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Chapter 6 Complement

Chapter 6 Complement

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Chapter 6 Complement

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  1. Chapter 6Complement

  2. The end of 19 century Jules Bordet (1870-1961)

  3. Fresh serum containing an antibacterial antibody was added to the bacteria at physiologic temperature (37℃),bacteria were lysed. • If the serum was heated to 56℃ or more , it lost its lytic capacity. • This loss of lytic capacity was not due to decay of antibody activity because antibodies are heat-stable and even heated serum was capable of agglutinating the bacteria. • Bordet concluded that the serum must contain another , heat-labile component that assists the lytic function of antibodies, and this component was later given the name “complement”

  4. Definition of complement system: A system of serum and cell surface proteins (including more than 30 proteins ) that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune response.

  5. Contents • PartⅠ The components and propertiesof complement system • Part Ⅱ Activation of complement system • Part Ⅲ Regulation of complement system • Part Ⅳ Complement receptors • Part Ⅴ Biological functions of complement • Part Ⅵ Complement and disease

  6. PartⅠ The components and propertiesof complement system (I) The components and nomenclature of complement system (II) Physical and chemical features of complement

  7. (I). The components and nomenclature of complement system • Components participating complement activation • Classical pathway: C1 (C1q,C1r,C1s),C2, C3, C4 • MBL(mannan-binding lectin) pathway: MBL, MASP( MBL-associated serine protease) • Alternative pathway: factor B, factor D • Common terminal pathway:C5,C6,C7,C8,C9

  8. 2.Regulatory components of complement system factorI, factor H, S protein, properdin(factor P), C1 inhibitor(C1 INH) , C4-binding protein(C4BP), SP40/40, membrane cofactor protein(MCP), decay accelerating factor(DAF), homologous restriction factor(HRF), membrane inhibitor of reactive lysis(MIRL) 3.Complement receptors CR1~CR5, C3aR, C2aR, C4aR, etc

  9. Nomenclature of the complement system • Intrinsic components in classical pathway:C1~C9 • Intrinsic components in alternative pathway: factor D • Regulatory proteins:C1INH,C4BP • Cleaved fragments:C3a, C3b; C2a, C2b • Activated components:C1 • Inactivated components:iC3b • Complement receptor:CR

  10. (Ⅱ). The physical and chemical features of complement 1. Synthesized sites: liver, macrophage, small intestine epithelium 2. The concentration of complement in serum is stable( 10% of serum proteins) , C3 is the highest in all of complement components:1~2 g/L 3. Heat–labile feature: 56℃ 30min—inactivation 0~10℃ for 3~5 days 4. The concentration of complement is the highest in the serum of guinea pig.

  11. PartⅡ Activation of the complement system • Thesoluble proteins of the complement system are synthesized in the liver and are secreted as non-active forms called zymogens. Zymogen: The cleavage is required for activation • The cleavage of a zymogen usually produces a large active fragment with enzymatic activity and a small fragment with inflammatory effects.

  12. Three different pathways of complement activation: 1.Classical pathway: from C1 by Ag-Ab 2.Alternative pathway: from C3 by the surface of microbe 3.MBL pathway: from C4 and C2 by binding of MBL mannan on the surface of microbes Terminal pathway : formation of MAC (membrane attack complex), same in the three pathways

  13. (C4b,2a) (C4b,2a,3b)

  14. Ⅰ. The Classical pathway of complement activation 1.Initiating substances: antigen-antibody complex or immune complex 2.Components: C1q ,C1r,C1s,C4,C2,C3,5,6,7,8,9 3.Process: C1q,C1r,C1s C4,C2,C3,5,6,7,8,9

  15. The process of complement activation in classical pathway: 1. Initiation step: recognizing unit (C1qrs), activated C1 2.Activation step: activating unit( C4,C2,C3), C3 convertase and C5 convertase 3. Effector step: membrane-attack complex (MAC) , C5~9

  16. 1. Initiation step recognizing unit (C1qrs) --- activated C1 • IgG1~3 and IgM can activate complement by classical pathway • The complement component C1 binds to the Fc part of the antibodies(CH2 of IgG or CH3 of IgM), and then is turned into activated C1 (C1)

  17. pentamer monomer

  18. C1q=6 6 2 C1r+2C1s+6C1q = C1

  19. C1q 2 C1r 2 C1s The first protein in the classical pathway is C1

  20. IgG The C1 must bind to at least two IgG molecules that are close enough together so that it can bind to both of them at the same time. • IgMThe C1 must bind at least 2 CH3 domains of one IgM molecule to be activated. IgM is the best complement activator because it is a pentamer.

  21. Bacteria with antigenic proteins on the surface

  22. After antibody binds to antigen on the surface of a pathogen,complement-binding sites are exposed

  23. IgM is the best activator of complement.

  24. C1 binds to at least two IgG molecules to be activated

  25. Binding of two or more of the C1q globular domains causes activation of C1r, which then make C1s activated.

  26. 2. Activation step Formation of C3 convertase(C4b2a) and C5 convertase(C4b2a3b)

  27. (1)Formation of C3 convertase(C4b2a) C1 C4,C2 C4b2a (C3 convertase) C4a,C2b

  28. C4 The activated C1 cleaves C4 into C4b and C4a.

  29. C4b C1 cleaves C4 to produce C4b and C4a. C4a The C4b fragment binds to the surface of the pathogen.

  30. C4b C1 then cleaves C2 into C2b and C2a. C2

  31. C4b The activated C1 then cleaves C2 into C2b and C2a. C2b C2a

  32. C4b and C2b together form the C3 convertase(C4bC2a) C2a C4b C3 convertase

  33. (2) Formation of C5 convertase C1 C4,C2 C4b2a (C3 convertase) C4a,C2b C3 C4b2a3b (C5 convertase) C3a • This is the most important step in the classical pathway

  34. C3 C3 C3 C3 convertase cleaves C3 to C3a and C3b C3 convertase

  35. C3 C3 C3 convertase cleaves C3 into C3a and C3b. C3a C3b C3 convertase

  36. C3b C3b The C3b covalently binds to C4b2a to form C4b2a3b complex,C5 convertase C3a C3a C5 convertase

  37. C4b2a C2b 4b2a

  38. C4b2a C4b2a C2a C4b,2a,3b C4b,2a,3b C4b,2a,3b

  39. IgM/IgG –Ag complex C1q : r : s Ca++ Ca++ Mg++ C4b + C2 C4 C4b2a (C3 convertase) C4b2a3b C4a C2b C3 C3b C3a Classical pathway (C5 convertase)

  40. 3. Effector step: Common terminal pathway Formation of the Membrane Attack Complex (MAC) MAC: a lytic complex of the terminal components of the complement cascade, including C5,6,7,8 and multiple copies of C9, that forms in the membrane of target cells. The MAC causes lethal ionic and osmotic changes in cells.