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Complement system done

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Complement

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Complement system done

  1. 1. COMPLEMENT SYSTEM DR. MALEEHA ASLAM
  2. 2. Complement system (nomenclature) • Protective cascading system- composed of 25 proteins • Can be activated via Classical and Alternate pathways • Culminates in three useful results– phagocytosis, lysis and inflammation • Classical pathway C1- C9= C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 • Alternate pathway = factors B, D, and IF, properdin (P) • C3b inactivator, anaphylotoxin inhibitors
  3. 3. Activation product of complement proteins (nomenclature) When enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released in the microenvironment Letter “b” is usually added to the larger, membrane-binding, peptide and “a” to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane- binding moiety is C2a; the smaller one is C2b) Activated component are usually over-lined: e.g. C1qrs
  4. 4. GENERAL PROPERTIES OF COMPLEMENT SYSTEM • PRESENT IN NORMAL SERA • DOES NOT INCREASE ON IMMUNIZATION • DESTROYED AT 56oC IN 30 MINUTES • NOT A SINGLE SUBSTANCE- COMPLEX • IN CLASSICAL PATHWAY- 9 PROTEINS COMPLEX • IN ALTERNATE PATHWAY- 13 PROTEINS COMPLEX • IgM, IgG-1,2,3 REACT WITH COMPLEMENT • ACTIVATION BY ANTIGEN ANTIBODY COMPLEX • ACTIVATION BY POLYSAC/ ENZYMES – ALTERNATE PATHWAY • INACTIVATORS AND INHIBITORS PRESENT IN SERUM
  5. 5. COMPLEMENT FUNCTIONS • Host benefit: – opsonization to enhance phagocytosis – phagocyte attraction and activation – lysis of bacteria and infected cells – regulation of antibody responses – clearance of immune complexes – clearance of apoptotic cells • Host detriment: – Inflammation, anaphylaxis
  6. 6. Pathways of complement activation CLASSICAL PATHWAY ALTERNATIVE PATHWAY activation of C5 LYTIC ATTACK PATHWAY antibody dependent LECTIN PATHWAY antibody independent Activation of C3 and generation of C5 convertase
  7. 7. CLASSICAL PATHWAY 3 GROUPS • RECOGNITION UNIT CI( C1q, C1r, C1s) •ACTIVATION COMPLEX C4,C2,C3 •MEMBRANE ATTACK COM C5,C6,C7,C8,C9 ALTERNATE PATHWAY IMPORTANT PROTEINS •FACTOR B- C3 PROACTIVATOR •FACTOR D- C3 PROACTIVATOR CONVERTASE – SPLIT FACTOR B
  8. 8. Activation of Complement
  9. 9. THE CLASSICAL AND ALTERNATE PATHWAYS
  10. 10. Components of the Classical Pathway C4C2 C3 C1 complex Ca++ C1r C1s C1q
  11. 11. Ca++ C1r C1s C1q C4 C4a b Classical Pathway Generation of C3-convertase
  12. 12. Generation of C3-convertase C4b Mg++ C4a Ca++ C1r C1s C1q C2 C2b a C2a _____ C4b2a is C3 convertase
  13. 13. Classical Pathway Generation of C5-convertase C4b Mg++ C4a Ca++ C1r C1s C1q C2b C2a C3 C3a b ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway
  14. 14. ALTERNATE PATHWAY
  15. 15. Components of the alternative pathway C3 B D P
  16. 16. Spontaneous C3 activation C3 H2O i B D Generation of C3 convertase C3iBb complex has a very short half life b C3 C3a b
  17. 17. B D bC3b If spontaneously-generated C3b is not degraded C3-activation the amplification loop C3C3a b
  18. 18. C3a C3a BbC3b C3bC3 BbB D bb C3a C3-activation the amplification loop C3b
  19. 19. C3a C3a BbC3b BbBbC3b C3a C3-activation the amplification loop C3bC3b
  20. 20. Control of spontaneous C3 activation via DAF C3b DAF prevents the binding of factor B to C3b B Autologous cell membrane DAF CR1
  21. 21. Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb Bbb C3b Autologous cell membrane DAF CR1 B b
  22. 22. C3b stabilization and C5 activation C3b C3b finds an activator (protector) membrane C3 C3a b B D b P This is stable C5 convertase of the alternative pathway
  23. 23. C5-convertase of the two pathways C3b Bb C3b C5-convertase of the Alternative Pathway C4b C2a C3b C5-convertase of the Classical and lectin Pathways
  24. 24. Generation of C5 convertase leads to the activation of the Lytic pathway Lytic pathway
  25. 25. Components of the lytic pathway C6 C 9 C8 C7 C5
  26. 26. Lytic pathway C5-activation C3b C2 aC4b C5 b C5a
  27. 27. Lytic pathway assembly of the lytic complex C5 b C6 C7
  28. 28. Lytic pathway: insertion of lytic complex into cell membrane C5 b C6 C7 C8 C 9 C 9 C 9 C 9C 9 C 9 C 9 C 9 C 9
  29. 29. Products and their Control Factors Fragment Activity Effect Control Factor (s) C2a Prokinin, accumulation of fluids Edema C1-INHIBITOR C3a Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction Anaphylaxis C3a-INACTIVATOR C3b Opsonin, phagocyte activation Phagocytosis Factors H and I C4a Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction Anaphylaxis (least potent)   C3a-INACTIVATOR C4b Opsonin Phagocytosis C4-BP and Factor I C5a Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction Anaphylaxis (most potent) C3a-INACTIVATORChemotaxis, stimulation of
  30. 30. Biological Activities of Classical Pathway Components Component Biological Activity C2b Prokinin; cleaved by plasmin to yield kinin, which results in edema C3a Anaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis C3b Opsonin Activation of phagocytic cells C4a Anaphylaotoxin C4b Opsonin
  31. 31. Product Biological Effects Regulation Biological properties of C-activation products anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release C5a (chemotactic factor) carboxy- peptidase-B (C3-INA) C5b67 protein-Schemotaxis, attaches to other membranes
  32. 32. Biological effects of C5a
  33. 33. Control of Classical Pathway Components Component Regulation All C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q C3a C3a-inactivator (C3a-INA; Carboxypeptidase B) C3b Factors H and I; Factor H facilitates the degradation of C3b by Factor I C4a C3a-INH C4b C4 binding protein (C4-BP) and Factor I; C4-BP facilitates degradation of C4b by Factor I; C4-BP also prevents the association of C2a with C4b thus blocking formation of C3 convertase
  34. 34. Complement deficiencies and disease Pathway/Component Disease Mechanism Classical Pathway      C1INH Hereditary angioedema Overproduction of C2b (prokinin)   C1, C2, C4 Predisposition to SLE Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation Alternative Pathway      Factors B or D Susceptibility to pyogenic (pus- forming) bacterial infections Lack of sufficient opsonization of bacteria   C3 Susceptibility to bacterial infections Lack of opsonization and inability to utilize the membrane attack pathway   C5, C6, C7 C8, and C9 Susceptibility to Gram-negative infections Inability to attack the outer membrane of Gram-negative bacteria  Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria  Factors H or I C3 deficiency and susceptibility to bacterial infections Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3
  35. 35. C1-inhibitor deficiency: hereditary angioedema

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