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Transcript
THE COMPLEMENT SYSTEM The complement system • The complement system is a set of plasma proteins that act in a cascade to attack and kill extracellular pathogens. • Approximately 30 components: – – – – activating molecules complement receptors regulator factors membrane proteins wich inhibit the lysis of host cells • Most of the complement proteins and glycoproteins are produced in the liver in an inactive form (zymogen). Activation is induced by proteolitic cleavage. Amplification of the complement cascade inactive precursors limited proteolysis enzyme activating surface Activating surface needed! Pathways of complement activation Cellular and Molecular Immunology, 7th ed., 2014 Elservier INITIATION OF THE CLASSICAL PATHWAY The C1 complex Collagen „legs” Gobular „heads” C1 is always present in serum but it can operate only on an activating surface Low affinity binding to the Fc region of antibody conformational change activation Multiple interaction with immune complexes C-reactive protein also activates the classical pathway At least two molecules of IgG bound to pathogens or soluble antigens are required to activate the complement cascade Different isotypes of antibodies activate the complement system differently Binding of IgM to antigen on a pathogen’s surface initiates the classical pathway of complement activation INITIATION OF THE LECTIN PATHWAY Glycosylation of proteins is different in various species Prokaryotic cells Eukaryotic cells Mannose Glucoseamine Mannose Galactose Neuraminic acid (sialic acid) Mannose-binding lectin and ficolin bind mannose and N-acetylglucosamin, respectively Cellular and Molecular Immunology, 7th ed., 2014 Elservier The activated MBL complex cleaves C4 and C2 to produce C4b and C2a, which associate to form the classical C3 convertase INITIATION OF THE ALTERNATIVE PATHWAY C3, the central component of the complement system Strong covalent binding (3 900 000 000 000 000 molecules/ml) Formation and action of the soluble C3 convertase that initiates the alternative pathway of complement activation Alternative pathway is instantly inactivated on eukariotic cell surfaces (in the presence of sialic acid molecules) C3b can derive from classical or the lectin pathway too Cellular and Molecular Immunology, 7th ed., 2014 Elservier The early steps of complement activation by the alternative, classical, and lectin pathways Complement receptors on phagocytes trigger the uptake and breakdown of C3b-coated pathogens C3a and C5a contribute to local inflammatory responses The membrane-attack complex (MAC) assembles to generate a pore in the lipid bilayer membrane Membrane attack complex (MAC) SUMMARY Complement receptors Cellular and Molecular Immunology, 7th ed., 2014 Elservier REGULATION OF THE COMPLEMENT SYSTEM C1 inhibitor (C1INH) binds to C1r and C1s and dissociates them from C1q C1 inhibitor (C1INH) permanently inhibits C1r and C1s Formation and stability of the alternative C3 convertase on cell surfaces is determined by complement control proteins Factor H inhibits binding of only Bb to C3b and is thus a regulator of the alternative but not the classical pathway DAF: decay-accelerating factor MCP: membrane cofactor protein DAF and MCP also disrupt C3 convertase C4b2a C4-binding protein (C4BP) can also serve as cofactor for factor I–mediated inhibition of C3 convertase CD59 prevents assembly of the membrane attack complex on human cells Regulation of complement system Factor I C1Inh DAF C4BP CR1 MCP LECTIN PATHWAY CD59 Properdin DAF positive feedback Fact-H CR1 MCP Factor I membrane protein soluble molecule Deficiencies of complement system – cascade molecules Deficiencies of regulatory molecules, receptors