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)
Activation product of complement proteins (nomenclature) Activated component are usually over-lined: e. g. C 1 qrs 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. , C 3 b/C 3 a, C 4 b/C 4 a, C 5 b/C 5 a), EXCEPT C 2 (the larger, membranebinding moiety is C 2 a; the smaller one is C 2 b)
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 15
Control of Classical Pathway Components Component Regulation All C 1 -inhibitor (C 1 -INH); dissociates C 1 r and C 1 s from C 1 q C 3 a-inactivator (C 3 a-INA; Carboxypeptidase B) C 3 b Factors H and I; Factor H facilitates the degradation of C 3 b by Factor I C 4 a C 3 a-INH C 4 b C 4 binding protein (C 4 -BP) and Factor I; C 4 -BP facilitates degradation of C 4 b by Factor I; C 4 -BP also prevents the association of C 2 a with C 4 b thus blocking formation of C 3 convertase 16
C 1 -inhibitor deficiency: hereditary angioedema
Components of mannose-binding lectin pathway C 4 MASP 2 MBL C 2 MASP 1
Mannose-binding lectin pathway C 2 b C 4 a MASP 1 MASP 2 MBL _____ C 4 b 2 a is C 3 convertase; it will lead to the generation of C 5 convertase C 4 b C 4 a 2 CC 2 C 4 b C 2 a
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 C 3 b C 3 a C 3 b Bb 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
ﺍﻧﻮﺍﻉ ﻣﻮﻟکﻮﻟﻬﺎی کﻨﺘﺮﻟی n n n n n C 1 INH Membrane cofacto protein(MCP) Complement receptor-1(CR-1) Decay accelerating factor(DAF) factor H C 4 -binding protein(C 4 bp) CD 59 Factor I S-protein
Control of spontaneous C 3 activation via DAF prevents C 3 b factor B to C 3 b B DAF the binding of CR 1 Autologous cell membrane
Control of spontaneous C 3 activation via DAF dislodges factor Bb C 3 b Bb DAF C 3 b-bound Bb CR 1 Autologous cell membrane
Control of spontaneous C 3 activation via CR 1 Bb H Bb C 3 b DAF I i. C 3 b CR 1 DAF C 3 b Autologous cell membrane I i. C 3 b CR 1
Degradation of spontaneously produced C 3 b C 3 c I C 3 b C 3 dg i. C 3 b
C 3 b stabilization and C 5 activation C 3 a C 3 b finds an activator (protector) membrane P C 3 b This is stable C 5 convertase D of the alternative pathway Bb C 3 b
C 3 b regulation on self and activator surfaces 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 C 2 b (prokinin) C 3 a (anaphylatoxin) Biological Effects edema Regulation C 1 -INH mast cell degranulation; carboxypeptidase- B enhanced vascular (C 3 -INA) permeability; anaphylaxis
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
Complement levels may be decreased due to: a) hereditary (relatively rare) b)acquired deficiency 1) increased consumption 2) decreased production n Complement protein levels are usually increased, along with other unrelated proteins called acute phase proteins, during acute or chronic inflammation n 50
Decreased complement levels may be seen with: n n n n Recurrent microbial infections (usually bacterial) Autoimmune diseases, including SLE and vasculitis Hereditary angioedema Acquired angioedema Various types of kidney disease, including: glomerulonephritis, lupus nephritis, membranous nephritis, Ig. A nephropathy Malnutrition Septicemia Serum sickness (immune complex disease) 51
- Slides: 49