complement system

C3bBb
1. C3a
2. (C3b)2Bb
Classical pathway
1. C1
  1. C1q:(C1r: C1s)2
  2. C1q
    1. 6 subunit
    2. tail
      1. collagen-like
    3. Head
      1. Fc portion of Ab
      2. pathogen surface
      3. conformational change of C1q
      4. conformational change of C1r
      5. Cleave/Activate C1s
  3. C1r
    1. 2 C1r in a C1
    2. To cleave and activate C1s
  4. C1s
    1. 2 C1s in a C1
    2. inactivated by C1INH
    3. To cleave C4
      1. C4a
      2. C4b
      3. bind to the surface
      4. via thioester bond S-C=O
      5. S-C=O + R-OH --> S-H + R-C=O
      6. Or hydrolysis
      7. hydrolysis of thioester bond
      8. S-C=O + H2O --> S-H + COOH
      9. Inactive C4b
      10. C4b:C2
      11. by C1s
      12. C2a
      13. C2 kinin
      14. edema
      15. C4b2b
      16. C2b as serine protease
      17. cleaves ~1000 C3
      18. C3a
      19. proinflammation
      20. C3b
      21. coat the pathogen
      22. thioester bond, too
      23. Inactivation
      24. by DAF, C4BP, or CR1
      25. displace C2b on C4b
      26. by factor I
      27. C4c
      28. C4d
      29. C4b2b3b
      30. Inactivation
      31. CR1 and H displace C4b2b on C3b
      32. By factor I
      33. iC3b
      34. C4b2b3b5
      35. C5
      36. C5a
      37. stongly proinflammatory!!
      38. C5b
      39. C5b67
      40. membrane-bound by C7
      41. C5b678
      42. bind to C5b by C8beta
      43. insert to membrane by C8alpha-gamma
      44. induce polymerization of C9
      45. C5b6789
      46. polymerize of C9
      47. 10-16 molecule of C9
      48. MAC
      49. membrane-attack complex
      50. 10nm in diameter
      51. 15nm "high"
MBL pathway
1. mannose-binding lectin pathyway
2. MBL
  1. 2-6 heads
  2. MASP-1
    1. ?
  3. MASP-2
    1. homogenous to C1r and C1s
    2. cleave C4 and C2
3. MBL deficiency
  1. vulnerable to infection
Alternative pathway
1. C3
  1. C3(H2O)
    1. With factor B
    2. C3(H2O)B
      1. by factor D
      2. Ba
      3. C3(H2O)Bb
      4. Cleaves many C3
      5. C3a
      6. C3b
      7. mostly hydrolysis
      8. some bound to surface
      9. C3bB
      10. by factor D
      11. NOT a zymogen
      12. Circulating
      13. Ba
      14. function?
      15. C3bBb
      16. bound to host cell surface
      17. CR1
      18. complement receptor 1
      19. CD35
      20. compete with factor B for membrane-bound C3b
      21. Displace Bb on C3b
      22. C3bCR1
      23. by Factor I
      24. plasma
      25. iC3bCR1
      26. Factor H
      27. plasma
      28. compete with Bb for C3b
      29. displace Bb on C3b
      30. high affinity!!
      31. C3b-factor H-factor I
      32. iC3b
      33. by factor I
      34. C3dg
      35. DAF
      36. aka. CD55
      37. decay-accelerating factor
      38. Membrane-bound
      39. compete with factor B for membrane-bound C3b
      40. Displace Bb on C3b
      41. C3bDAF
      42. MCP
      43. membrane cofactor of proteolysis
      44. CD46
      45. C3bBbMCP
      46. by factor I
      47. iC3bBbMCP
      48. on pathogens
      49. Factor P
      50. properdin
      51. Binding to pathogen
      52. Stablize C3bBb
      53. Deficiency
      54. susceptible to Neisseria
      55. C3bBb-factorP
      56. C3a
      57. (many) C3b
Complement receptor
1. CR1
  1. complement receptor 1
  2. CD35
  3. ligand
    1. C3b, iC3b, C4b
  4. phagocytosis
    1. require C5a-C5a receptor costimulation
  5. Promote C3b, C4b decay
    1. iC3b
2. CR2
  1. CD21
  2. Ligand
    1. iC3b
    2. C3dg
      1. Augment B cell resonse if CR2-C3dg
  3. EBV receptor
  4. B cell co-receptor
    1. CR2-C3dg
  5. cell type
    1. B cell, follicular DC
3. CR3
  1. ligand
    1. iC3b
  2. CD11b:CD18
  3. phagocytosis
  4. No costimulation needed!
  5. Cell type
    1. Macrophage
    2. PMN
    3. follicular DC
4. CR4
  1. ligand
    1. iC3b
  2. CD11c:CD18
  3. phagocytosis
  4. Cell type
    1. Macrophage
    2. PMN
    3. DC
5. C5a receptor
  1. ligand
    1. C5a
  2. a G protein
  3. cell type
    1. macrophage
    2. mast cell
6. C3a receptor
  1. ligand
    1. C3a
  2. a G protein
  3. Cell type
    1. macrophage
    2. mast cell
Complement fragments
1. Anaphylatoxins
2. C5a
  1. strongly proinflammatory
  2. smooth muscle contraction
  3. increase vessel premeability
  4. induce adhesion molecules
    1. recruit neutrophil
    2. recruit monocyte
  5. Induce CR1 and CR3
  6. activate mast cell
  7. release histamine and TNF-alpha
Regulation
1. Inactivation of C1
  1. C1INH
    1. serpin
    2. C1 inhibitor
    3. bind to C1r:C1s
      1. dissociation with C1q
    4. C1INH deficiency
      1. hereditary angioneurotic edema
      2. C2a
      3. C2 kinin
      4. angioedema
      5. increased kallikrein
      6. induced by tissue damage
      7. inhibited by C1INH
      8. uncontrolled production of bradykinin
      9. Corrected by C1INH replacement
2. Inactivation of C4b2b
  1. DAF
  2. C4BP
  3. CR1
  4. displace C2b from C4b
    1. Protease I
      1. serum
      2. C4c
      3. C4d
3. Inactivation of C4b2b3b
  1. CR1
  2. Factor H
  3. displace C4b2b on C3b
    1. By factor I
    2. iC3b
      1. by factor I
      2. C3dg
4. Binding domain on C4b and C3b
  1. SCR
    1. short concensus repeat
  2. aka. CCP
    1. complement control protein
  3. aka, sushi domain
5. Inactivation of C5b67
  1. C8beta
    1. anchor it on the membrane
  2. protectin
    1. CD59
    2. with GPI tail
      1. glycosylphosphatydylinositol tail
      2. Mutation of GPI synthesis
      3. PNH
      4. paroxysmal nocturnal hemoglobinuria
      5. AIHA
    3. inhibit binding of C9 to C5b678