6. 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
7. Pathways of complement activation CLASSICAL PATHWAY ALTERNATIVE PATHWAY LECTIN PATHWAY activation of C5 LYTIC ATTACK PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase
8. Components of the Classical Pathway C4 C2 C3 C1 complex Ca ++ C1r C1s C1q
9. Classical Pathway Generation of C3-convertase C4 Ca ++ C1r C1s C1q C4a b
10. Classical Pathway Generation of C3-convertase C4b Mg ++ C4a C2 _____ C4b2a is C3 convertase Ca ++ C1r C1s C1q C2b a C2 a
11. Classical Pathway Generation of C5-convertase C4b Mg ++ C4a C2b C3 ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Ca ++ C1r C1s C1q C2 a C3a b
12. Biological Activities of Classical Pathway Components Opsonin C4b Anaphylaotoxin C4a Opsonin Activation of phagocytic cells C3b 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 C3a Prokinin; cleaved by plasmin to yield kinin, which results in edema C2b Biological Activity Component
13. Control of Classical Pathway Components 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 C4b C3a-INH C4a Factors H and I; Factor H facilitates the degradation of C3b by Factor I C3b C3a-inactivator (C3a-INA; Carboxypeptidase B) C3a C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q All Regulation Component
16. Mannose-binding lectin pathway C4 C2 _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP1 MASP2 MBL C4b C4a C4b C2b C2a C2a
28. C3b stabilization and C5 activation C3 B D P This is stable C5 convertase of the alternative pathway C3b C3b finds an activator (protector) membrane C3a b b
30. C5-convertase of the two pathways C3b B b C3b C5-convertase of the Alternative Pathway C5-convertase of the Classical and lectin Pathways C4b C2a C3b
31. Generation of C5 convertase leads to the activation of the Lytic pathway Lytic pathway
38. Biological properties of C-activation products Product Biological Effects Regulation as C3, but less potent (C3-INA) C4a (anaphylatoxin) opsonization; phagocytosis C4b (opsonin) C4-BP, factor I C3b (opsonin) opsonization; phagocyte activation factors H & I
39. Biological properties of C-activation products Product Biological Effects Regulation 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-S chemotaxis, attaches to other membranes
40. Complement Deficiencies and Disease Classical Pathway Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation Predisposition to SLE C1, C2, C4 Overproduction of C2b (prokinin) Hereditary Angioedema C1INH Mechanism Disease Pathway Component
41. Complement Deficiencies and Disease Lectin Pathway Inability to initiate lectin pathway Susceptibility to bacterial infections in infants or immunosuppressed MBL Mechanism Disease Pathway Component
42. Complement Deficiencies and Disease Alternative Pathway Inability to attack the outer membrane of Gram-negative bacteria Susceptibility to Gram-negative infections C5, C6, C7 C8, or C9 Lack of opsonization and inability to utilize the membrane attack pathway Susceptibility to bacterial infections C3 Lack of sufficient opsonization of bacteria Susceptibility to pyogenic (pus-forming) bacterial infections Factors B or D Mechanism Disease Pathway/Component
43. Complement Deficiencies and Disease Alternative Pathway cont. Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3 C3 deficiency and susceptibility to bacterial infections Factors H or I Lack of opsonization of bacteria Susceptibility meningococcal meningitis Properdin (X-linked) Mechanism Disease Pathway Component
Complement refers, historically, to fresh serum capable of lysing antibody (Ab)-coated cells . This activity is destroyed (inactivated) by heating serum at 56 C for 30 minutes. The lytic activity of complement is decreased in certain diseases, e.g. SLE, serum sickness, chronic infections, complement deficiencies, etc.
Chelating agents dismantle the C1 complex and are anti-complementary. Heat destroys the C2 component. Sample for C measurement should be drawn in a green-top vial (no EDTA), must be kept cold and tested as soon as possible.
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