Skip to main content
Log in

Membrane signaling by complement C5b-9, the membrane attack complex

  • The Year in Complement
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The terminal complement complexes C5b-7, C5b-8 and C5b-9 are able to generate nonlethal cell signals. One universal consequence of a cell being targeted by C5b-8 or C5b-9 is an influx of Ca2+. In addition, other second messengers, including cAMP, inositol phosphate intermediates and arachidonate metabolites, are generated by the terminal complement complexes in specific cell types. In vivo, terminal complement complexes have been found in a wide variety of inflammatory processes in humans and in experimental animal models. Some of these models of inflammation putatively induced by terminal complement complexes have been tested in complement-deficient animals, and indeed no inflammation results, which supports the critical role of the terminal complement complexes in the pathogenesis of the lesion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shin M, Carney D: Cytotoxic action and other metabolic consequences of terminal complement proteins. Prog Allergy 1988;40:44–81.

    PubMed  CAS  Google Scholar 

  2. Morgan B: Effects of the membrane attack complex of complement on nucleated cells. Curr Top Microbiol Immunol 1992;178:115–140.

    PubMed  CAS  Google Scholar 

  3. Colten H: Tissue-specific regulation of inflammation. J Appl Physiol 1992;72:1–7.

    Article  PubMed  CAS  Google Scholar 

  4. Fries LF III, Frank MM: Molecular mechanisms of complement action; in Stamatoyannopoulos G, Nienhuis AW, Leder P, Majerus PW (eds): The Molceular Basis of Blood Diseases. Philadelphia, Saunders, 1987, chapt 13, pp 450–498.

    Google Scholar 

  5. Meri S, Pangburn M: Discrimination between activators and nonactivators of the alternative pathway of complement: Regulation via a sialic acid/polyanion binding site on factor H: Proc Natl Acad Sci USA 1990;87:3982–3986.

    Article  PubMed  CAS  Google Scholar 

  6. Lachmann P, Thompson R: Reactive lysis: The complement-mediated lysis of unsensitized cells. II. The characterization of activated reactor as C56 and the participation of C8 and C9. J Exp Med 1970;131: 643–657.

    Article  PubMed  CAS  Google Scholar 

  7. Baker P, Rubin L, Lint T, McLeod B, Gewurz H: Binding of the complement intermediate C56 to zymosan in acute phase sera. Clin Exp Immunol 1975;20:113–124.

    PubMed  CAS  Google Scholar 

  8. Hammer C, Nicholson A, Mayer M: On the mechanism of cytolysis by complement: Evidence on the insertion of the C3b and C7 subunits of the C5b, 6,7 complex into the phospholipid bilayer of the erythrocyte membrane. Proc Natl Acad Sci 1975;75:5076–5080.

    Article  Google Scholar 

  9. Bhakdi S, Tranum-Jensen J: Molecular nature of the complement lesion. Proc Natl Acad Sci USA 1978; 75:5655–5659.

    Article  PubMed  CAS  Google Scholar 

  10. Mayer MM: Mechanism of cytolysis by complement. Proc Natl Acad Sci USA 1972;69:2954–2958.

    Article  PubMed  CAS  Google Scholar 

  11. Ramm L, Whitlow M, Mayer M: The relationship between channel size and the number of C9 molecules in the C5b-9 complex. J Immunol 1985;134:2594–2599.

    PubMed  CAS  Google Scholar 

  12. Rumfeld W, Morgan B, Campbell A: The ninth complement component in rheumtoid arthritis, Behçet's disease and other rheumatic diseases. Br J Rheumatol 1986;25:266–270.

    Article  PubMed  CAS  Google Scholar 

  13. Bhakdi S: Functions and relevance of the terminal complement sequence; in Kazatchkine MD (ed): Complement and Immunologic Disease. London, Balliere Tindall, 1988, pp. 363–385.

    Google Scholar 

  14. Bhakd S, Kaflein R, Halstensen T, hugo F, Preissner K, Mollnes T: Compelement S-protein (vitronectin) is associated with cytolytic membrane-bound C5b-9 complexes. Clin Exp Immunol 1988;74: 459–464.

    Google Scholar 

  15. Lint T, Behrends C, Gewurz H: Serum lipoproteins and C567-INH activity. J Immunol 1977;119:883–889.

    PubMed  CAS  Google Scholar 

  16. Podack E, Kolb W, Müller-Eberhard H: The C5b-9 complex: Formation, isolation, and inhibition of its activity by lipoprotein and the S-protein of human serum. J Immunol 1978;120:1841–1848.

    PubMed  CAS  Google Scholar 

  17. Okada H, Nagami Y, Tahakashi K, Okada N, Hideshima T, Takizawa H, Kondo J: 20 kDa homologous restriction factor of complement resembles T cell activating protein. Biochem Biophys Res Commun 1989;162:1553–1559.

    Article  PubMed  CAS  Google Scholar 

  18. Sugita Y, Nakano Y, Tomita M: Isolation from human erythrocytes of a new membrane protein which inhibits the formation of complement transmembrane channels. J Biochem (Tokyo) 1988;104:633–637.

    CAS  Google Scholar 

  19. Davies A, Simmons DL, Hale G, Harrison RA, Tighe H, Lachmann PJ, Waldmann H: CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. J Exp Med 1989;170:637–654.

    Article  PubMed  CAS  Google Scholar 

  20. Holguin MH, Fredrick LR, Bernshaw NJ, Wilcox LA, Parker CJ: Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest 1989;84:7–17.

    Article  PubMed  CAS  Google Scholar 

  21. Hänsch GM, Schönermark S, Roelcke D: paroxysmal nocturnal hemoglobinuria type III: Lack of an erythrocyte membrane protein restricting the lysis by C5b-9. J Clin Invest 1987;80:7–12.

    Article  PubMed  Google Scholar 

  22. Zalman L, Wood M, Müller-Eberhard HJ: Isolation of a human erythrocyte membrane protein capable of inhibiting expression of homologous complement transmembrane channels. Proc Natl Acad Sci USA 1986; 83:6975–6979.

    Article  PubMed  CAS  Google Scholar 

  23. Carney D, Lang T, Shin M: Multiple signal messengers generated by terminal complement complexes and their role in terminal complement complex elimination. J Immunol 1990;145:623–629.

    PubMed  CAS  Google Scholar 

  24. Niculescu F, Rus H, Shin S, Lang T, Shin M: Generation of diacyglycerol and ceramide during homologous complement activation. J Immunol 1993;150:213–224.

    Google Scholar 

  25. Berridge M: Inositol triphosphate and calcium signalling. Nature 1993;361:315–325.

    Article  PubMed  CAS  Google Scholar 

  26. Morgan B, Dankert J, Esser A: Recovery of human neutrophils from complement attack: Removal of the membrane attack complex by endocytosis and exocytosis. J Immunol 1987;138:246–253.

    PubMed  CAS  Google Scholar 

  27. Koski C, Ramm L, Hammer C, Mayer M, Shin M: Cytolysis of nucleated cells by complement: Cell death displays multi-hit characteristics. Proc Natl Acad Sci USA 1983; 80:3816–3820.

    Article  PubMed  CAS  Google Scholar 

  28. Ramm L, Whitlow M, Koski C, Shin M, Mayer M: Elimination of complement channels from the plasma membranes of U937, a nucleated mammalian cell line: Temperature dependence of the elimination rate. J Immunol 1983;131:1411–1415.

    PubMed  CAS  Google Scholar 

  29. Halperin JA, Nicholson-Weller A, Brugnara C, Tosteson DC: Complement induces a transient increase in membrane permeability in unlysed erythrocytes. J Clin Invest 1988;82:594–600.

    Article  PubMed  CAS  Google Scholar 

  30. Halperin JA, Brugnara C, Nicholson-Weller A: Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes. J Clin Invest 1989;83:1466–1471.

    Article  PubMed  CAS  Google Scholar 

  31. Iida K, Whitlow M, Nussenzweig V: Membrane vesiculation protects erythrocytes from destruction by complement. J Immunol 1990;147:2638–2642.

    Google Scholar 

  32. Halperin JA, Taratuska A, Rynklewicz M, Nicholson-Weller A: Transient changes in erythrocyte membrane permeability are induced by sublytic amounts of the complement membrane attack complex (C5b-9). Blood 1993;81:200–205.

    PubMed  CAS  Google Scholar 

  33. Carney D, Koski C, Shin M: Elimination of terminal complement intermediates from the plasma membrane of nucleated cells: The rate of disappearance differs for cells carrying C5b-7 or C5b-8 or a mixture of C5b-8 with a limited number of C5b-9. J Immunol 1985;134:1804–1809.

    PubMed  CAS  Google Scholar 

  34. Campell AK, Morgan BP: Monoclonal antibodies demonstrate protection of polymorphonuclear leukocytes against complement attack. Nature 1985;317:164–166.

    Article  Google Scholar 

  35. Sims PJ, Wiedmer T: Repolarization of the membrane potential of blood platelets after complement damage: Evidence for a Ca++-dependent exocytotic elimination of C5b-9 pores. Blood 1986;68:556–561.

    PubMed  CAS  Google Scholar 

  36. Wiedmer T, Sims P: Participation of protein kinases in complement C5b-9 induced shedding of platelet plasma membrane vesicles. Blood 1991;78:2880–2886.

    PubMed  CAS  Google Scholar 

  37. Roberts P, Morgan B, Campbell A: 2-Chloroadenosine inhibits complement-induced reactive oxygen metabolite production and recovery of human polymorphonuclear leukocytes attacked by complement. biochem Biophys Res Commun 1985; 126:692–697.

    Article  PubMed  CAS  Google Scholar 

  38. Cybulsky A: Release of arachidonic acid by complement C5b-9 complex in glomerular epithelial cells. Am J Physiol 1991;261:F427-F436.

    PubMed  CAS  Google Scholar 

  39. Shirazi Y, McMorris FA, Shin ML: Arachidonic acid mobilization and phosphoinositide turnover by the terminal complement complex, C5b-9, in rat oligodendrocyte × C6 glioma cell hybrids. J Immunol 1989;142:4385–4391.

    PubMed  CAS  Google Scholar 

  40. Hänsch GM, Seitz M, Martinotti G, Betz M, Rauterberg EW, Gemsa D: Macrophages release arachidonic acid, prostaglandin E2, and thromboxane in response to late complement components. J Immunol 1984; 133:2145–2150.

    PubMed  Google Scholar 

  41. Imagawa DK, Barbour SE, Morgan BP, Wright TM, Shin HS, Ramm LE: Role of complement C9 and calcium in the generation of arachidonic acid and its metabolites from rat polymorphonuclear leukocytes. Mol Immunol 1987;24:1263–1271.

    Article  PubMed  CAS  Google Scholar 

  42. Seeger W, Hartmann R, Neuhoff H, Bhakdi S: Local complement activation, thromboxane-mediated vasoconstriction, and vascular leakage in isolated lungs: Rols of the terminal complement sequence. Am Rev Respir Dis 1989;139:88–99.

    PubMed  CAS  Google Scholar 

  43. Hänsch GM, Betz M, Gunther J, Rother KO, Sterzel B: The complement membrane attack complex stimulates the prostanoid production of cultured glomerular epithelial cells. Int Arch Allergy Appl Immunol 1988;85:87–93.

    PubMed  Google Scholar 

  44. Betz M, Seitz M, Hänsch GM: Thromboxane B2 synthesis in human platelets induced by the late complement components C5b-9. Int Arch Allergy Appl Immunol 1987;82:313–316.

    PubMed  CAS  Google Scholar 

  45. Imagawa D, Osifchin N, Ramm L, Koga P, Hammer C, Shin H, Mayer M: Release of arachidonic acid and formation of oxygenated derivatives after complement attack on macrophages: Role of channel formation. J Immunol 1986;136:4637–4643.

    PubMed  CAS  Google Scholar 

  46. Sandberg A, Raisz L, Wahl L, Simmons H: Enhancement of complement-mediated prostaglandin synthesis and bone resorption by arachidonic acid and inhibition by certisol. Prostaglandins Leukotrienes Med 1982;8:419–427.

    CAS  Google Scholar 

  47. Suttorp N, Bhakdi S: Terminal complement complex and endothelial cells. Z Kardiol 1989;78(suppl 6):140–142.

    PubMed  Google Scholar 

  48. Shirazi Y, Imagawa D, Shin M: Release of leukotriene B4 from sublethally injured oligodendrocytes by terminal complement complexes. J Neurochem 1987;48:271–278.

    Article  PubMed  CAS  Google Scholar 

  49. Peppelenbosh M, Tertoolen L, den Hertog J, de Laat S: Epidermal growth factor activates calcium channels by phospholipase A2/5-lipoxygenase-mediated leukotriene C4 production. Cell 1992;69:295–303.

    Article  Google Scholar 

  50. Green H, Barrow P, Goldberg B: Effect of antibody and complement on permeability control in ascites tumor cells and erythrocytes. J Exp Med 1959;110:699–713.

    Article  PubMed  CAS  Google Scholar 

  51. Biesecker G: The complement SC5b-9 complex mediates cell adhesion through a vitronectin receptor. J Immunol 1990;145:209–214.

    PubMed  CAS  Google Scholar 

  52. Suzuki S, Pierschbacher M, Hayman E, Nguyen K, Ohgren Y, Ruoslahti E: Domain structure of vitronectin: Alignment of active sites. J Biol Chem 1984;259:15307–15314.

    PubMed  CAS  Google Scholar 

  53. Suzuki S, Oldberg A, Hayman E, Pierschbacher M, Ruoslahti E: Complete amino acid sequence of human vitronectin deduced from cDNA: Similarity of cell attachment sites in vitroncetin and fibronectin. EMBO J 1985;4:2519–2524.

    PubMed  CAS  Google Scholar 

  54. Hallett M, Luizo J, Campbell A: Stimulation of Ca2+-dependent chemiluminescence in rat polymorphonuclear leukocytes by polystyrene beads and the non-lytic action of complement. Immunology 1981; 44:569–574.

    PubMed  CAS  Google Scholar 

  55. Lovett D, Hänsch G, Goppelt M, Resch K, Gemsa D: Activation of glomerular mesangial cells by the terminal membrane attack complex of complement. J Immunol 1987; 138:2473–2480.

    PubMed  CAS  Google Scholar 

  56. Sims P, Faioni E, Wiemer T, Shattil S: Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988;263:18205–18212.

    PubMed  CAS  Google Scholar 

  57. Sanders M, Alexander E, Koski C, Shin M, Sano Y, Frank M: Terminal complement complexes (SC5b-9) in cerebrospinal fluid in autoimmune nervous system diseases. Ann NY Acad Sci 1988;540:381–383.

    Article  Google Scholar 

  58. Engel A, Arahata KD: The membrane attack complex of complement at the endplate in myasthenia gravis. Ann NY Acad Sci 1987;505: 326–352.

    Article  PubMed  CAS  Google Scholar 

  59. Biesecker G: Membrane attack complex of complement as a pathologic mediator. Lab Invest 1983;49:237–249.

    PubMed  CAS  Google Scholar 

  60. Vanguri P, Shin M: Hydrolysis of myelin basic protein in human myelin by terminal complexes. J Biol Chem 1988;263:7228–7234.

    PubMed  CAS  Google Scholar 

  61. Dalakas M: Medical progress: Polymyositis, dermatomyositis, and inclusion body myositis. N Engl J Med 1991;325:1487–1497.

    PubMed  CAS  Google Scholar 

  62. Morgan B: Complement attack on nucleated cells: Resistance, recovery, and non-lethal effects. Biochem J 1989;264:1–14.

    PubMed  CAS  Google Scholar 

  63. Groggel G, Adler S, Rennke H, Couser W, Salant D: Role of the terminal complement pathway in experimental membranous nephropathy in the rabbit. J Clin Invest 1983; 2:1948–1957.

    Article  Google Scholar 

  64. Groggel G, Salant D, Darby C, Rennke H, Couser W: Role of the terminal complement pathway in the heterologous phase of anti-glomerular basement membrane nephritis in the rabbit. Kidney Int 1985;27:643–651.

    Article  PubMed  CAS  Google Scholar 

  65. Baker P, Ochi R, Johnsor SM, Campbell C, Campbell WG: Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am J Pathol 1989;135:185–194.

    PubMed  CAS  Google Scholar 

  66. Pruchno C, Burns M, Schulze M, Johnson R, Baker P, Alpers C, Couser W: Urinary excretion of the C5b9 membrane attack complex of complement is a marker of immune disease activity in autologous immune complex nephritis. Am J Pathol 1991;138:203–211.

    PubMed  CAS  Google Scholar 

  67. Adler A, Striker L, Striker G, Perkinson D, Hibbert J, Couser W: Studies of progressive glomerular sclerosis in the rat. Am J Pathol 1986;123:553–562.

    PubMed  CAS  Google Scholar 

  68. Mollnes T, Lea T, Mellbye O, Pable J, Grand O, Harboe M: complement activation in synovial fluid and tissue from patients with juvenile rheumatoid arthritis. Arthritis Rheum 1986;29:715–721.

    Article  PubMed  CAS  Google Scholar 

  69. Morgan B, Daniels R, Williams R: Measurement of membrane attack complex of complement in rheumatoid arthritis. Clin Exp Immunol 1988;73:473–478.

    PubMed  CAS  Google Scholar 

  70. Boom B, Out-Luiting C, Baldwin W, Westedt M, Daha M, Vermeer B: Membrane attack complex of complement in leukocytoclastic vasculitis of the skin: Presence and possible pathogenetic role. Arch Dermatol 1987;123:1192–1195.

    Article  PubMed  CAS  Google Scholar 

  71. Dalmasso A, Vercellotti G, Fischel R, Bolman R, Bach F, Platt J: Mechanism of complement activation in the hyperacute rejection of percine organs transplanted into primate recipients. Am J Pathol 1992;140: 1157–1166.

    PubMed  CAS  Google Scholar 

  72. Weisman H, Bartow T, Leppo M, Marsh HJ, Carson G, Concino M, Boyle M, Roux K, Weisfeldt M, Fearon D: Soluble human complement receptor type 1: In vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 1990;249:146–151.

    Article  PubMed  CAS  Google Scholar 

  73. Thomsen H, Schulz A, Bhakdi S: Immunohistochemical C5b-9 complement complex demonstration in early stages of myocardial necrosis using paraffin sections. Z Rechtsmed 1990;103:199–206.

    Article  PubMed  CAS  Google Scholar 

  74. Homeister J, Satoh P, Lucchesi B: Effects of complement activation in the isolated heart. Role of the terminal complement components. Circ Res 1992;71:303–319.

    PubMed  CAS  Google Scholar 

  75. Berger H, Taratuska A, Smith T, Halperin J: Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat. Am J Physiol 1993, in press.

  76. Halperin JA, Taratuska A, Nicholson-Weller A: Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells. J Clin Invest 1993;91(5):1974–1978.

    Article  PubMed  CAS  Google Scholar 

  77. Benzaquen L, Nicholson-Weller A, Halperin JA: Release of basic fibroblast growth factor and platelet-derived growth factor from endothelial cells by terminal complement proteins C5b-9: Role in atherosclerosis and other proliferative disorders. Submitted.

  78. Floege J, Eng E, Lindner V, Alpers C, Young B, Reidy M, Johnson R: Rat glomerular mesangial cells synthesize basic fibroblast growth factor: Release, upregulated synthesis, and mitogenicity in mesangial proliferative glomerulonephritis. J Clin Invest 1992;90:2362–2369.

    Article  PubMed  CAS  Google Scholar 

  79. Auda G, Holme E, Davidson J, Zoma A, Veitch J, Whaley K: Measurement of complement activation products in patients with chronic rheumatic diseases. Rheumatol Int 1990;10:185–189.

    Article  PubMed  CAS  Google Scholar 

  80. Niculescu F, Hugo F, Rus H, Vlaicu R, Bhakdi S: Quantitative evaluation of the terminai C5b-9 complement complex by ELISA in human atherosclerotic arteries. Clin Exp Immunol 1987;69:477–483.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicholson-Weller, A., Halperin, J.A. Membrane signaling by complement C5b-9, the membrane attack complex. Immunol Res 12, 244–257 (1993). https://doi.org/10.1007/BF02918256

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02918256

Key Words

Navigation