Complement system
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The document provides a comprehensive overview of the complement system, discovered in 1894, highlighting its lytic activities, functions in immune responses, and the proteins involved in its pathways. It details the classical, alternative, and lectin pathways of activation, the roles of its components, and the biological effects of activation products. Additionally, the document discusses deficiencies in the complement system and their implications for susceptibility to infections and other diseases.
Complement system
- 2. Complement: History Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min
- 3. 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
- 4. Proteins of the complement system (nomenclature) • C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 • factors B, D, H and I, properdin (P) • mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) • C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), Complement receptor 1 (CR1), protein- S (vitronectin)
- 5. • C-activation: alteration of C proteins such that they interact with the next component • C-fixation: utilization of C by Ag-Ab complexes • Hemolytic units (CH50): dilution of serum which lyses 50% of a standardized suspension of Ab-coated r.b.c • C-inactivation: denaturation (usually by heat) of an early C-component resulting in loss of hemolytic activity • Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component Definitions
- 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 activation of C5 LYTIC ATTACK PATHWAY antibody dependent LECTIN PATHWAY antibody independent Activation of C3 and generation of C5 convertase
- 8. Components of the Classical Pathway C4 C3 C1 complex
- 9. Classical Pathway Generation of C3-convertase
- 10. Classical Pathway Generation of C3-convertase C4b _____ C4b2a is C3 convertase
- 11. Classical Pathway Generation of C5-convertase C4b C3b ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway
- 12. 12 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
- 13. 13 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
- 15. Components of mannose-binding lectin pathway MBL MASP1
- 16. Mannose-binding lectin pathway MBL _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP1
- 17. Components of the alternative pathway C3
- 18. Spontaneous C3 activation C3 i Generation of C3 convertase C3iBb complex has a very short half life b C3b
- 19. b C3b If spontaneously-generated C3b is not degraded C3-activation the amplification loop C3b
- 20. C3b C3 b C3-activation the amplification loop C3b b
- 21. C3b C3b C3 b b C3-activation the amplification loop C3b
- 24. Control of spontaneous C3 activation via DAF C3b DAF prevents the binding of factor B to C3b Autologous cell membrane CR1
- 25. Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb b b C3b Autologous cell membrane CR1
- 26. Autologous cell membrane C3b C3b iC3b Control of spontaneous C3 activation via CR1 CR1 CR1
- 27. Degradation of spontaneously produced C3b C3b C3b iC3b iC3b C3dg C3dg C3c C3c
- 28. C3b stabilization and C5 activation C3b C3b finds an activator (protector) membrane C3b b This is stable C5 convertase of the alternative pathway
- 29. C3b regulation on self and activator surfaces C3b
- 30. C5-convertase of the two pathways C3b C3b C5-convertase of the Alternative Pathway C4b C3b C5-convertase of the Classical and lectin Pathways
- 31. Generation of C5 convertase leads to the activation of the Lytic pathway Lytic pathway
- 32. Components of the lytic pathway C6 C 9 C7
- 34. Lytic pathway assembly of the lytic complex b C6 C7
- 35. Lytic pathway: insertion of lytic complex into cell membrane b C6 C7 C 9 C 9 C 9 C 9C 9 C 9 C 9 C 9 C 9
- 36. Biological effects of C5a
- 37. Product Biological Effects Regulation Biological properties of C-activation products C2b (prokinin) edema C1-INH C3a (anaphylatoxin) mast cell degranulation; enhanced vascular permeability; anaphylaxis carboxy- peptidase- B (C3-INA)
- 38. Product Biological Effects Regulation Biological properties of C-activation products 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. 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-S chemotaxis, attaches to other membranes
- 40. 40 Complement Deficiencies and Disease Classical Pathway Pathway Component Disease Mechanism 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
- 41. 41 Complement Deficiencies and Disease Lectin Pathway Pathway Component Disease Mechanism MBL Susceptibility to bacterial infections in infants or immunosuppressed Inability to initiate lectin pathway
- 42. 42 Complement Deficiencies and Disease Alternative Pathway Pathway/Component Disease Mechanism 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, or C9 Susceptibility to Gram- negative infections Inability to attack the outer membrane of Gram- negative bacteria
- 43. 43 Complement Deficiencies and Disease Alternative Pathway cont. Pathway Component Disease Mechanism 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
Editor's Notes
- #3: Complement refers, historically, to fresh serum capable of lysing antibody (Ab)-coated cells. This activity is destroyed (inactivated) by heating serum at 56EC for 30 minutes. The lytic activity of complement is decreased in certain diseases, e.g. SLE, serum sickness, chronic infections, complement deficiencies, etc.
- #9: 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.