Complement System


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Complement System

  1. 1. COMPLEMENT SYSTEM<br />Fe A. Bartolome, MD, FPASMAP<br />Department of Microbiology<br />Our Lady of Fatima University<br />
  2. 2. <ul><li>Consists of approx. 20 proteins that are present in normal human serum  synthesized mainly by liver
  3. 3. Heat-labile  inactivated by heating serum at 560C for 30 minutes
  4. 4. Able to augment the effects of other components of the immune system
  5. 5. Important component of innate host defenses</li></li></ul><li><ul><li>Three main effects:</li></ul>Lysis of cells (bacteria, allografts, tumor cells)<br />Generation of mediators of inflammation<br />Opsonization – enhancement of phagocytosis<br />
  6. 6. <ul><li>Sequential activation of complement components occurs via one of three pathways:</li></ul>Classic pathway<br />Lectin pathway<br />Alternative or Properdin pathway<br /><ul><li>Lectin and alternative pathways are more important the first time we are infected by microorganisms because antibody required to activate the classic pathway is not yet present</li></li></ul><li>Classic Pathway<br /><ul><li>Part of acquired or adaptive immunity
  7. 7. Activated by Ag-Ab complexes
  8. 8. Immunoglobulins involved: IgM and IgG (except IgG4)
  9. 9. Involves activation of C1
  10. 10. Composed of C1q, C1r, and C1s  binds to Fc portion of IgG and IgM
  11. 11. Requires calcium for activation</li></li></ul><li>Classic Pathway<br /><ul><li>Other activators include:</li></ul>Viruses – Murine and Retroviruses<br />Bacteria – Mycoplasma<br />Polyanions, especially bound to cations<br />a. PO43- - DNA, lipid A, cardiolipin<br />b. SO42- - dextran, heparin, chondroitin<br />Arrays of terminal mannan groups<br />
  12. 12. Classic Pathway<br />
  13. 13. Classic Pathway<br />
  14. 14. Classic Pathway<br />
  15. 15. Alternative Pathway<br /><ul><li>Also known as the Properdin Pathway
  16. 16. Part of innate immunity
  17. 17. Bypasses C1, C4, and C2
  18. 18. Does not require an antigen-binding protein
  19. 19. Does not wait for antibody to be formed for activation
  20. 20. Acts synergistically with the classical pathway</li></li></ul><li>Alternative Pathway<br /><ul><li>Usually activated by products of micro-organisms like endotoxin
  21. 21. Other activators include:</li></ul>Complexes containing IgA<br />Some virus-infected cells (e.g. EBV)<br />Many gram negative and gram positive organisms<br />Parasites – Trypanosomes, Leishmania<br />Dextran SO4<br />Erythrocytes<br />Carbohydrates (agarose)<br />
  22. 22. Alternative Pathway<br />
  23. 23. Alternative Pathway<br />
  24. 24. Lectin Pathway<br /><ul><li>Also known as the MBL Pathway
  25. 25. Activated by binding of mannose-binding lectin (or mannose-binding protein) to surface of microbes bearing mannan(polymer of the sugar mannose) in a calcium dependent manner
  26. 26. Binding causes activation of MASP (MBP- associated serine proteases)  cleave C2 and C4</li></li></ul><li>Lectin Pathway<br />
  27. 27. <ul><li>All three pathways lead to production of C3b  central molecule of complement cascade
  28. 28. Presence of C3b on surface of a microbe marks it as foreign and targets it for destruction
  29. 29. C3b with two important functions:</li></ul>Combines with other complement components to generate C5 convertase<br />Opsonizes bacteria<br />
  30. 30.
  31. 31.
  32. 32. Biologic Effects:<br />Opsonization<br /><ul><li>C3b & C1q; enhance phagocytosis</li></ul>Chemotaxis<br /><ul><li>C5a and C5,6,7 complex  attract neutrophils
  33. 33. C5a – enhance adhesiveness of neutrophils to the endothelium</li></ul>Anaphylatoxin (C3a, C4a, C5a)<br /><ul><li>Cause degranulation of mast cells
  34. 34. Bind directly to smooth muscles of bronchioles  bronchospasm</li></li></ul><li>Biologic Effects:<br />Cytolysis (MAC)<br /><ul><li>Disrupt the membrane & the entry of water and electrolytes into the cell</li></ul>Enhancement of antibody production<br /><ul><li>Binding of C3b to its receptors on the surface of activated B cells  enhanced antibody production</li></li></ul><li>
  35. 35. Regulation of Complement System<br />C1 inhibitor (C1-INH)<br /><ul><li>Important regulator of classic pathway
  36. 36. A serine protease inhibitor (serpin)
  37. 37. Irreversibly binds to and inactivates C1r and C1s, as well as MASP in lectin pathway</li></ul>Factor H<br /><ul><li>Regulate alternative pathway
  38. 38. Reduce amount of C5 convertase available
  39. 39. With both cofactor activity for the factor I- mediated C3b cleavage, and decay accelerating activity against C3bBb (C3 convertase)</li></li></ul><li>Regulation of Complement System<br />Properdin<br /><ul><li>Protects C3b and stabilizes C3 convertase</li></ul>Factor I<br /><ul><li>Cleaves cell-bound or fluid phase C3b and C4b  inactivates C3b and C4b</li></ul>Decay accelerating factor (DAF)<br /><ul><li>Glycoprotein on surface of human cells
  40. 40. Prevents assembly of C3bBb or accelerates disassembly of preformed convertase  no formation of MAC
  41. 41. Acts on both classical and alternative</li></li></ul><li>Regulation of Complement System<br />C4b-binding protein (C4BP)<br /><ul><li>Inhibits the action of C4b in classical pathway
  42. 42. Splits C4 convertase and is a cofactor for factor I</li></ul>Complement Receptor 1 (CR-1)<br /><ul><li>Co-factor for factor I, together with CD46</li></ul>Protectin (CD59) and Vitronectin (S protein)<br /><ul><li>Inhibits formation of MAC by binding C5b678
  43. 43. Present on “self” cells to prevent complement from damaging them</li></li></ul><li>
  44. 44. Clinical Aspects<br />Deficiency of C5-C8 & Mannan-binding lectin<br /><ul><li>Predispose to severe Neisseriabacteremia</li></ul>Deficiency of C3<br /><ul><li>Severe, recurrent pyogenic sinus & resp. tract infections</li></ul>Deficiency of C1 esterase inhibitor<br /><ul><li>Angioedema inc. capillary permeability and edema</li></ul>Deficiency of DAF<br /><ul><li>Increased complement-mediated hemolysis  paroxysmal nocturnal hemoglobinuria</li></li></ul><li>Clinical Aspects<br />Transfusion mismatches<br /><ul><li>Activation of complement  generate large amounts of anaphylatoxins & MAC  red cell hemolysis</li></ul>Autoimmune diseases<br /><ul><li>Immune complexes bind complement  low complement levels + activate inflammation  tissue damage</li></ul>Severe liver disease<br /><ul><li>Deficient complement proteins  predispose to infection with pyogenic bacteria</li></li></ul><li>Clinical Aspects<br />Factor I deficiency<br /><ul><li>Low levels of C3 in plasma due to unregulated activation of alternative pathway  recurrent bacterial infections in children
  45. 45. Mutations in factor I gene  implicated in development of Hemolytic Uremic Syndrome</li>