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Complement

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Complement

  1. 1. Introduction • Complement – A series of serum and membrane expressed proteins involved in the effector role of the immune response to pathogens • Made up of approximately 30 circulating and membrane-bound proteins. • Synthesized in the liver and by cells involved in the inflammatory response.
  2. 2. Founders Jules Bordet & Paul Ehrlich
  3. 3. Key role in defense against many foreign invaders. • Most important functions are: • Production of opsonins • Production of anaphylatoxins • Direct killing of organisms • Enhancing antigen-specific immune response • Maintaining homeostasis
  4. 4. Complement Activation Pathways • Involves a “cascade” of successive components. • Enhances a small initiating signal. • Components are cleaved into activated fragments. • Fragments induce intense inflammatory responses to eliminate infectious agents.
  5. 5. Pathways of the complement activation • Distinct recognition events for each pathway – Classical - C-reactive protein – Lectin – Mannose-binding lectin (MBL) – Alternative – serum factors B, D, and P
  6. 6. The Classical Pathway • Antigen-Antibody complexes are main activators of this pathway. • Activated by the formation of soluble Ag- Ab complexes or binding of Ab (IgM or IgG) to Ag on a target cell. • C-reactive protein binds to the surface of many bacteria and are also activators.
  7. 7. Component Protein Complex C1
  8. 8. The C1 qrs complex
  9. 9. Classical Pathway
  10. 10. C4BP exclusively regulates the classical pathway
  11. 11. IgM Antibody
  12. 12. IgM and IgG molecules Binding
  13. 13. C1q binds to IgM and IgG molecules
  14. 14. Activation Effectiveness • IgM is more effective at activating complement than IgG • C1q binds to the CH2 domain of Ig and requires at least two adjacent Fc regions • Activation of the Thiol-Ester bond and covalent attachment to antigen
  15. 15. The Lectin Pathway • Antibody-independent pathway • Activated by mannose-binding lectin to mannose residues on foreign surface • Binding activates MASP-1 and MASP-2 that cleave and activate C4 and C2 • Cleaved C4 and C2 generate C3 convertase • Converges with the classical pathway at activation of C3
  16. 16. Mannose-binding Lectin Pathway
  17. 17. The Alternative Pathway • Does not require Ag-Ab complex formation • Initiated by foreign cell surface proteins • Produces active C3 and C5 convertase • Active C3 is generated spontaneously • Host cells regulate the progression
  18. 18. Alternative Pathway
  19. 19. Factor H exclusively regulates the alternative pathway
  20. 20. C3 and C5 convertases of each pathway
  21. 21. Activation of C3 • Cleavage of C3 is a critical step in all three pathways. • C3 convertases split C3 into two fragments: C3a---smaller, fluid-phase anaphylatoxin C3b---larger, continues the sequential activation of successive components
  22. 22. Activities of activated C3 • C3a promotes inflammation • C3b fixation to surfaces leads to opsonization • C3b fixation leads to immune complex clearance • Generation of the C5 Convertase activity
  23. 23. Activation of C5 • Cleavage of C5 produces two fragments: C5a---released into the fluid phase, potent anaphylatoxin C5b---binds to the cell surface, nucleus for binding the terminal complement components
  24. 24. The Terminal Sequence • Terminal components of the complement cascade: C5b, C6, C7, C8, and C9 • Components are common to all pathways • Bind to each other and form a MAC • Results in cell lysis
  25. 25. Formation of the membrane attack complex (MAC)
  26. 26. Formation of MAC
  27. 27. Polymerized C9 (poly-C9)
  28. 28. Poly-C9
  29. 29. The “MAC” Attack (membrane lesion – side on view)
  30. 30. Regulation Of Complement Activity • Regulators may: – dissociate the convertase – cleave the complement component that is left on the cell surface – Act as a cofactor for this cleavage
  31. 31. Why doesn’t complement attack our own tissues? • Inhibiting the classical pathway
  32. 32. Biological Activities Of Complement • Production of Opsonins • Production of Anaphylatoxins • Lysis of Cells • Enhancing B Cell Response to Antigens • Controlling the Formation and Clearance of Immune Complexes • Removing Dead and Dying Cells • Responses to Viruses
  33. 33. Enhancing B Cell Responses to Antigens
  34. 34. Removal of Immune Complexes
  35. 35. Removal of Necrotic cells and Subcellular Membranes
  36. 36. Responses to Viruses
  37. 37. Complement Proteins Neutralize Viruses
  38. 38. Uncoated Epstein-Barr Virus (EBV)
  39. 39. Complement Deficiencies • SLE – C1, C4, or C2 deficiencies • Membranoproliferative Glomerulonephritis – C3 deficiency, rare • Properdin and factor B and D defects
  40. 40. Complement deficiency and disease • C3 deficiency – severe, recurrent life- threatening infections with encapsulated microbes • C1 inhibitor deficiency – hereditary angioneurotic edema • C1, C2, C4 deficiency – autoimmune disease • DAF deficiency – paroxysmal nocturnal hemogloblinuria (PHN); RBC hemolysis
  41. 41. Detection of complementary deficiency by ELISA • Complement concentration in plasma reflects activity of the immune system – Activated complement components are unstable and extensive formation of immune complexes may deplete complement faster than it can be replaced by the liver. • Complement Fixation Assay – Detects immune complexes
  42. 42. The Assay Contains Three Components and Three Steps Components: 1. The test system • Incubate serum + test antigen 1. Complement • Add complement 1. The indicator system • Add the indicator system
  43. 43. Complement Fixation Assay (positive test)
  44. 44. Complement Fixation Assay (negative test)

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