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Complement

Complement. Complement: History. Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min. COMPLEMENT. Important Innate Immunity

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Complement

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  1. Complement

  2. Complement: History Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min

  3. COMPLEMENT • Important Innate Immunity • Complement - a system of non-specific proteins in normal human serum - ability to lyse or damage microbial cells or virally infected cells • Activated sequentially in a cascade

  4. COMPLEMENT • consists of about 21 serum proteins - liver being the main source • heat-labile - inactivated at 56o C for 30 min. • Main nine functional proteins C1, C2….C9

  5. Complement functions • Host benefit: • opsonization to enhance phagocytosis • phagocyte 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

  6. Proteins of the complementsystem (nomenclature) • C1(qrs), 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)

  7. 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.c • 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

  8. 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 in 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), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b)

  9. 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

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

  11. C1r C1r C1s C1s C1q C1qrs breakdown C1Inh

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

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

  14. 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

  15. Biological Activities of Classical Pathway Components

  16. Control of Classical Pathway Components

  17. C1-inhibitor deficiency:hereditary angioedema

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

  19. 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

  20. Components of thealternative pathway D C3 B P

  21. b i b C3a Spontaneous C3 activation Generation of C3 convertase D H2O B C3 C3 C3iBb complex has a very short half life

  22. C3b b b C3a C3-activationthe amplification loop If spontaneously-generated C3b is not degraded D B C3

  23. B C3b b B b b DAF CR1 Autologous cell membrane Control of spontaneousC3 activation via DAF DAF dislodges C3b-bound factor Bb

  24. 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

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

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

  27. C5a b C3b C4b C2 a Lytic pathwayC5-activation C5

  28. C7 C5 b Lytic pathwayassembly of the lytic complex C6

  29. C8 C6 C7 C5 b Lytic pathway:insertion of lytic complex into cell membrane C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9

  30. Biological effects of C5a

  31. Opsonization and phagocytosis

  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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