Complement:Terminal Pathway tence of fibrin oy human are cell adhesion molecules.mac affects vascular tone by References vaso ilator Byrne GW.McCurry KR.Martin MJ.McClellan SM.Platt JL and several diseases.In rheumatoid arthritis.the severity of joint disease correlates with complement activation in the Hugh TE163149-15 joint space and eviden Esser AF (1994)The membrane attack complex of en tory eicosanoids and cytokines from rheumatoid synovial dise the ov CA CB,and C9 e e) MAC forms on mvelin membranes undergoing autoim- kKMand M()Gemmof the gene mune attack and renders myelin basic protein more mistry38:5162-5166 myelin ephritic lesions in kidney. athero olog178:115 140 scleroti plaques and ischaemic myocardium. or comp order g4503-52 roxysmal ent. he olo em GPI lin ad Protei MM CD59and other comple nt regulatory proteins to the cel System in Health and Diseuse,pp.119-148.New York: membrane.The result is increased susceptibility to the ER and TschoppJ()Polymerization of the ninth MAC in particular tructure resembli sed by na the membrane c edings of the Narional Academy of Sciences of the USA79 venous thrombosis due to the p oagulant effects of and a general Further Reading SY MAC tio Flo severe reiection reaction that can quickly transplanted organ.Complement activation is initiated (ed.)(199 by binding of natural a dies to th s TC.Lublin DM,Ro Thi problem in the field of xenotransplantation where organs Clinical Aspects and Relevance to from phylogenetically disparate Morgan BP ()C Par s in Microbiolo urre of mor for Berlin:Sp -Verlag sion of infectious ao ents in relation to primate complement regulatory proteins such as DAF and CD59 re species- elective in their action and are most eftective complemer gy140:49-6 same sp mplemen planted organs from a pig is not adequately protected Health and dise .Ne York Marcel Dekker. from damage by human MAC.Efforts are underway to man PJ (19 2)Inn produce transgenic pigs that express human regulatory hews3123-42. ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net tence of fibrin clots. MACalso promotes attachment of leucocytes to endothelial cells by inducing expression of P selectin on the surface and the synthesis of E selectin, which are cell adhesion molecules. MACaffects vascular tone by stimulating release of prostaglandins (PGI2) that act as vasodilators. It also promotes de novo synthesis of thromboxanes (TxA2) that function as vasoconstrictors. MACis believed to have a role in the pathogenesis of several diseases. In rheumatoid arthritis, the severity of joint disease correlates with complement activation in the joint space and evidence indicates that MACattack and recovery is ongoing within the joint. MAChas also been shown to stimulate production and release of inflamma￾tory eicosanoids and cytokines from rheumatoid synovial cells and to stimulate collagenase synthesis in synovial fibroblasts. In demyelinating diseases of the central nervous system (e.g. multiple sclerosis), evidence suggests MACforms on myelin membranes undergoing autoim￾mune attack and renders myelin basic protein more susceptible to proteolytic degradation. It can also elicit pro-inflammatory responses in myelin-producing oligo￾dendrocytes as well as facilitate their lysis. MAChas been identified in glomerulonephritic lesions in kidney, athero￾sclerotic plaques and ischaemic myocardium. The hereditary haematological disorder paroxysmal nocturnal haemoglobinuria (PNH) is caused by an inability to synthesize the GPI linkage used to anchor CD59 and other complement regulatory proteins to the cell membrane. The result is increased susceptibility to the effects of complement activation and MACin particular. Manifestations of this disorder include haemolytic anae￾mia and haemoglobinuria caused by increased red cell lysis; venous thrombosis due to the procoagulant effects of MACon platelets and endothelial cells; and a general abnormality in the function of cells of the haematopoietic system, all of which lack normal CD59. MACalso has a role in hyperacute graft rejection, a severe rejection reaction that can quickly destroy a transplanted organ. Complement activation is initiated by binding of natural antibodies to the endothelium of the transplanted organ. This ultimately leads to thrombosis, interstitial oedema and necrosis. This is a significant problem in the field of xenotransplantation where organs from phylogenetically disparate species are grafted into recipients. Currently, the pig is being considered as a potential donor for human transplantations because of cost, ease of breeding and fewer concerns about transmis￾sion of infectious agents in relation to primates. However, complement regulatory proteins such as DAF and CD59 are species-selective in their action and are most effective against complement from the same species, i.e. homo￾logous complement. Thus, the endothelium in trans￾planted organs from a pig is not adequately protected from damage by human MAC. Efforts are underway to produce transgenic pigs that express human regulatory proteins on their cell surface, thus making their organs resistant to attack by human MAC(Byrne et al., 1997). References Byrne GW, McCurry KR, Martin MJ, McClellan SM, Platt JL and Logan JS (1997) Transgenic pigs expressing human CD59 and decay￾accelerating factor produce an intrinsic barrier to complement￾mediated damage. Transplantation 63: 149–155. DiScipio RG and Hugli TE (1985) The architecture of complement component C9 and poly(C9). Journal of Biological Chemistry 260: 14802–14809. Esser AF (1994) The membrane attack complex of complement: assembly, structure and cytotoxic activity. Toxicology 87: 229–247. Hobart MJ, Fernie BA and DiScipio RG (1995) Structure of the human C7 gene and comparison with the C6, C8A, C8B, and C9 genes. Journal of Immunology 154: 5188–5194. Kaufman KM and Sodetz JM (1994) Genomic structure of the human complement protein C8g: homology to the lipocalin gene family. Biochemistry 33: 5162–5166. Mold C(1998) Cellular responses to the membrane attack complex. In: Volanakis JE and Frank MM (eds) The Human Complement System in Health and Disease, pp. 309–325. New York: Marcel Dekker. Morgan BP (1992) Effects of the membrane attack complex on nucleated cells. Current Topics in Microbiology and Immunology 178: 115–140. Mu¨ller-Eberhard HJ (1986) The membrane attack complex of comple￾ment. Annual Reviews of Immunology 4: 503–528. Plumb ME and Sodetz JM (1998) Proteins of the membrane attack complex. In: Volanakis JE and Frank MM (eds) The Human Complement System in Health and Disease, pp. 119–148. New York: Marcel Dekker. Podack ER and Tschopp J (1982) Polymerization of the ninth component of complement (C9): formation of poly(C9) with a tubular ultrastructure resembling the membrane attack complex of comple￾ment. Proceedings of the National Academy of Sciences of the USA 79: 574–578. Further Reading Flower DR (1996) The lipocalin protein family: structure and function. Biochemical Journal 318: 1–14. Gallager RB (ed.) (1991) The biology of complement. Immunology Today (special issue), 12: 291–342. Liszewski MK, Farries TC, Lublin DM, Rooney IA and Atkinson JP (1996) Control of the complement system. Advances in Immunology 61: 201–283. Morgan BP (1990) Complement: Clinical Aspects and Relevance to Disease. London: Academic Press. Parker CM (ed.) (1992) Current Topics in Microbiology and Immunology, Vol. 178: Membrane Defenses Against Attack by Complement and Perforins. Berlin: Springer-Verlag. Platt JL (1998) New directions for organ transplantation. Nature 392 (supplement): 11–17. Stanley KK (1988) The molecular mechanism of complement C9 insertion and polymerisation in biological membranes. Current Topics in Microbiology and Immunology 140: 49–65. Volanakis JE and Frank MM (eds) (1998) The Human Complement System in Health and Disease. New York: Marcel Dekker. Wu¨rzner R, Orren A and Lachman PJ (1992) Inherited deficiencies of the terminal components of human complement. Immunodeficiency Re￾views 3: 123–147. Complement: Terminal Pathway 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net