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Complement

Complement. Abdul Ghaffar Microbiology and Immunology. 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 functions. Host benefit: opsonization to enhance phagocytosis

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Complement

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  1. Complement Abdul Ghaffar Microbiology and Immunology

  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 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 apoptic cells • Host detriment: • Inflammation, anaphylaxis

  4. 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 Ab-coated r.b.c in a suspension • 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

  5. 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), • C1 receptor (CR1), protein-S (vitronectin)

  6. 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 on is C2b)

  7. 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

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

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

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

  11. 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

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

  13. 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

  14. Components of thealternative pathway D C3 B P

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

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

  17. C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a

  18. Bb C3b C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a C3a

  19. Bb Bb C3b C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

  20. Bb Bb C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

  21. C3b DAF CR1 Autologous cell membrane Control of spontaneousC3 activation via DAF DAF prevents the binding of factor B to C3b B

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

  23. DAF B b B b C3b C3b CR1 CR1 iC3b iC3b Control of spontaneousC3 activation via CR1 H I I DAF Autologous cell membrane

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

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

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

  32. 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

  33. C1r C1r C1s C1s C1q C1qrs breakdown C1Inh

  34. C1-inhibitor deficiency:angioedema

  35. Biological effects of C5a

  36. Opsonization and phagocytosis

  37. 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

  38. 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

  39. 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-C (C3-INA) C5b67 chemotaxis, attaches to other membranes protein-S Biological properties of C-activation products

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