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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
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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
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Proteins of the complementsystem (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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• 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
Definitions
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Activation product of complement proteins (nomenclature)
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, membrane-binding moiety is C2a; the smaller one is C2b)
Activated component are usually over-lined: e.g. C1qrs
Pathways of complement activation
CLASSICALPATHWAY
ALTERNATIVEPATHWAY
activationof C5
LYTIC ATTACKPATHWAY
antibodydependent
LECTINPATHWAY
antibodyindependent
Activation of C3 andgeneration of C5 convertase
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Components of the Classical Pathway
C4C2 C3
C1 complex
Ca++
C1r C1s
C1q
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Ca++
C1r C1s
C1q
C4
C4a
b
Classical Pathway Generation of C3-convertase
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Classical Pathway Generation of C3-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2
C2ba
C2a
_____
C4b2a is C3 convertase
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Classical Pathway Generation of C5-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2b
C2a
C3
C3a
b
________
C4b2a3b is C5 convertase; it leads into the Membrane
Attack Pathway
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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
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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
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C1-inhibitor deficiency:hereditary angioedema
Components of mannose-binding lectin pathway
C4
MBL C2 MASP1
MASP2
Mannose-binding lectin pathway
C4
MBL
C4b
C4a
C4b
C2
C2b
C2a
C2a
_____
C4b2a is C3 convertase; it will lead to the generation of
C5 convertaseMASP1
MASP2
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Components of thealternative pathway
C3 B
D
P
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Spontaneous C3 activation
C3
H2O
iB
D
Generation of C3 convertase
C3iBb complex has a very short half life
b C3
C3a
b
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B
D
bC3b
If spontaneously-generated C3b is not degraded
C3-activationthe amplification loop
C3C3a b
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C3a
B
D
BbC3b
C3 b
C3-activationthe amplification loop
C3b
C3a
b
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C3a
C3a BbC3b
C3bC3 BbB
D
bb
C3a
C3-activationthe amplification loop
C3b
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C3a
C3a BbC3b
BbBbC3b
C3a
C3-activationthe amplification loop
C3bC3b
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C3a
C3a BbC3b
BbBb
C3a
C3-activationthe amplification loop
C3bC3b
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Control of spontaneousC3 activation via DAF
C3b
DAF prevents
the binding of
factor B to C3b
B
Autologous cell membrane
DA
F
CR1
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Control of spontaneousC3 activation via DAF
DAF dislodges
C3b-bound
factor Bb
B bb C3b
Autologous cell membrane
DA
F
CR1
B b
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Autologous cell membrane
C3b C3b
Bb
H
I
iC3b
Control of spontaneousC3 activation via CR1
B b
I
iC3b DA
F
CR1DA
F
CR1
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Degradation of spontaneously produced C3b
C3b
C3b
iC3biC3b
II
C3dgC3dg
C3c C3c
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C3b stabilization andC5 activation
C3b
C3b finds an activator (protector) membrane
C3
C3a
bB
D
b
PThis is stable C5 convertase
of the alternative pathway
C3b regulation on self and activator surfaces
C3b
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C5-convertase of the two pathways
C3b Bb C3b
C5-convertase of the Alternative Pathway
C4b C2a C3b
C5-convertase of the Classical and lectin
Pathways
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Generation of C5 convertase leads to the activation of the
Lytic pathway
Lytic pathway
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Components of the lytic pathway
C6
C9
C8
C7C5
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Lytic pathwayC5-activation
C3b C2 aC4b
C5 b
C5a
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Lytic pathwayassembly of the lytic complex
C5 b
C6
C7
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Lytic pathway:insertion of lytic complex into cell membrane
C5 b
C6
C7C8
C9
C9
C9
C9C9
C9 C
9C9
C9
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Biological effects of C5a
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Product Biological Effects Regulation
Biological properties of C-activation products
C2b (prokinin) edema C1-INH
C3a (anaphylatoxin)
mast cell degranulation; enhanced vascular permeability; anaphylaxis
carboxy-peptidase- B (C3-INA)
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Product Biological Effects Regulation
Biological properties of C-activation products
as C3, but less potent
(C3-INA)C4a (anaphylatoxin)
opsonization; phagocytosis
C4b (opsonin)
C4-BP, factor I
C3b (opsonin)
opsonization; phagocyte activation
factors H & I
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Product Biological Effects Regulation
Biological properties of C-activation products
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-Schemotaxis, attaches to other membranes
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Complement Deficiencies and DiseaseClassical Pathway
Pathway Component Disease Mechanism
C1INH HereditaryAngioedema
Overproduction of C2b (prokinin)
C1, C2, C4 Predisposition to SLE
Opsonization of immunecomplexes help keepthem soluble, deficiencyresults in increasedprecipitation in tissuesand inflammation
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Complement Deficiencies and DiseaseLectin Pathway
Pathway Component Disease Mechanism
MBL Susceptibility to bacterial infections in infants orimmunosuppressed
Inability to initiate lectin pathway
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Complement Deficiencies and DiseaseAlternative 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 Gram-negative infections
Inability to attack the outer membrane of Gram-negative bacteria
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Complement Deficiencies and DiseaseAlternative 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