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SISTEMA DO COMPLEMENTO Maria Imaculada Muniz-Junqueira Imunologia Médica O que é o sistema do complemento? O que é o sistema do complemento? Conjunto de proteínas (séricas ou presentes na superfície das células) Naturalmente inativas Interagem entre si – cada proteína adquire atividade enzimática pela ação de outra protease (zimógeno). Funcionam de enzima para a próxima proteína da cadeia Altamente regulada Gera produtos com função microbicida “The destruction of the vibrios, the bacteriolysis, depends, according to Bordet, on the cooperation of two bodies. One is the thermostable antibody of bacteriolytic immunization formed in the immunized animal and present in its serum; the other exists already in the normal animal; it does not stand up to heating nor to preservation, and does not increase during immunization”. “A destruição dos vibriões, a bacteriólise, depende da cooperação de dois corpos. Um é o anticorpo bacteriolítico, termoestável, formado após a imunização do animal e presente em seu soro; o outro já existe no soro do animal normal; ele não resiste ao aquecimento nem à preservação, e não aumenta após a imunização” Jules Bordet (1870–1961), the director of the Pasteur Institute in Brussels, was awarded the Nobel Prize for Medicine for his work in 1919. Lachmann P, Complement before molecular biology. Molecular Immunology, 43: 496–508 ; 2006. O sistema do complemento Imunidade Inata? ou Imunidade Adquirida? Sistema do complemento faz parte do braço efetor dos anticorpos Duncan RC,Wijeyewickrema LC, Pike RN. The initiating proteases of the complement system: Controlling the cleavage. Biochimie,90; 387 a 395; 2008. Quais as vias de ativação do sistema do complemento? Como o sistema do complemento é ativado? Kuby J, Immunology Via clássica de ativação do complemento Via alternativa de ativação do complemento Late steps of complement activation and formation of the MAC. A schematic view of the cell surface events leading to formation of the MAC is shown. Cell-associated C5 convertase cleaves C5 and generates C5b, which becomes bound to the convertase. C6 and C7 bind sequentially, and the C5b,6,7 complex becomes directly inserted into the lipid bilayer of the plasma membrane, followed by stable insertion of C8. Up to 15 C9 molecules may then polymerize around the complex to form the MAC, which creates pores in the membrane and induces cell lysis. C5a released on proteolysis of C5 stimulates inflammation. Structure of the MAC in cell membranes. A. Complement lesions in erythrocyte membranes are shown in this electron micrograph. The lesions consist of holes approximately 100 Å in diameter that are formed by poly-C9 tubular complexes. B. For comparison, membrane lesions induced on a target cell by a cloned CTL line are shown in this electron micrograph. The lesions appear morphologically similar to complement-mediated lesions, except for a larger internal diameter (160 Å). CTL- and NK cell-induced membrane lesions are formed by tubular complexes of a polymerized protein (perforin), which is homologous to C9 (see Chapter 13). C. A model of the subunit arrangement of the MAC is shown. The transmembrane region consists of 12 to 15 C9 molecules arranged as a tubule, in addition to single molecules of C6, C7, and C8 α and γ chains. The C5bα, C5bß, and C8ß chains form an appendage that projects above the transmembrane pore. (From Podack ER. Molecular mechanisms of cytolysis by complement and cytolytic lymphocytes. Journal of Cellular Biochemistry 30:133-170, 1986. Copyright 1986 Wiley-Liss. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) MAC LTC Kuby J, Immunology Kuby J, Immunology Regulation of C1 activity by C1 INH. C1 INH displaces C1r2s2 from C1q and terminates classical pathway activation. Edema angioneurótico hereditário: deficiência Inibidor C1 Inhibition of the formation of C3 convertases. Several membrane proteins present on normal cells displace either C2a from the classical pathway C3 convertase (A) or Bb from the alternative pathway C3 convertase (B) and stop complement activation. Hemoglobinúria paroxística noturna: DAF e CD59 não estão expressos na superfície das hemácias Funções dos componentes do complemento Funções dos componentes do complemento Kuby J, Immunology Kuby J, Immunology Imunocomplexos Colesterol Burmester G-R, Pezzuto A, Color Atlas of Immunology Burmester G-R, Pezzuto A, Color Atlas of Immunology Burmester G-R, Pezzuto A, Color Atlas of Immunology Role of complement in B cell activation. B cells express a complex of the CR2 complement receptor, CD19, and CD81. Microbial antigens that have bound the complement fragment C3d can simultaneously engage both the CR2 molecule and the membrane Ig on the surface of a B cell. This leads to the initiation of signaling cascades from both the BCR complex and the CR2 complex, because of which the response to C3d-antigen complexes is greatly enhanced compared with the response to antigen alone. Inhibition of the formation of C3 convertases. Several membrane proteins present on normal cells displace either C2a from the classical pathway C3 convertase (A) or Bb from the alternative pathway C3 convertase (B) and stop complement activation. Hemoglobinúria paroxística noturna: DAF e CD59 não estão expressos na superfície das hemácias Functions of complement. The major functions of the complement system in host defense are shown. Cell-bound C3b is an opsonin that promotes phagocytosis of coated cells (A); the proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation (B); and the MAC lyses cells (C). Funções dos componentes do complemento Via alternativa de ativação do complemento Via clássica de ativação do complemento Formação do complexo de ataque a membrana Edema angioneurótico hereditário: deficiência Inibidor C1 Factor I-mediated cleavage of C3b. In the presence of cell membrane-bound cofactors (MCP or CR1), plasma factor I proteolytically cleaves C3b attached to cell surfaces, leaving an inactive form of C3b (iC3b). Factor H and C4-binding protein can also serve as cofactors for factor I-mediated cleavage of C3b. The same process is involved in the proteolysis of C4. Kuby J, Immunology Nur’ain Salehen, Cordula Stover The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen. Vaccine (2008) 26, 451—459 Duncan RC,Wijeyewickrema LC, Pike RN. The initiating proteases of the complement system: Controlling the cleavage. Biochimie,90; 387 a 395; 2008.
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