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Complement functions Host benefit: Host detriment:
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
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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)
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Pathways of complement activation
CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY
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Components of the Classical Pathway
C1r C1s C1q C4 C2 C3 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. C1 complex
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Classical Pathway Generation of C3-convertase
b Ca++ C1r C1s C1q C4
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Classical Pathway Generation of C3-convertase
C2b a C4a Ca++ C1r C1s C1q _____ C4b2a is C3 convertase Mg++ C4b
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Classical Pathway Generation of C5-convertase
C2b C4a Ca++ C1r C1s C1q C3a b ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Mg++ C4b C3 C2 a
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Generation of C5 convertase leads to the activation of the
Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway
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Components of the lytic pathway
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Lytic pathway C5-activation
b C5a C5 C3b C4b C2 a
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Lytic pathway assembly of the lytic complex
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Lytic pathway: insertion of lytic complex into cell membrane
9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9
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Biological Activities of Classical Pathway Components
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
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Components of the alternative pathway
D C3 B P
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Spontaneous C3 activation
Generation of C3 convertase D b i H2O B C3a b C3 C3 C3iBb complex has a very short half life
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C3-activation the amplification loop
If spontaneously-generated C3b is not degraded b D B C3a b C3b C3
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C3-activation the amplification loop
b D Bb B b C3a C3b C3b C3 Bb C3b C3a C3a
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C3-activation the amplification loop
Bb Bb C3b C3b C3b Bb C3b C3a C3a C3a
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C3-activation the amplification loop
Bb Bb C3b C3b Bb C3b C3a C3a C3a
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C5-convertase of the two pathways
C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway Bb C4b C2a C3b C3b C3b
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Biological effects of C5a
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Biological properties of C-activation products
Biological Effects Regulation C3b (opsonin) opsonization; phagocyte activation factors H & I as C3, but less potent (C3-INA) C4a (anaphylatoxin) opsonization; phagocytosis C4b (opsonin) C4-BP, factor I
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Biological properties of C-activation products
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
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