The complement system consists of approximately 20 proteins that are mainly synthesized by the liver and play an important role in innate immunity. It has three main effects: lysis of cells, generation of inflammatory mediators, and enhancement of phagocytosis. There are three pathways of complement activation: the classical, lectin, and alternative pathways. The classical pathway is part of acquired immunity and requires antigen-antibody complexes, while the lectin and alternative pathways are part of innate immunity and activate in response to microbial surfaces. Complement activation leads to opsonization and lysis of pathogens as well as inflammatory responses. The system is tightly regulated to prevent damage to host cells. Deficiencies in complement proteins predispose individuals to certain infections

1. COMPLEMENT SYSTEMFe A. Bartolome, MD, FPASMAPDepartment of MicrobiologyOur Lady of Fatima University

2. Consists of approx. 20 proteins that are present in normal human serum  synthesized mainly by liver

3. Heat-labile  inactivated by heating serum at 560C for 30 minutes

4. Able to augment the effects of other components of the immune system

5. Important component of innate host defensesThree main effects:Lysis of cells (bacteria, allografts, tumor cells)Generation of mediators of inflammationOpsonization – enhancement of phagocytosis

6. Sequential activation of complement components occurs via one of three pathways:Classic pathwayLectin pathwayAlternative or Properdin pathwayLectin 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 presentClassic PathwayPart of acquired or adaptive immunity

7. Activated by Ag-Ab complexes

8. Immunoglobulins involved: IgM and IgG (except IgG4)

9. Involves activation of C1

10. Composed of C1q, C1r, and C1s  binds to Fc portion of IgG and IgM

11. Requires calcium for activationClassic PathwayOther activators include:Viruses – Murine and RetrovirusesBacteria – MycoplasmaPolyanions, especially bound to cationsa. PO43- - DNA, lipid A, cardiolipinb. SO42- - dextran, heparin, chondroitinArrays of terminal mannan groups

12. Classic Pathway

13. Classic Pathway

14. Classic Pathway

15. Alternative PathwayAlso known as the Properdin Pathway

16. Part of innate immunity

17. Bypasses C1, C4, and C2

18. Does not require an antigen-binding protein

19. Does not wait for antibody to be formed for activation

20. Acts synergistically with the classical pathwayAlternative PathwayUsually activated by products of micro-organisms like endotoxin

21. Other activators include:Complexes containing IgASome virus-infected cells (e.g. EBV)Many gram negative and gram positive organismsParasites – Trypanosomes, LeishmaniaDextran SO4ErythrocytesCarbohydrates (agarose)

22. Alternative Pathway

23. Alternative Pathway

24. Lectin PathwayAlso known as the MBL Pathway

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. Binding causes activation of MASP (MBP- associated serine proteases)  cleave C2 and C4Lectin Pathway

27. All three pathways lead to production of C3b  central molecule of complement cascade

28. Presence of C3b on surface of a microbe marks it as foreign and targets it for destruction

29. C3b with two important functions:Combines with other complement components to generate C5 convertaseOpsonizes bacteria

32. Biologic Effects:OpsonizationC3b & C1q; enhance phagocytosisChemotaxisC5a and C5,6,7 complex  attract neutrophils

33. C5a – enhance adhesiveness of neutrophils to the endotheliumAnaphylatoxin (C3a, C4a, C5a)Cause degranulation of mast cells

34. Bind directly to smooth muscles of bronchioles  bronchospasmBiologic Effects:Cytolysis (MAC)Disrupt the membrane & the entry of water and electrolytes into the cellEnhancement of antibody productionBinding of C3b to its receptors on the surface of activated B cells  enhanced antibody production

35. Regulation of Complement SystemC1 inhibitor (C1-INH)Important regulator of classic pathway

36. A serine protease inhibitor (serpin)

37. Irreversibly binds to and inactivates C1r and C1s, as well as MASP in lectin pathwayFactor HRegulate alternative pathway

38. Reduce amount of C5 convertase available

39. With both cofactor activity for the factor I- mediated C3b cleavage, and decay accelerating activity against C3bBb (C3 convertase)Regulation of Complement SystemProperdinProtects C3b and stabilizes C3 convertaseFactor ICleaves cell-bound or fluid phase C3b and C4b  inactivates C3b and C4bDecay accelerating factor (DAF)Glycoprotein on surface of human cells

40. Prevents assembly of C3bBb or accelerates disassembly of preformed convertase  no formation of MAC

41. Acts on both classical and alternativeRegulation of Complement SystemC4b-binding protein (C4BP)Inhibits the action of C4b in classical pathway

42. Splits C4 convertase and is a cofactor for factor IComplement Receptor 1 (CR-1)Co-factor for factor I, together with CD46Protectin (CD59) and Vitronectin (S protein)Inhibits formation of MAC by binding C5b678

43. Present on “self” cells to prevent complement from damaging them

44. Clinical AspectsDeficiency of C5-C8 & Mannan-binding lectinPredispose to severe NeisseriabacteremiaDeficiency of C3Severe, recurrent pyogenic sinus & resp. tract infectionsDeficiency of C1 esterase inhibitorAngioedema inc. capillary permeability and edemaDeficiency of DAFIncreased complement-mediated hemolysis  paroxysmal nocturnal hemoglobinuriaClinical AspectsTransfusion mismatchesActivation of complement  generate large amounts of anaphylatoxins & MAC  red cell hemolysisAutoimmune diseasesImmune complexes bind complement  low complement levels + activate inflammation  tissue damageSevere liver diseaseDeficient complement proteins  predispose to infection with pyogenic bacteriaClinical AspectsFactor I deficiencyLow levels of C3 in plasma due to unregulated activation of alternative pathway  recurrent bacterial infections in children

45. Mutations in factor I gene  implicated in development of Hemolytic Uremic Syndrome