OIA1010 COMPLEMENT SYSTEM

Introduction

Part of effector arm of innate & acquired immune system

Complement component synthesised in liver

Invovle sequential/cascade activation

Type of Activation Pathway

Classical Pathway (IgG & IgM - C1)

Activated when C1 binds to Fc receptors in antigen-Ig complex:

C1 activated by IgM>IgG3>IgG1>IgG2; IgG4, IgD, IgA, IgE not bind C1

C-reactive protein (CRP) bind to foreign substance -> activate

(1) Antigen-antibody complex -> conformational changes in non-antigen binding (Fc) portion -> exposes binding site for C1 component -> sequential activation of C4, C2, C3

(2) C1: macromolecules complex (C1qr2s2) -> split into small soluble C4a (anaphylatoxin) & large C4b (bind to cell membrane)

(3) C4b when Mg2+ present: split C2 to C2a & C2b -> smaller C2b diffuse away & larger C2a attach to C4b -> C4bC2a complex -> C3 convertase & activate C3

(4) C3 convertase activate C3 molecules -> split to C3a & C3b (C3b binds to C4b2a -> trimolecular complex (C5 convertase)

(5) C5 convertase split C5 to C5a (diffuse away) & C5b (attach to C6 -> initiate C5b-9 complex aka. membrane attack complex (MAC))

C3 convertase (serine protease)

C4bC2a & C3bBb -> cleave only C3

Innate immunity: eventuate in opsonisation release inflammatory peptides, form C5 convertase & cell lysis

C5 convertase

Assembly of MAC initiated by proteolytic cleavage of C5 by C5 convertase at target surface -> C5a and C5b

C5b transient ability to associate tightly with C6 -> C5bC6 interact with C7-C9 -> create MAC

Membrane Attack Complex (MAC)

Alternative Pathway (initiate by C3b from classical)

Activated directly by foreign substance

Factors B, D and properdin (factor P)

Over-activity regulated by inhibitory proteins on host cells

Triggered by contact of various protein, lipids, carbohydrate on microbes

C3bBb: alternative pathway C3 convertase (stabilised by properdin: amplification loop)

Amplification loop: balance between two competing cycles both acting on C3b: C3 feedback cycle enhance amplification while C3 breakdown cycle downregulates it

Lectin Pathway (initiate by MBL (mannan binding lectin): recognise surface carbohydrate structure)

Activators: terminal mannose residue expressed by G-positive & G-negative bacteria, fungi and yeast particles

Activated when MBL binds to terminal mannose residue of proteins and polysaccharides found on bacteria

Pattern-recognition molecule that binds to carbohydrate motifs present

MBL-associated serine protease 1 (MASP-1) cleave C4 and C2 to form C4bC2a (C3 convertase) while MASP-2 directly cleaves C3

Terminal Pathway

Involve C5b through C9: binds to form MAC -> cell lysis

Anaphylatoxins (C3a, C4a, C5a)

Smooth muscle contraction, histamine release and enhance vascular permeability

Mediate chemotaxis, inflammation and generate cytotoxic oxygen radicals

Key Functions of Complement System

Enhance B cell response

Removal of immune complex

Removal of necrotic cells and subcellular membranes

Inhibitors of Complement Activity

Uncontrolled complement activation: generate potent inflammatory induces & depletion of complement components

Complement Deficiency

Systemic lupus erythematosus (SLE)

Pyogenic infection

Glomerulonephritis

Recurrent bacterial infection