Post on 15-Feb-2016
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Complement system
Tiana Milanda
Chapter 4
Complement: History
o Discovered in 1894 by Bordet
o It represents lytic activity of fresh serum
o Its lytic activity is destroyed when heated at 56ºC for 30 min
Complement System• Complement
– Consists of over 30 proteins• Designated by 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)
• Cascade of reactions eventually– Destroy microorganisms by
• Cytolysis• Inflammation• Phagocytosis by opsonizationGram-negative bacteria more susceptible
Pathways of complement activation
CLASSICALPATHWAY
ALTERNATIVEPATHWAY
activationof C5
LYTIC ATTACKPATHWAY
antibodydependent
LECTINPATHWAY
antibodyindependent
Activation of C3 andgeneration of C5 convertase
Classsical Pathway
• Classical pathway– Initiated by antibody –
antigen reaction
Components of the Classical Pathway
C4C2 C3
C1 complex
Ca++
C1r C1s
C1q
C1s is an enzyme and cleaves C4 and C2
Ca++
C1r C1s
C1q
C4
C4a
b
Classical Pathway Generation of C3-convertase
Cleavage of C4 by C1s produces C4a and C4b
Classical Pathway Generation of C3-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2
C2ba
C2 a
C1s binds C2 and C2 is cleaved by C1s. C2b is released but C2a remains bound to C4b on the surface. C4b2a is C3 Convertase
Classical Pathway Generation of C5-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2b
C2 a
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 OpsoninActivation of phagocytic cells
C4a Anaphylotoxin
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
C1-inhibitor deficiency:hereditary angioedema
Lectin Pathway
• Lectin pathway– Released by
macrophages ingesting microbes
– Lectins initiate complement
Components of mannose-binding lectin pathway
C4
MBL C2 MASP1
MASP2
Pathogen
• mannose binding lectin (MBL), MBL associated serine proteases (MASP-1, MASP-2)
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 convertase
MASP1MASP2
Binding to lectins cause autocatalytic activationof MASPs, which then cleave C4 & C2
C5-convertase
C4b C2a C3b
C5-convertase of the Classical and lectin Pathways
Alternative Pathway
• Alternative pathway– Activated between
complement proteins and microbe
Components of thealternative pathway
C3 fB
fD
P
• fB = factors B, fD, H and I, properdin (P)
Spontaneous C3 activation
C3
H2O
B
D
Generation of C3 convertase
fB activate fD which then cut fB releasingBa, while Bb becomes an active proteaseC3Bb complex has a very short half life
b C3
C3a
b
B
D
bC3b
If spontaneously-generated C3b is not degraded
C3-activationthe amplification loop
C3C3a b
C3a
B
D
BbC3b
C3 b
C3-activationthe amplification loop
C3b
C3a
b
C3a
C3a BbC3b
BbBb
C3a
C3-activationthe amplification loop
C3bC3b
Control of spontaneousC3 activation via DAF
C3b
DAF prevents
the binding of
factor B to C3bB
Autologous cell membrane
DA
F
CR1
Control of spontaneousC3 activation via DAF
DAF dislodges
C3b-bound
factor BbB bb C3b
Autologous cell membrane
DA
F
CR1
B b
C3b stabilization andC5 activation
C3b
C3b finds an activator (protector) membrane
C3
C3a
bB
D
b
P This is stable C5 convertase of the alternative pathway
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
Pathways of complement activation
CLASSICALPATHWAY
ALTERNATIVEPATHWAY
activationof C5
LYTIC ATTACKPATHWAY
antibodydependent
LECTINPATHWAY
antibodyindependent
Activation of C3 andgeneration of C5 convertase
Complement System
Components of the lytic pathway
C6
C9
C8
C7
C5
Lytic pathwayC5-activation
C3b C2 aC4b
C5 b
C5a
Lytic pathwayassembly of the lytic complex
C5 b
C6
C7
C5b first binds C6 and then C7from the plasma. Membrane boundC5b67 recruits C8 and C9 to formthe Membrane Attack Complex (MAC)
Lytic pathway:insertion of lytic complex into cell membrane
C5 b
C6
C7C8
C9C9 C9 C9C9C9 C9 C9 C9
Soluble Pattern Recognition Receptors-Complement
activation pathways
Biological effects of C5a
Links to Specific Immunity• Phagocytosis continues to be common way to kill pathogenic
cells in both specific and non-specific response
• Inflammation works to allow both specific and non-specific immune response to accelerate
• Fever also allows for better performance in both specific and non-specific function
• Specific immune response and “antigen presentation” further stimulates non-specific actions like phagocytosis, complement.