliferative glomerulonephritis in mice deficient in complement the functional role of CD59 in the kidney. However, mice with factor H. Nat Genet 31, 424–428, 2002 a targeted deletion of the Cd59b gene develop severe hemolytic 8. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, anemia in addition to male infertility (29). It is likely that the Jozsi M, Neumann HPH, Remuzzi G, Zipfel PF: Mutations in relative roles of the different complement regulatory proteins, factor H reduce binding affinity of C3b and heparin and surface such as Cd59a, Cd59b, and DAF, in protecting self cells from attachment to endothelial cells in hemolytic uremic syndrome. complement attack vary depending on the tissue or site of J Clin Invest 111: 1181–1190, 2003 complement attack as well as on the mechanism and degree of 9. Lin RC, Herman J, Henry L, Daniels GL: A family showing inheritance of the Inab phenotype. Transfusion 28: 427–429, activation. 1988 Why are studies on complement regulatory proteins of in- 10. Telen MJ, Green AM: The Inab phenotype: Characterization of terest to clinical nephrologists? Recent progress in molecular the membrane protein and complement regulatory defect. Blood biologic techniques has made feasible a variety of new ap- 74: 437–441, 1989 proaches utilizing recombinant complement inhibitors. The 11. Reid ME, Mallinson G, Sim RB, Poole J, Pausch V, Merry AH, first application of reagents produced by molecular techniques Liew YW, ReTanner MJ: Biochemical studies on red blood cells to the treatment of renal disease arising from perturbed com- from a patient with the Inab phenotype (decay-accelerating factor plement activation in vivo was reported by Couser et al. nearly