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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

Molecular Immunology_Seminar_16.05.20182

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


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.


C3dC3dg

B cellactivation

Clearance ofapoptotic

cells

Overview

5

Overview


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


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.


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


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



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.


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


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


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


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


C3C3bC3a

Anaphylatoxin

B

D

Bb Ba

C3

C3a C3bC5-Convertase

C3-Convertase

C5

C5aC5b

Alternative Pathway

C6

C7

C8

C9


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.



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)



Anaphylatoxin C5a enhances phagocytosis of microrganisms opsonized in innate immune response



Distribution and

function of cell-

surfaced recepters

for complement

proteins


Effect of Complement Factors

1. Opsonization

20

C5a—chemoattraction

C3a, C4a----activationC3a, C4a---increased

vascular permeability

anaphylotoxins2. Inflammation


C3a increases the inflammatory response by binding to mast cells and causing them to release histamine

Inflammatory response by C3a and C5a


Regulation of Complement activation


C1INH (C1 inhibitor)bind to active enzymes C1r:C1s that causes dissociation from C1q.


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


Factor H Competes with Bb to bind to C3b and also acts as cofactor for Factor I


Functions of Complement proteins

28 Molecular Immunology_Seminar_16.05.2018

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

29 Molecular Immunology_Seminar_16.05.2018

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