CD B T NK NKT!! 1

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1 CD B T NK NKT!! 1

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12 Biological effects of C5a 12

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14 Opsonization and phagocytosis 14

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16 come.htm 16

17 munol-sta.htm 17

18 Abdul Ghaffar Microbiology and Immunology 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 18

19 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 apoptic cells Host detriment: Inflammation, anaphylaxis 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 Ab-coated r.b.c in a suspension 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 19

20 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), C1 receptor (CR1), protein-s (vitronectin) 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., /C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membranebinding moiety is C2a; the smaller on is C2b) 20

21 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 Components of the Classical Pathway C1r C1s Ca ++ C1q C2 C3 C4 C1 complex 21

22 Classical Pathway Generation of C3-convertase C4a C1r C1s C1q Ca ++ b C4 Classical Pathway Generation of C3-convertase C4a C1r C1s Ca ++ a C2 C2b C1q Mg ++ C4b2a is C3 convertase C4b C2a 22

23 Classical Pathway Generation of C5-convertase C4a C1r C1s C1q Ca ++ Mg ++ C2b C3a C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway C4b C2a C3 b Components of mannose-binding lectin pathway C4 MASP2 MBL C2 MASP1 23

24 Mannose-binding lectin pathway C4a MASP1 C2b MASP2 MBL C4b2a is C3 convertase; it will lead to the generation of C5 convertase C4b C2 C2a C4b C2a Components of the alternative pathway D C3 B P 24

25 Spontaneous C3 activation Generation of C3 convertase H 2 O C3 i D B b C3a C3iBb complex has a very short half life C3-activation the amplification loop If spontaneously-generated is not degraded D C3a B b C3 b 25

26 C3-activation the amplification loop D C3 b B b C3a C3a Bb C3-activation the amplification loop D C3 b B b Bb C3a C3a C3a Bb 26

27 C3-activation the amplification loop Bb Bb C3a C3a C3a Bb C3-activation the amplification loop Bb Bb C3a C3a C3a Bb 27

28 Control of spontaneous C3 activation via DAF DAF prevents the binding of factor B to B DAF CR1 Autologous cell membrane Control of spontaneous C3 activation via DAF DAF dislodges -bound B b B b factor Bb DAF CR1 Autologous cell membrane 28

29 Control of spontaneous C3 activation via CR1 B b H Bb DAF I CR1 i DAF Autologous cell membrane i CR1 I Degradation of spontaneously produced C3c I C3dg i C3c I C3dg i 29

30 stabilization and C5 activation finds an activator (protector) membrane P D C3a This is stable C5 convertase of the alternative pathway B b C3 b regulation on self and activator surfaces 30

31 C5-convertase of the two pathways C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway C4b C2a Bb Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway 31

32 Components of the lytic pathway C5 C6 C7 C8 C 9 Lytic pathway C5-activation C5a C5 b C4b C2 a 32

33 Lytic pathway assembly of the lytic complex C6 C7 C5 b Lytic pathway: insertion of lytic complex into cell membrane C6 C8 C7 C5 b C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 33

34 C1qrs breakdown C1Inh C1r C1s C1q C1r C1s C1-inhibitor deficiency: angioedema 34

35 Biological properties of C-activation products Product Biological Effects Regulation C2b (prokinin) C3a (anaphylatoxin) edema mast cell degranulation; enhanced vascular permeability; anaphylaxis C1-INH carboxypeptidase- B (C3-INA) Biological properties of C-activation products Product Biological Effects Regulation (opsonin) C4a (anaphylatoxin) C4b (opsonin) opsonization; phagocyte activation as C3, but less potent opsonization; phagocytosis factors H & I (C3-INA) C4-BP, factor I 35

36 Biological properties of C-activation products Product Biological Effects Regulation C5a (chemotactic factor) C5b67 anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release chemotaxis, attaches to other membranes carboxypeptidase-c (C3-INA) protein-s 36