Complement 2

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Complement 2

  1. 1. Complement: history <ul><li>Discovered in 1894 by Bordet </li></ul><ul><li>It represents lytic activity of fresh serum </li></ul><ul><li>Its lytic activity destroyed when heated at 56C for 30 min </li></ul>
  2. 2. Complement functions <ul><li>Host benefit: </li></ul><ul><ul><li>opsonization to enhance phagocytosis </li></ul></ul><ul><ul><li>phagocyte attraction and activation </li></ul></ul><ul><ul><li>lysis of bacteria and infected cells </li></ul></ul><ul><ul><li>regulation of antibody responses </li></ul></ul><ul><ul><li>clearance of immune complexes </li></ul></ul><ul><ul><li>clearance of apoptic cells </li></ul></ul><ul><li>Host detriment: </li></ul><ul><ul><li>Inflammation, anaphylaxis </li></ul></ul>
  3. 3. Definitions <ul><li>C-activation : alteration of C proteins such that they interact with the next component </li></ul><ul><li>C-fixation : utilization of C by Ag-Ab complexes </li></ul><ul><li>Hemolytic units : dilution of serum which lyses a proportion (usually 50%) of Ab-coated r.b.c (CH50) </li></ul><ul><li>C-inactivation : denaturation (usually by heat) of an early C-component resulting in C-hemolytic activity </li></ul><ul><li>Convertase/esterase : altered C-protein which acts as a proteolytic enzyme for another C-component </li></ul>
  4. 4. Proteins of the complement system (nomenclature) <ul><li>C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 </li></ul><ul><li>factors B, D, H and I, properdin (P) </li></ul><ul><li>mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) </li></ul><ul><li>C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), </li></ul><ul><li>C1 receptor (CR1), protein-S (vitronectin) </li></ul>
  5. 5. 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) Activated component are usually overlined: e.g. C1qrs
  6. 6. Pathways of complement activation CLASSICAL PATHWAY ALTERNATINE PATHWAY LECTIN PATHWAY activation of C5 LYTIC ATTACK PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase
  7. 7. Components of the Classical Pathway C4 C2 C3 C1 complex Ca ++ C1r C1s C1q
  8. 8. Classical Pathway Generation of C3-convertase C4 Ca ++ C1r C1s C1q C4a b
  9. 9. Classical Pathway Generation of C3-convertase C4b Mg ++ C4a C2 C4b2a is C3 convertase Ca ++ C1r C1s C1q C2b a C2 a
  10. 10. Classical Pathway Generation of C5-convertase C4b Mg ++ C4a C2b C3 C 4b2a3b is C 5 convertase; it leads into the Membrane Attack Pathway Ca ++ C1r C1s C1q C2 a C3a b
  11. 11. Components of mannose-binding lectin pathway C4 C2 MASP MASP2 MBL
  12. 12. Mannose-binding lectin pathway C4 C2 C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP MASP2 MBL C4b C4a C4b C2b C2a C2a
  13. 13. Components of the alternative pathway C3 B D P
  14. 14. Spontaneous C3 activation C3 H 2 O B D C3 Generation of C3 convertase This C3b molecule has a very short half life i C3a b b
  15. 15. C3-activation the amplification loop B D If spontaneously-generated C3b is not degraded C3 b C3b C3a b
  16. 16. C3-activation the amplification loop C3a B D C3 B b C3b b C3b C3a b
  17. 17. C3-activation the amplification loop C3a C3a C3 B D B b C3b C3b B b b b C3a C3b
  18. 18. C3-activation the amplification loop C3a C3a C3a B b C3b B b B b C3b C3b C3b
  19. 19. C3-activation the amplification loop C3a C3a C3a B b C3b B b B b C3b C3b
  20. 20. Control of spontaneous C3 activation via DAF DAF prevents the binding of factor B to C3b B C3b Autologous cell membrane DAF CR1
  21. 21. Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb B b b C3b Autologous cell membrane DAF CR1 B b
  22. 22. Control of spontaneous C3 activation via CR1 Autologous cell membrane H I I DAF C3b C3b B b iC3b B b iC3b CR1 DAF CR1
  23. 23. Degradation of spontaneously produced C3b C3b C3b iC3b iC3b I I C3dg C3dg C3c C3c
  24. 24. C3b stabilization and C5 activation C3 C5 B D P This leads to membrane attack pathway C3b C3b finds an activator (protector) membrane C3a b b C5a b
  25. 25. C5- convertase of the two pathways C3b B b C3b C5-convertase of the Alternative Pathway C5-convertase of the Classical and lectin Pathways C4b C2a C3b
  26. 26. Generation of C5 convertase leads to the activation of the Lytic pathway Lytic pathway
  27. 27. Components of the lytic pathway C6 C 9 C5 C8 C7
  28. 28. Lytic pathway C5-activation C5 C3b C2 a C4b b C5a
  29. 29. Lytic pathway assembly of the lytic complex C6 C5 b C7
  30. 30. 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 C5 b C6 C7 C8
  31. 31. C3b regulation on self and activator surfaces C3b
  32. 32. C1qrs breakdown C 1 I nh C1r C1s C1q C1r C1s
  33. 33. C1-inhibitor deficiency: angioedema Image unavailable due to copyright
  34. 34. Biological effects of C5a
  35. 35. Opsonization and phagocytosis
  36. 36. Biological properties of C-activation products Product Biological Effects Regulation C2b (prokinin) edema C1-INH C3a (anaphylatoxin) mast cell degranulation; enhanced vascular permeability; anaphylaxis carboxy-peptidase- B (C3-INA)
  37. 37. Biological properties of C-activation products Product Biological Effects Regulation as C3, but less potent (C3-INA) C4a (anaphylatoxin) opsonization; phagocytosis C4b (opsonin) C4-BP, factor I C3b (opsonin) opsonization; phagocyte activation factors H & I
  38. 38. Biological properties of C-activation products Product Biological Effects Regulation anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release C5a ( chemotactic factor ) carboxy-peptidase-C (C3-INA) C5b67 protein-S chemotaxis, attaches to other membranes

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