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Complement SystemActivation of Membrane attacking complex (MAC)
and its effect and regulation
Suvasini Modi
Figure- 1https://en.wikipedia.org/wiki/Complement_system
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Content
Introduction
Activation of Membrane attacking complex (MAC)
Effect and regulation of Complement Factors
Role of Complement Receptors
Role of Small Fragments
Summary
3
Introduction
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The term "complement" was coined byPaul Ehrlich to describe the activity inserum, which could "complement" theability of specific antibody to cause lysisof bacteria.Complement system is composed ofmore than 25 different proteinsproduced by hepatocytes, macrophagesand intestinal epithelial cells.
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C3dC3dg
B cellactivation
Clearance ofapoptotic
cells
Overview
5
Overview
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Figure -3
Classical Pathway Alternative PathwayLectin Pathway
Antibody binds to specific antigen on pathogen surface
Mannose-binding proteinbinds pathogen surface
Pathogen surface creates environment conducive tocomplement activation
Complement Activation
Formation of C3 and C5 convertases
Membrane Attack PathwayCytolysis of some pathogens
Opsonization & phagocytosisof some pathogens
Inflammatory response
Clearance ofImmune complexes
Clearance of Apoptotic Cells
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Formation of C3 convertase
Once C1 is activated, it activates 2 other complement proteins, C2
and C4 by cleaving it
C2 is cleaved into C2a and C2b
C4 is cleaved into C4a and C4b
Both C2a and C4b bind together on the surface of the bacteria
C2b and C4a diffuse away
This C4b2a bind together to form active C3 complex that cleaves the
C3 into C3a and C3b.
C4b2a3b is the C3 convertase
C3a acts as an opsonin.
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Regulation and stability of C3 convertase
The Complement activation takes place in the surface of the pathogens
or the damaged tissues and not on the host cells.
Amplification of the complement system dependent on the stability of
C3 convertase- C3bBb
Stability controlled
Positive Regulator Negative Regulator
Eg. Properdin (factorP) Eg. Decay-accelerating factor (DAF), Complement Receptor 1 (CR1), Factor H, Membrane cofactor of
Proteolysis
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CR1 being negative regulator for theComplement proteins.
DAF Factor H competes with Bb to bind toC3b
Convertase formation prevented bycleaving it into inactive form iC3b, alongwith Factor I and MCP (membraneproteolysis cofactor).
All the complement proteins are inzymogen forms except Factor D, as it ishighly specific to its binding site C3b that isfound only on pathogen and not host
Figure 2.27 Immunobiology ,9/e (Garland Science 2012)
Negative Regulatory Proteins
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Figure 2.25 Immunobiology ,9/e (Garland Science 2012)
Amplification of C3 convertase and formation of
C5 convertase
Together with other components, attached C3b forms C5
convertase
C3b after the cleavage of the C3 into C3a and C3b; binds
covalently through thioester bond on the pathogen surface or is
inactivated by hydrolysis.
Thus, C3 increases the number of C3b on the pathogen
surface in order to carry out immunological reactions.
C5 activates specific protease that cleave C5 into C5a and
C5b (only if bound to C3b part).
C5a also acts as an opsonin, that induces phagocytosis.
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Membrane Attacking Complex (MAC) formation
MAC
Confirmational changes allow the C5b67 complex to insert itself into the membrane that further helps C8-C9 to form MAC.C8 C8β (binds to C5b that in turn insert the C8α-γ into the lipid layer)
C8α-γ ( induces Polymerization to form MAC
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MAC has Hydrophobic external face (allowing to
associate with lipid layer) and hydrophilic
internal channel (100 A0 diameter) leading to
homeostasis and disruption of proton gradient
thus penetration of lysozymes, eventually
destruction of the cell.
MAC Formation
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C1C1
Activated
C4b2a
C3 CONVERTASE
C5
C9C8C7C6
Bacterium
IgG
IgM
C4 C2
C4a C4b C2a C2b
C3
C3aC3b
C4b2a3b
C5 CONVERTASE
C5a C5bLysis
MEMBRANE ATTACK
COMPLEX
C5-C9
MAC
Summery of
Classical Pathway
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C3 C3b
C5
C6C7C8C9
BacteriumFactor D
Ba Bb
C3
C3a C3b
C3bBb3b
Alternative C5 convertase
C5b
C5a
Lysis
MEMBRANE ATTACK
COMPLEX
C5-C9
MAC
Factor B
C3bB C3bBb
Alternative C3 convertase
Properdin
Summery of
Alternative Pathway
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C3C3bC3a
Anaphylatoxin
B
D
Bb Ba
C3
C3a C3bC5-Convertase
C3-Convertase
C5
C5aC5b
Alternative Pathway
C6
C7
C8
C9
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Role of Complement Receptors (CRs)
The important role is to facilitate phagocytosis.
There are several CRs: CR1(CD35), CR2 (CD21), CR3(CD11b:CD18), CR4
(CD11c:CD18), CRIg (complement receptor for immunoglobulin family) , C5a and
C3a
CR1 expressed on the neutrophils and macrophages, when bind to C3b stimulates
phagocytosis in presence of the immune mediators.
Other complement receptors, bind to inactive form of CD3 that remain remain attached
on pathogen surface.
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Figure 2.32 Immunobiology ,9/e (Garland Science 2012)
C3b regulatory Protein
iC3b (Recognized by CRs except CR1 to carry phagocytosis)
Factor I and CR1 Cleave iC3b to C3c (leaves) and C3dg bound that activates phagocytosis via CR2 (Found on B-cells)
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Figure 2.31 Immunobiology ,9/e (Garland Science 2012)
Anaphylatoxin C5a enhances phagocytosis of microrganisms opsonized in innate immune response
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Figure 2.30 Immunobiology ,9/e (Garland Science 2012)
Distribution and
function of cell-
surfaced recepters
for complement
proteins
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Effect of Complement Factors
1. Opsonization
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C5a—chemoattraction
C3a, C4a----activationC3a, C4a---increased
vascular permeability
anaphylotoxins2. Inflammation
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C3a increases the inflammatory response by binding to mast cells and causing them to release histamine
Inflammatory response by C3a and C5a
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Regulation of Complement activation
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C1INH (C1 inhibitor)bind to active enzymes C1r:C1s that causes dissociation from C1q.
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DAF and CR1 displace C2a from C4b2aFactor H Competes with Bb to bind to C3b and also acts as cofactor for Factor IMCP along with CR1 catalyzes C3b to iC3b
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Factor H Competes with Bb to bind to C3b and also acts as cofactor for Factor I
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Functions of Complement proteins
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SUMMARY POINTS
Complement system can be activated directly or indirectly bypathogen bound antibody.There are positive and negative regulators of the ComplementSystem.Activation of C3 convertase is the central activity in activation ofcomplement system.Function of Complement System-
a) Opsonizationb) Inflammatory responsec) Clearance of immune complexesd) Lysis
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Thank you for Attention!!!!
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