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Complement

Complement. Complement: History. Discovered in 1894 by Bordet It was used to refer to a heat-labile serum component Its lytic activity destroyed when heated at 56°C for 30 min However it is now known that complement contributes to many other functions. Complement Functions. Host benefit:

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Complement

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  1. Complement

  2. Complement: History Discovered in 1894 by Bordet It was used to refer to a heat-labile serum component Its lytic activity destroyed when heated at 56°C for 30 min However it is now known that complement contributes to many other functions

  3. Complement Functions • Host benefit: • opsonization to enhance phagocytosis • phagocytes attraction and activation • lysis of bacteria and infected cells • regulation of antibody responses • clearance of immune complexes • clearance of apoptotic cells • Host detriment: • Inflammation, anaphylaxis

  4. Proteins of the complementsystem • Complement comprises over 20 different serum proteins • These proteins are produced by a variety of cells: • Hepatocytes, macrophages, gut epithelial cells • Some components can bind to Immunoglobulins • While others are proenzymes that when activated can cleave and activate other components

  5. Proteins of the complementsystem (nomenclature) • C1(q r s), C2, C3, C4, C5, C6, C7, C8, C9 • factors B, D, H and I, properdin (P) • mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) • C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), Complement receptor 1 (CR1), protein-S (vitronectin)

  6. Definitions • C-activation: alteration of C proteins such that they interact with the next component • C-fixation: utilization of C by Ag-Ab complexes • Hemolytic units (CH50): dilution of serum which lyses 50% of a standardized suspension of Ab-coated R.B.Cs • C-inactivation: denaturation (usually by heat) of an early C-component resulting in loss of hemolytic activity • Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component

  7. Activated component are usually over-lined: e.g. C1qrs Activation product of complement proteins (nomenclature) When enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released into the microenvironment Letter “b” is usually added to the larger,membrane-binding, peptide and “a” to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a) EXCEPTION: C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b)

  8. antibody independent antibody dependent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY Pathways of complement activation LECTIN PATHWAY ALTERNATIVE PATHWAY CLASSICAL PATHWAY

  9. C1r C1s C1q Ca++ Components of the Classical Pathway C4 C2 C3 C1 complex

  10. C4a C1r C1s C1q b Ca++ Classical Pathway Generation of C3-convertase C4

  11. C2b C1r C1s a C1q Ca++ C2 a Classical Pathway Generation of C3-convertase C2 C4a _____ C4b2a is C3 convertase Mg++ C4b

  12. C1r C3a C1s C1q Ca++ C2 a b Classical Pathway Generation of C5-convertase C2b C4a ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Mg++ C3 C4b

  13. Biological Activities of Classical Pathway Components

  14. Control of Classical Pathway Components

  15. Components of mannose-binding (lectin) pathway • Mannose Binding Lectin (MBL), • which binds to bacterial surface with mannose-containing polysaccharides • MBL associated serine proteases (MASP-1 MASP-2)

  16. MBL Components of mannose-binding lectin pathway C4 MASP2 C2 MASP1

  17. C2a C2a C2b C4a C4b C4b MBL Mannose-binding lectin pathway _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase C4 C2 MASP2 MASP1

  18. Components of thealternative pathway • C3 • factors B & D • properdin (P)

  19. Control and regulation of the alternative pathway • Factor I & H • DAF • Complement receptor 1

  20. The alternative pathway can be activated by: • Many gram-negative bacteria: Neisseria meningitidis and N. gonorrhoea • Some gram-positive bacteria • Certain viruses and parasites • Aggregated immunoglobulina(particularly IgA) the result is lysis of these organisms

  21. Activation of the alternative pathway • Spontaneous hydrolysis of C3 to produce C3i • C3i cleaves Factor B into Bb • The C3iBb complex acts as C3 convertase(has very short half life) • Once C3b is formed Factor B binds to it and becomes susceptible to cleavage by Factor D • C3bBb is a more stable C3 convertase which continues to generate more C3b(amplfication loop)

  22. Components of thealternative pathway D C3 B P

  23. C3c C3c C3dg C3dg C3b C3b I I iC3b iC3b Degradation of spontaneously produced C3b

  24. C3b stabilization andC5 activation • When C3b finds the appropriate surface it binds to factor B, which is cleaved by Factor D to produce C3 convertase(C3bBb) (which is more stable) • C3 convertase(C3bBb) is further stabilized by Poperdin

  25. C3a C3b finds an activator (protector) membrane C3b b b C3b stabilization andC5 activation This is stable C5 convertase of the alternative pathway D P B C3

  26. C3b regulation on self and activator surfaces C3b

  27. C2a C3b C4b C5-convertase of the two pathways C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway Bb C3b C3b

  28. Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway

  29. C8 C7 Components of the lytic pathway C6 C5 C 9

  30. Lytic pathway • C5-convertase (of the Classical and lectin Pathways or the Alternative Pathway) cleaves C5 into C5a & C5b • C5b associates with C6 &C7 and insrets into the cell membrane • Then C8 binds, followed by several molecules of C9 • C9 molecules form a pore in the membrane • C5bC6C7C8C9 is MAC

  31. Biological effects of C5a

  32. Product Biological Effects Regulation C2b (prokinin) edema C1-INH C3a (anaphylatoxin) carboxy-peptidase- B (C3-INA) mast cell degranulation; enhanced vascular permeability; anaphylaxis Biological properties of C-activation products

  33. Product Biological Effects Regulation C3b (opsonin) opsonization; phagocyte activation factors H & I C4a (anaphylatoxin) as C3, but less potent (C3-INA) C4b (opsonin) opsonization; phagocytosis C4-BP, factor I Biological properties of C-activation products

  34. Product Biological Effects Regulation C5a (chemotactic factor) anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release carboxy-peptidase-B (C3-INA) C5b67 chemotaxis, attaches to other membranes protein-S Biological properties of C-activation products

  35. Complement Deficiencies and DiseaseClassical Pathway

  36. Complement Deficiencies and DiseaseLectin Pathway

  37. Complement Deficiencies and DiseaseAlternative Pathway

  38. Complement Deficiencies and DiseaseAlternative Pathway cont.

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