12 SISTEMA DO COMPLEMENTO

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SISTEMA DO COMPLEMENTO
Maria Imaculada Muniz-Junqueira
Imunologia Médica
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O que é o sistema do complemento?
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O que é o sistema do complemento?
Conjunto de proteínas (séricas e 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
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“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 a 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.
Peter Lachmann P, Complement before molecular biology. 
Molecular Immunology, 43: 496–508 ; 2006. 
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O sistema do complemento 
Imunidade Inata?
ou 
Imunidade Adquirida?
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Ramo efetor dos anticorpos
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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?
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Como o sistema do complemento é ativado?
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Kuby J, Immunology
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Via clássica de 
ativação do complemento 
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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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Via alternativa de 
ativação do complemento 
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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.
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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
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Kuby J, Immunology
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Kuby J, Immunology
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Regulation of C1 activity by C1 INH. C1 INH displaces C1r2s2 from C1q and terminates classical pathway activation.
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Edema angioneurótico hereditário: deficiência Inibidor C1 
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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
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Funções dos componentes do complemento
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Kuby J, Immunology
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Kuby J, Immunology
Imunocomplexos
Colesterol
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Burmester G-R, Pezzuto A, Color Atlas of Immunology
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Burmester G-R, Pezzuto A, Color Atlas of Immunology
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Burmester G-R, Pezzuto A, Color Atlas of Immunology
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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.
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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
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Via alternativa de 
ativação do complemento 
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Via clássica de 
ativação do complemento 
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Formação do complexo de ataque a membrana 
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Edema angioneurótico hereditário: deficiência Inibidor C1 
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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.
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Kuby J, Immunology
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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
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O que é o sistema do complemento?
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O que é o sistema do complemento?
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Imunidade Inata
Imunidade Adquirida
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Ramo efetor dos anticorpos
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Renee C. Duncan1, Lakshmi C. Wijeyewickrema1, Robert N. Pike. The initiating proteases of the complement system:
Controlling the cleavage. Biochimie 90 (2008) 387e395
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C1 binding to the Fc portions of IgM and IgG. C1 must bind to two or more Fc portions to initiate the complement cascade. The Fc portions of soluble pentameric IgM are not accessible to C1 (A). After IgM binds to surface-bound antigens, it undergoes a shape change that permits C1 binding and activation (B). Soluble IgG molecules will also not activate C1 because each IgG has only one Fc region (C), but after binding to cell surface antigens, adjacent IgG Fc portions can bind and activate C1 (D).
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Structure of C1. C1q consists of six identical subunits arranged to form a central core and symmetrically projecting radial arms. The globular heads at the end of each arm, designated H, are the contact regions for immunoglobulin. C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1rand C1s contain the catalytic domains of these proteins. One C1r2s2 tetramer wraps around the radial arms of the C1q complex in a manner that juxtaposes the catalytic domains of C1r and C1s.
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Renee C. Duncan1, Lakshmi C. Wijeyewickrema1, Robert N. Pike. The initiating proteases of the complement system:
Controlling the cleavage. Biochimie 90 (2008) 387e395
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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.
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LTC
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.)
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Regulation of C1 activity by C1 INH. C1 INH displaces C1r2s2 from C1q and terminates classical pathway activation.
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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.
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Regulation of formation of the MAC. The MAC is formed on cell surfaces as an end result of complement activation. The membrane protein CD59 and S protein in the plasma inhibit formation of the MAC.
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Funções
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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.
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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). 
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The early steps of complement activation by the alternative and classical pathways. The alternative pathway is activated by C3b binding to various activating surfaces, such as microbial cell walls, the classical pathway is initiated by C1 binding to antigen-antibody complexes, and the lectin pathway is activated by binding of a plasma lectin to microbes. The C3b that is generated by the action of the C3 convertase binds to the microbial cell surface or the antibody and becomes a component of the enzyme that cleaves C5 (C5 convertase) and initiates the late steps of complement activation. The late steps of all three pathways are the same (not shown here), and complement activated by all three pathways serves the same functions.
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Internal thioester bonds of C3 molecules. A schematic view of the internal thioester groups in C3 and their role in forming covalent bonds with other molecules is shown. Proteolytic cleavage of the α chain of C3 converts it into a metastable form in which the internal thioester bonds are exposed and susceptible to nucleophilic attack by oxygen (as shown) or nitrogen atoms. The result is the formation of covalent bonds with proteins or carbohydrates on the cell surfaces. C4 is structurally homologous to C3 and has an identical thioester group.
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The alternative pathway of complement activation. Soluble C3 in plasma undergoes slow spontaneous hydrolysis of its internal thioester bond, which leads to the formation of a fluid-phase C3 convertase (not shown) and the generation of C3b. If the C3b is deposited on the surfaces of microbes, it binds factor B and forms the alternative pathway C3 convertase. This convertase cleaves C3 to produce more C3b, which binds to the microbial surface and participates in the formation of a C5 convertase. The C5 convertase cleaves C5 to generate C5b, the initiating event in the late steps of complement activation.
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Via clássica The classical pathway of complement activation. Antigen-antibody complexes that activate the classical pathway may be soluble, fixed on the surface of cells (as shown), or deposited on extracellular matrices. The classical pathway is initiated by the binding of C1 to antigen-complexed antibody molecules, which leads to the production of C3 and C5 convertases attached to the surfaces where the antibody was deposited. The C5 convertase cleaves C5 to begin the late steps of complement activation.
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Formação do complexo de ataque a membrana Pathways of complement activation. The activation of the complement system may be initiated by three distinct pathways, all of which lead to the production of C3b (the early steps). C3b initiates the late steps of complement activation, culminating in the production of peptides that stimulate inflammation (C5a) and polymerized C9, which forms the membrane attack complex, so called because it creates holes in plasma membranes. The principal functions of major proteins produced at different steps are shown. The activation, functions, and regulation of the complement system are discussed in much more detail in Chapter 14.
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Edema angioneurótico hereditário
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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.
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