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Complement

Complement. Parham – Chapter 2, pp 33 – 42 Chapter 9, pp 272 - 275. Function of complement. Innate immunity - Recognition of microbial pathogens Opsonization of pathogens Recruitment of inflammatory cells Lysis and death of pathogens. Three complement activation pathways.

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Complement

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  1. Complement Parham – Chapter 2, pp 33 – 42 Chapter 9, pp 272 - 275 H. HogenEsch 2009

  2. Function of complement • Innate immunity - Recognition of microbial pathogens • Opsonization of pathogens • Recruitment of inflammatory cells • Lysis and death of pathogens H. HogenEsch 2009

  3. Three complement activation pathways H. HogenEsch 2009

  4. Complement pathways • Amplification • Factors produced by liver as zymogens • Different pathways converge onto C3 • C3 is complement factor of highest serum concentration (1.2 mg/ml) H. HogenEsch 2009

  5. C3  C3b H. HogenEsch 2009

  6. Formation of alternative C3 convertase H. HogenEsch 2009

  7. Action of alternative C3 convertase - amplification H. HogenEsch 2009

  8. Alternative pathway C3 spontaneous hydrolysis – “tickover” activated C3 (iC3) Hydrolysis of thioester bond iC3B Factor D Ba Soluble C3 convertase iC3Bb C3a C3bBb Alternative C3 convertase H. HogenEsch 2009

  9. Regulators of complement activation H. HogenEsch 2009

  10. Opsonization via C3b H. HogenEsch 2009

  11. Complement receptors H. HogenEsch 2009

  12. Activation of C5  terminal pathway H. HogenEsch 2009

  13. Terminal pathway  Membrane Attack Complex H. HogenEsch 2009

  14. Regulation of MAC H. HogenEsch 2009

  15. Potency: C5a > C3a > C4a Effects: Vasodilation, increased vascular permeability Smooth muscle contraction Mast cell degranulation Chemotaxis of neutrophils Anaphylatoxins H. HogenEsch 2009

  16. Ag/Ab complexes C1q, r, s C4 Serine proteases C4a C2 Mediators of inflammation C2b C3 convertase C4b2a C3 C3a C5 convertase C4b2bC3b Classical pathway H. HogenEsch 2009

  17. Ability of isotypes to activate complement pathway H. HogenEsch 2009

  18. Classical pathway of complement activation H. HogenEsch 2009

  19. Classical pathway activation by antibodies and CRP H. HogenEsch 2009

  20. Multiple IgG required for complement activation IgG H. HogenEsch 2009

  21. Amplification by alternative C3 convertase H. HogenEsch 2009

  22. C4 haplotype Absence of C4A (13%)  increased susceptibility to systemic lupus erythematosus. Absence of C4B (18%)  increased susceptibility to infections. H. HogenEsch 2009

  23. MBP – bacterial surface MASP1/MASP2 C4 C2 C4b2a Lectin pathway Mannose Binding Protein MBP-Associated Serine Protease H. HogenEsch 2009

  24. Role of erythrocyte CR1 H. HogenEsch 2009

  25. Clinical Case • Richard Crafton, 17 years old, had a severe attack of abdominal pain • Surgery – normal appendix, swollen jejunum • History: • prone to severe colic as infant, repeated abdominal pain since age 14 yrs. • severe swelling following minor injury • Lab tests: • Deficiency of C1-inhibitor • Low serum C4, normal C3 H. HogenEsch 2009

  26. Questions. • Which other complement component do you expect to be decreased? • Why do patients with hereditary angioneurotic edema not have increased susceptibility to infectious diseases? H. HogenEsch 2009

  27. Activation of Factor XII activation of kallikrein plasminogen plasmin kininogen bradykinin C2 kinin C2a activation of C1 C2 edema Inhibition by C1INH H. HogenEsch 2009

  28. Hereditary angioneurotic edema • Deficiency of C1INH • Autosomal dominant • Increase of bradykinin, decrease of C4 and C2 • Recurrent episodes of edema in the skin, GI tract, UG tract, and larynx • Abdominal, pelvic pain, suffocation H. HogenEsch 2009

  29. Clinical Case Morris Townsend (25 years old) was admitted to a hospital with pneumonia. This was his 28th admission to a hospital – previous diagnoses include pneumonia, sinusitis, middle ear infection, abscesses – all caused by pyogenic bacteria Normal lymphocyte count, normal immunoglobulin concentrations Serum level C3 27 mg/dl (normal 100-200), undetectable factor B. Absence of factor I. H. HogenEsch 2009

  30. Questions • The frequency of hospital admissions decreased when Morris grew older. Why? • What changes in complement levels would you expect upon infusion of factor I? H. HogenEsch 2009

  31. Factor I deficiency • Autosomal recessive • Increased susceptibility to infections caused by extracellular bacteria (Staphylococcus aureus, Proteus vulgaris, Pseudomonas aeruginosa, Haemophilus influenzae) H. HogenEsch 2009

  32. Paroxysmal nocturnal hemoglobinuria • Intermittent intravascular hemolysis • Defect of both CD59 and DAF (Glycosyl phosphatidyl inositol -anchored proteins) H. HogenEsch 2009

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