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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 COMPLEMENT Important Innate Immunity Complement - a system of non-specific proteins in normal human serum - ability to lyse or damage microbial cells or virally infected cells Activated sequentially in a cascade 3 COMPLEMENT consists of about 21 serum proteins liver being the main source heat-labile - inactivated at 56o C for 30 min. Main nine functional proteins C1, C2….C9 4 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 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), proteinS (vitronectin) Definitions • 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 Activation product of complement proteins (nomenclature) Activated component are usually over-lined: e.g. C1qrs 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, membranebinding moiety is C2a; the smaller one is C2b) Pathways of complement activation CLASSICAL PATHWAY antibody dependent LECTIN PATHWAY ALTERNATIVE PATHWAY antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY Components of the Classical Pathway C3 C1 complex C4 C1qrs breakdown C1Inh Classical Pathway Generation of C3-convertase Classical Pathway Generation of C3-convertase _____ C4b2a is C3 convertase C4b Classical Pathway Generation of C5-convertase ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway C4b C3b 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 15 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 16 C1-inhibitor deficiency: hereditary angioedema Components of mannose-binding lectin pathway MBL MASP1 Mannose-binding lectin pathway _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP1 MBL Components of the alternative pathway C3 Spontaneous C3 activation Generation of C3 convertase C3 i b C3b C3iBb complex has a very short half life C3-activation the amplification loop If spontaneously-generated C3b is not degraded C3b b C3 b Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb b C3b CR1 Autologous cell membrane C5-convertase of the two pathways C5-convertase of the Classical and lectin Pathways C3b C4b C5-convertase of the Alternative Pathway C3b C3b Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway Components of the lytic pathway C7 C6 C 9 Lytic pathway C5-activation b C4b C3b Lytic pathway assembly of the lytic complex C6 C7 b Lytic pathway: insertion of lytic complex into cell membrane C6 C7 CC C C C9 9 9 9C 9C C C9 9 9 9 b Biological effects of C5a Opsonization and phagocytosis Biological properties of C-activation products Product C2b (prokinin) C3a (anaphylatoxin) Biological Effects edema Regulation C1-INH mast cell degranulation; carboxypeptidase- B enhanced vascular (C3-INA) permeability; anaphylaxis Biological properties of C-activation products Product Biological Effects Regulation C3b (opsonin) opsonization; phagocyte activation factors H & I C4a as C3, but less (anaphylatoxin) potent (C3-INA) C4b (opsonin) C4-BP, factor I opsonization; phagocytosis Biological properties of C-activation products Product Biological Effects Regulation C5a (chemotactic factor) anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release carboxypeptidase-B (C3-INA) C5b67 chemotaxis, attaches to other membranes protein-S 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 44 Complement Deficiencies and Disease Lectin Pathway Pathway Component MBL Disease Susceptibility to bacterial infections in infants or immunosuppressed Mechanism Inability to initiate lectin pathway 45 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 Gramnegative infections Inability to attack the outer membrane of Gramnegative bacteria 46 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 47 48 49 50 51 52 53 54 55 56 57 58