Complement functions Host benefit opsonization to enhance phagocytosis
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) • C 1(qrs), C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9 • factors B, D, H and I, properdin (P) • mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) • C 1 inhibitor (C 1 -INH, serpin), C 4 -binding protein (C 4 -BP), decay accelerating factor (DAF), Complement receptor 1 (CR 1), protein. S (vitronectin)
Pathways of complement activation CLASSICAL PATHWAY antibody dependent LECTIN PATHWAY ALTERNATIVE PATHWAY antibody independent Activation of C 3 and generation of C 5 convertase activation of C 5 LYTIC ATTACK PATHWAY
Components of the Classical Pathway C 1 r C 1 s Ca++ C 1 q C 2 C 1 complex C 3 C 4
Classical Pathway Generation of C 3 -convertase C 1 r C 1 s Ca++ C 1 q C 4 b C 4 a
Classical Pathway Generation of C 3 -convertase C 4 a C 1 r C 1 s Ca++ C 1 q a 2 C C 2 b _____ Mg++ C 4 b 2 a is C 3 convertase C 4 b C 2 a
Classical Pathway Generation of C 5 -convertase C 4 a C 1 r C 1 s Ca++ C 1 q Mg++ C 2 b C 3 a ____ C 4 b 2 a 3 b is C 5 convertase; it leads into the Membrane Attack Pathway C 4 b C 2 a C 3 b
Lytic pathway Generation of C 5 convertase leads to the activation of the Lytic pathway
Components of the lytic pathway C 7 C 6 C 5 C 8 C 9
Lytic pathway C 5 -activation C 5 a C 5 b C 4 b C 2 a C 3 b
Lytic pathway assembly of the lytic complex C 6 C 7 C 5 b
Lytic pathway: insertion of lytic complex into cell membrane C 6 C 8 CC C 9 9 9 9 C 9 C C C 9 9 C 7 C 5 b
Biological Activities of Classical Pathway Components Component Biological Activity C 2 b Prokinin; cleaved by plasmin to yield kinin, which results in edema C 3 a 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 C 3 b Opsonin Activation of phagocytic cells C 4 a Anaphylaotoxin C 4 b Opsonin 13
Components of the alternative pathway D C 3 B P
Spontaneous C 3 activation Generation of C 3 convertase H 2 O C 3 i D Bb C 3 a C 3 i. Bb complex has a very short half life
C 3 -activation the amplification loop If spontaneously-generated C 3 b is not degraded D C 3 a C 3 b Bb C 3 b
C 3 -activation the amplification loop D Bb C 3 a C 3 a Bb C 3 b
C 3 -activation the amplification loop Bb C 3 a Bb C 3 b
C 3 -activation the amplification loop Bb C 3 a Bb C 3 b
C 5 -convertase of the two pathways C 5 -convertase of the Classical and lectin Pathways C 4 b C 2 a C 3 b C 5 -convertase of the Alternative Pathway C 3 b Bb C 3 b
Biological effects of C 5 a
Biological properties of C-activation products Product Biological Effects Regulation C 3 b (opsonin) opsonization; phagocyte activation factors H & I C 4 a as C 3, but less (anaphylatoxin) potent (C 3 -INA) C 4 b (opsonin) C 4 -BP, factor I opsonization; phagocytosis
Biological properties of C-activation products Product Biological Effects Regulation C 5 a (chemotactic factor) anaphylactic as C 3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release carboxypeptidase-B (C 3 -INA) C 5 b 67 chemotaxis, attaches to other membranes protein-S
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