Complement

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Complement

  1. 1. COMPLEMENT THE LINK BETWEEN NON-SPECIFIC AND SPECIFIC IMMUNITY
  2. 2. 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 is destroyed when heated at 56°C for 30 min </li></ul>The Nobel Prize in Physiology or Medicine 1919
  3. 3. resistant active immunization blood sample Bordet's Classical Experiment serum (antisera) Fresh serum Serum (Heat inactivated at 56º C)
  4. 4. Hans Joaquim Muller-Eberhard (May 5, 1927- March 3, 1998).
  5. 5. <ul><li>The first part of the immune system that meets invaders such as bacteria is a group of proteins called the complement system . These proteins flow freely in the blood and can quickly reach the site of an invasion where they can react directly with antigens - molecules that the body recognizes as foreign substances. When activated, the complement proteins can </li></ul><ul><li>trigger inflammation </li></ul><ul><li>attract eater cells such as macrophages to the area </li></ul><ul><li>coat intruders so that eater cells are more likely to devour them </li></ul><ul><li>kill intruders </li></ul>
  6. 6. 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 apoptotic cells </li></ul></ul><ul><li>Host detriment: </li></ul><ul><ul><li>Inflammation, anaphylaxis </li></ul></ul>
  7. 7. Complement Components <ul><li>Classical </li></ul><ul><li>C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 </li></ul><ul><li>Alternative </li></ul><ul><li>Factors B, D, H and I, properdin (P) </li></ul><ul><li>Lectin Pathway </li></ul><ul><li>Mannose binding protein (MBP), MASP-1 MASP-2 </li></ul>
  8. 8. Pathways of Complement Activation CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY Activation of C5 MEMBRANE ATTACK COMPLEX (MAC) antibody dependent (Ac-Ag) antibody Independent (No Ac-Ag) Activation of C3 and generation of C5 convertase
  9. 9. Classical Pathway. C1 C1r C1s 1 2 3 4 5 6 Collagen- like tails C1q
  10. 10. Classical Pathway. Intact C1
  11. 11. Classical Pathway. Intact C1
  12. 12. Classical Pathway. Interaction with Ac Ac Ac Cell membrane Ag
  13. 14. Classical Pathway Ab C1qrs C4 b C4a
  14. 15. Ab C1qrs C4 b C2 b a
  15. 16. C4b2b (C3 convertase) Ab C1qrs C2 b C4 b
  16. 17. The Third Component of the Complement (C3) <ul><li>It is the most important component of the complement </li></ul><ul><li>It is synthezised by the liver and the macrophages </li></ul><ul><li>It exists in high concentration in serum </li></ul><ul><li>C4b2b (C3 convertase) can activate as many as 200 C3 molecules </li></ul>C3 b
  17. 18. C2 b C4 b C3 C3 C3 C3
  18. 19. b C4b2b3b (C5 convertase) C2 b C4 b C3 C3 C3 C3 a
  19. 20. Generation of C5 convertase leads to the activation of the lytic pathway Lytic pathway
  20. 21. b C2 b C4 b C3 C3 b C5 b a C5 b a
  21. 22. b C8 C9 Lysis and cell death C5b C6 C7
  22. 23. Membrane Attack Complex
  23. 24. Membrane Attack Complex
  24. 26. Membrane Attack Complex
  25. 27. Membrane Attack Complex
  26. 29. Alternative Pathway C3 is spontaneously formed in serum C3 b C3 b C3 b C3 b C3 b C3 b
  27. 30. LPS LPS Bacterial surface Lipopolysaccharide C3 b C3 b
  28. 31. LPS Bacterial surface C3bBb (C3 convertase) b C8 C9 C3 b B a D C3 b P C5b C6 C7
  29. 33. Mannose-Binding Protein Pathway Macrophages
  30. 34. Mannose-Binding Protein Pathway Bacterial Surface (rich in carbohydrates) MBP MASP-1 MASP-2 C4 b C4a
  31. 35. Mannose-Binding Protein Pathway Bacterial Surface (rich in carbohydrates) MBP MASP-1 MASP-2 b C4 b C2 b a
  32. 38. Opsonization and Phagocytosis
  33. 39. Biological Effects of C5a
  34. 42. 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)
  35. 43. 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
  36. 44. 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
  37. 46. C1-inhibitor deficiency: angioedema

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