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. 1983 Jun 1;157(6):1885–1905. doi: 10.1084/jem.157.6.1885

Localization of the membrane attack complex (MAC) in experimental immune complex glomerulonephritis

PMCID: PMC2187033  PMID: 6343549

Abstract

The role of the membrane attack complex (MAC) as a mediator of renal tissue injury was evaluated in rats affected by bovine serum albumin (BSA)-induced immune complex glomerulonephritis. Immunofluorescence studies revealed concurrent deposits of IgG, BSA, C3, and the MAC along glomerular capillary walls, although the MAC manifested a more restricted distribution than that observed for immune complexes. Immunoelectron microscopic techniques were utilized to demonstrate immune complexes, C3, and the MAC within dense deposits in the subepithelial aspect of the basement membrane. Visceral epithelial foot processes were fused in areas overlying large dense deposits and exhibited intense staining for the MAC, lesser reactivity for C3 but IgG was absent from the foot process membranes. Smaller granular deposits of immune complexes, C3, and the MAC were observed in the subendothelial region of the lamina rara interna and the lamina densa. Immune complexes may activate the classical complement pathway causing diffuse injury to the glomerular basement membrane (GBM), allowing subepithelial accumulation of complexes. These observations implicate the MAC as a mediator of GBM and juxtaposed podocyte membrane injury, thereby contributing to disruption of the glomerular filtration barrier. IgG and C3 were demonstrated within tubulointerstitial regions on the surface of collagen fibers in close proximity to the tubular basement membrane (TBM) of proximal convoluted tubules. Within the TBM, C3 localization was prominent with diminished reactivity for the MAC, but IgG was not detectable. The demonstration of C3 and scant MAC deposits in the TBM of nonimmunized control rats without evidence of interstitial IgG and C3 deposits suggests that both nonimmune and immune processes play a role in the pathogenesis of extraglomerular lesions. Evidence derived from these morphologic studies indicates that the MAC is associated with injury to the GBM, foot process membranes of visceral epithelium, and the TBM. Further experiments designed to selectively enhance or inhibit the deposition of MAC and assess consequent renal dysfunction are required to substantiate hypotheses concerning the in vivo membranolytic potential of the MAC in experimental immune complex glomerulonephritis.

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Selected References

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  1. ANDRES G. A., SEEGAL B. C., HSU K. C., ROTHENBERG M. S., CHAPEAU M. L. Electron microscopic studies of experimental nephritis with ferritin-conjugated antibody. Localization of antigen-antibody complexes in rabbit glomeruli following repeated injections of bovine serum albumin. J Exp Med. 1963 Apr 1;117:691–704. doi: 10.1084/jem.117.4.691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arisz L., Noble B., Milgrom M., Brentjens J. R., Andres G. A. Experimental chronic serum sickness in rats. A model of immune complex glomerulonephritis and systemic immune complex deposition. Int Arch Allergy Appl Immunol. 1979;60(1):80–88. doi: 10.1159/000232325. [DOI] [PubMed] [Google Scholar]
  3. Bhakdi S., Tranum-Jensen J., Klump O. The terminal membrane C5b-9 complex of human complement. Evidence for the existence of multiple protease-resistant polypeptides that form the trans-membrane complement channel. J Immunol. 1980 May;124(5):2451–2457. [PubMed] [Google Scholar]
  4. Biesecker G., Katz S., Koffler D. Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis. J Exp Med. 1981 Dec 1;154(6):1779–1794. doi: 10.1084/jem.154.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Biesecker G., Lavin L., Ziskind M., Koffler D. Cutaneous localization of the membrane attack complex in discoid and systemic lupus erythematosus. N Engl J Med. 1982 Feb 4;306(5):264–270. doi: 10.1056/NEJM198202043060503. [DOI] [PubMed] [Google Scholar]
  6. Biesecker G., Müller-Eberhard H. J. The ninth component of human complement: purification and physicochemical characterization. J Immunol. 1980 Mar;124(3):1291–1296. [PubMed] [Google Scholar]
  7. Biesecker G., Podack E. R., Halverson C. A., Müller-Eberhard H. J. C5b-9 dimer: isolation from complement lysed cells and ultrastructural identification with complement-dependent membrane lesions. J Exp Med. 1979 Feb 1;149(2):448–458. doi: 10.1084/jem.149.2.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bohrer M. P., Baylis C., Robertson C. R., Brenner B. M., Troy J. L., Willis W. T. Mechanisms of the puromycin-induced defects in the transglomerular passage of water and macromolecules. J Clin Invest. 1977 Jul;60(1):152–161. doi: 10.1172/JCI108751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Boselli J. M., Macarak E. J., Clark C. C., Brownell A. G., Martinez-Hernandez A. Fibronectin: its relationship to basement membranes. I. Light microscopic studies. Coll Relat Res. 1981 Sep;1(5):391–404. doi: 10.1016/s0174-173x(81)80024-6. [DOI] [PubMed] [Google Scholar]
  10. Brentjens J. R., O'Connell D. W., Pawlowski I. B., Andres G. A. Extra-glomerular lesions associated with deposition of circulating antigen-antibody complexes in kidneys of rabbits with chronic serum sickness. Clin Immunol Immunopathol. 1974 Sep;3(1):112–126. doi: 10.1016/0090-1229(74)90028-2. [DOI] [PubMed] [Google Scholar]
  11. Carlo J. R., Nagle R. B., Shin M. L. The nature of the receptor for complement (C3b) in the human renal glomerulus. Am J Clin Pathol. 1978 May;69(5):486–493. doi: 10.1093/ajcp/69.5.486. [DOI] [PubMed] [Google Scholar]
  12. Caulfield J. P., Farquhar M. G. Loss of anionic sites from the glomerular basement membrane in aminonucleoside nephrosis. Lab Invest. 1978 Nov;39(5):505–512. [PubMed] [Google Scholar]
  13. Cines D. B., Lyss A. P., Bina M., Corkey R., Kefalides N. A., Friedman H. M. Fc and C3 receptors induced by herpes simplex virus on cultured human endothelial cells. J Clin Invest. 1982 Jan;69(1):123–128. doi: 10.1172/JCI110422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cochrane C. G., Koffler D. Immune complex disease in experimental animals and man. Adv Immunol. 1973;16(0):185–264. doi: 10.1016/s0065-2776(08)60298-9. [DOI] [PubMed] [Google Scholar]
  15. DIXON F. J., FELDMAN J. D., VAZQUEZ J. J. Experimental glomerulonephritis. The pathogenesis of a laboratory model resembling the spectrum of human glomerulonephritis. J Exp Med. 1961 May 1;113:899–920. doi: 10.1084/jem.113.5.899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Daha M. R., Stuffers-Heiman M., Kijlstra A., van Es L. A. Isolation and characterization of the third component of rat complement. Immunology. 1979 Jan;36(1):63–70. [PMC free article] [PubMed] [Google Scholar]
  17. Dierich M. P., Mussel H. H., Scheiner O., Ehlen T., Burger R., Peters H., Schmitt M., Trepke S., Zimmer G. Differentiation of C3b receptors on human lymphocytes, phagocytes, erythrocytes and renal glomerulus cells by monoclonal antibodies. Immunology. 1982 Jan;45(1):85–96. [PMC free article] [PubMed] [Google Scholar]
  18. FARQUHAR M. G., PALADE G. E. Glomerular permeability. II. Ferritin transfer across the glomerular capillary wall in nephrotic rats. J Exp Med. 1961 Nov 1;114:699–716. doi: 10.1084/jem.114.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. FARQUHAR M. G., WISSIG S. L., PALADE G. E. Glomerular permeability. I. Ferritin transfer across the normal glomerular capillary wall. J Exp Med. 1961 Jan 1;113:47–66. doi: 10.1084/jem.113.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. FISHER E. R., HELLSTROM H. R. Mechanism of proteinuria: Functional and ultrastructural correlation of effects of infusion of homologous and heterologous protein (bovine serum albumin) in the rat. Lab Invest. 1962 Aug;11:617–637. [PubMed] [Google Scholar]
  21. Farquhar M. G. Editorial: The primary glomerular filtration barrier--basement membrane or epithelial slits? Kidney Int. 1975 Oct;8(4):197–211. doi: 10.1038/ki.1975.103. [DOI] [PubMed] [Google Scholar]
  22. Fearon D. T. Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte. J Exp Med. 1980 Jul 1;152(1):20–30. doi: 10.1084/jem.152.1.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. GREEN H., BARROW P., GOLDBERG B. Effect of antibody and complement on permeability control in ascites tumor cells and erythrocytes. J Exp Med. 1959 Nov 1;110:699–713. doi: 10.1084/jem.110.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gelfand M. C., Frank M. M., Green I. A receptor for the third component of complement in the human renal glomerulus. J Exp Med. 1975 Oct 1;142(4):1029–1034. doi: 10.1084/jem.142.4.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gelfand M. C., Shin M. L., Nagle R. B., Green I., Frank M. M. The glomerular complement receptor in immunologically mediated renal glomerular injury. N Engl J Med. 1976 Jul 1;295(1):10–14. doi: 10.1056/NEJM197607012950103. [DOI] [PubMed] [Google Scholar]
  26. Germuth F. G., Jr, Valdes A. J., Taylor J. J., Wise O., Rodriguez E. Fatal immune complex glomerulonephritis without deposits. Johns Hopkins Med J. 1975 May;136(5):189–192. [PubMed] [Google Scholar]
  27. Graham R. C., Jr, Karnovsky M. J. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: ultrastructural cytochemistry by a new technique. J Histochem Cytochem. 1966 Apr;14(4):291–302. doi: 10.1177/14.4.291. [DOI] [PubMed] [Google Scholar]
  28. Götze O., Müller-Eberhard H. J. Lysis of erythrocytes by complement in the absence of antibody. J Exp Med. 1970 Nov;132(5):898–915. doi: 10.1084/jem.132.5.898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson K. J., Ward P. A. Biology of disease. Newer concepts in the pathogenesis of immune complex-induced tissue injury. Lab Invest. 1982 Sep;47(3):218–226. [PubMed] [Google Scholar]
  30. Kazatchkine M. D., Fearon D. T., Appay M. D., Mandet C., Bariety J. Immunohistochemical study of the human glomerular C3b receptor in normal kidney and in seventy-five cases of renal diseases: loss of C3b receptor antigen in focal hyalinosis and in proliferative nephritis of systemic lupus erythematosus. J Clin Invest. 1982 Apr;69(4):900–912. doi: 10.1172/JCI110529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Koffler D., Schur P. H., Kunkel H. G. Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med. 1967 Oct 1;126(4):607–624. doi: 10.1084/jem.126.4.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kolb W. P., Müller-Eberhard H. J. Neoantigens of the membrane attack complex of human complement. Proc Natl Acad Sci U S A. 1975 May;72(5):1687–1689. doi: 10.1073/pnas.72.5.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Martinez-Hernandez A., Marsh C. A., Clark C. C., Macarak E. J., Brownell A. G. Fibronectin: its relationship to basement membranes. II. Ultrastructural studies in rat kidney. Coll Relat Res. 1981 Sep;1(5):405–418. doi: 10.1016/s0174-173x(81)80025-8. [DOI] [PubMed] [Google Scholar]
  34. Martinez-Hernandez A., Miller E. J., Damjanov I., Gay S. Laminin-secreting yolk sac carcinoma of the rat. Biochemical and electron immunohistochemical studies. Lab Invest. 1982 Sep;47(3):247–257. [PubMed] [Google Scholar]
  35. Matre R., Iversen B. M., Thunold S., Tønder O. Complement receptors in pathological human renal glomeruli. Scand J Immunol. 1978;7(5):399–404. doi: 10.1111/j.1365-3083.1978.tb00470.x. [DOI] [PubMed] [Google Scholar]
  36. Matre R., Tönder O. Complement receptors in human renal glomeruli. Scand J Immunol. 1976;5(4):437–441. doi: 10.1111/j.1365-3083.1976.tb00298.x. [DOI] [PubMed] [Google Scholar]
  37. Michael A. F., Blau E., Vernier R. L. Glomerular polyanion. Alteration in aminonucleoside nephrosis. Lab Invest. 1970 Dec;23(6):649–657. [PubMed] [Google Scholar]
  38. Moran J., Colasanti G., Amos N., Peters D. K. C3b receptors in glomerular disease. Clin Exp Immunol. 1977 May;28(2):212–217. [PMC free article] [PubMed] [Google Scholar]
  39. Müller-Eberhard H. J. Complement. Annu Rev Biochem. 1975;44:697–724. doi: 10.1146/annurev.bi.44.070175.003405. [DOI] [PubMed] [Google Scholar]
  40. Noble B., Milgrom M., Van Liew J. B., Brentjens J. R. Chronic serum sickness in the rat: influence of antigen dose, route of antigen administration and strain of rat on the development of disease. Clin Exp Immunol. 1981 Dec;46(3):499–507. [PMC free article] [PubMed] [Google Scholar]
  41. Podack E. R., Müller-Eberhard H. J. SC5b-9 complex of complement: formation of the dimeric membrane attack complex by removal of S-protein. J Immunol. 1980 Apr;124(4):1779–1783. [PubMed] [Google Scholar]
  42. Salant D. J., Belok S., Stilmant M. M., Darby C., Couser W. G. Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and aminonucleoside of puromycin on passive Heymann nephritis in rats. Lab Invest. 1979 Jul;41(1):89–99. [PubMed] [Google Scholar]
  43. Schreiber R. D., Morrison D. C., Podack E. R., Müller-Eberhard H. J. Bactericidal activity of the alternative complement pathway generated from 11 isolated plasma proteins. J Exp Med. 1979 Apr 1;149(4):870–882. doi: 10.1084/jem.149.4.870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Shin M. L., Gelfand M. C., Nagle R. B., Carlo J. R., Green I., Frank M. M. Localization of receptors for activated complement on visceral epithelial cells of the human renal glomerulus. J Immunol. 1977 Mar;118(3):869–873. [PubMed] [Google Scholar]
  45. Sobel A. T., Gabay Y. E., Lagrue G. Analysis of glomerular complement receptors in various types of glomerulonephritis. Clin Immunol Immunopathol. 1976 Jul;6(1):94–101. doi: 10.1016/0090-1229(76)90064-7. [DOI] [PubMed] [Google Scholar]
  46. Wiggins R. C., Bouma B. N., Cochrane C. G., Griffin J. H. Role of high-molecular-weight kininogen in surface-binding and activation of coagulation Factor XI and prekallikrein. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4636–4640. doi: 10.1073/pnas.74.10.4636. [DOI] [PMC free article] [PubMed] [Google Scholar]

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