Complement System

The complement system is part of the immune system that helps enhance the ability of antibodies and phagocytic cells to clear pathogens. It consists of a cascade of proteins that can amplify the immune response, leading to inflammation, cell lysis, and opsonization.

Complement System Pathways :

The complement system can be activated through three main pathways:

1. Classical Pathway 
2. Alternative Pathway 
3. Mannose Binding Lectin (MBL) Pathway 

Classical Pathway

The classical pathway begins with the formation of an antigen-antibody complex. This complex exposes a binding site for the C1 complex (composed of C1q, C1r & C1s)

1. C1q binds to the antigen bound antibody (Fc portion) where C1r and C1s are proteases which cleave C4 and C2 to form into two subunits and form C4b2a.
2. The C4b2a complex is also called the C3 convertase that breaks the C3 molecule into two subunits C3a and C3b.
3. The C3b unit combines with C4b2a  to form the C4a2a3b complex.
4. C4b2a3b is also called C5 convertase that breaks the C5 molecule into two subunits C5a & C5b.
5. Then the C5 unit binds to C6, C7, C8, C9 respectively, forming the Membrane Attack Complex (MAC) the C5b6b7b8b9b. This MAC causes a pore on the surface of the target cell and cell lysis occurs.

Alternative Pathway 

Alternative pathway is triggered by microbes or bacterial endotoxin by spontaneous hydrolysis of C3 factor/complement protein.

1. The C3 protein breaks into C3a and C3b subunits and combines with the larger subunit of factor B and forms C3bBb.
2.  The complex C3bBb is the C3 convertase that again breaks the C3 molecule into C3a and C3b subunits.
3. C3bBb complex combined with C3b and form С3Вb3b complex.
4. The C3bBb3b complex is the C5 convertase that breaks the C5 molecule into two fragments of C5a and C5b.
5. Then the C5b fragment breaks C6, C7, C8, C9 respectively and binds the larger subunits to form the Membrane Attack Complex (MAC)- C5b6bC7b8b9b. This MAC makes a hole on the surface of the target cell and lysis of the cell occurs.

Mannose Binding Lectin (MBL) Pathway:

MBL pathway is initiated by the binding of mannose binding lectin (MBL) to bacterial surfaces.

1. Binding of MBL to a pathogen  results in activation of MBL associated serine proteases 1 & 2. The association of MASP 1 and MASP 2 with MBL acts as a C1 complement molecule.
2. Formation of MASP complex results the activation and subsequent cleavage of C4 into C4a & C4b and also C2 into C2a and C2b.
3. The C4b fragment bind with C2a and form the C4b2a complex (C3 Convertase).
4. The C3 Convertase breaks the C3 molecule into C3a and C3b and forms C4b2a3b.
5. The C4b2a3b complex is the C5 convertase that break the C5 molecule into two fragments C5a and C5b. 
6. Then C5b fragment break subsequently with C6, C7, C8 and C9 respectively and bind with the larger subunits to form MAC, the C5b6b7b8b9b complex. This MAC makes a hole on the surface of the target cell and lysis of all occurs.

Features	Classical Pathway	Alternative Pathway	MBL Pathway
1. Activation trigger	Antigen-antibody complex (IgG, IgM)	Pathogen surfaces (spontaneous C3 hydrolysis)	MBL binding carbohydrates
2. Initiator	C1 complex	C3(H2O), Factor B, Factor D	MBL, MASP-1, MASP-2
3. C3 convertase	C4b2a	C3bBb	C4b2a
4. C5 convertase	C4b2a3b	C3bBb3b	C4b2a3b
5. Role	Links adaptive and innate immunity	Rapid pathogen recognition	Carbohydrate (Lectin) pattern recognition