Complement System

Complement: refers to the ability of these proteins to complement or augment the effects of other components of the immune system, such as antibody. It is an important component of out innate host defense.

3 main effects of complement:
1. Lysis of cells such as bacteria, allografts and tumor cells
2. Opsonisation, which is enhancement of phagocytosis
3. Generation of mediators that participate in inflammation and attract neutrophils

-Several complement components are proenzymes, which must be cleaved to form active enzymes.
-Activation of complement can occur via one of the three pathways: the classic pathway, the lectin pathway and the alternative pathway.
-The lectin and the alternative pathways are more important the first time we are infected by microorganism because the antibody required to trigger the classic pathway is not present. All three pathways lead to the production of C3b, the central molecule of the complement cascade.
-Presence of C3b on the surface of a microbe marks it as foreign and targets it for destruction.
-Functions of C3b: a) combines with other complement components to generate C5 convertase, the enzyme leading to the production of membrane attack complex b) opsonizes bacteria.


Classic pathway:
-antigen-antibody complex activate C1 to form a protease, which cleaves C2 and C4 to form a C4b,2b complex.
-C4b, 2b complex which is a C3 convertase cleaves C3 into two fragments, C3a and C3b
-C3a is an anaphylatoxin, while C3b forms a complex with C4b, 2b complex and produce C5 convertase (C4b, 2b, 3b)
-C5 convertase cleaves C5 to form C5a and C5b.
-C5a is an anaphylatoxin, while C5b binds to C6 and C7 to form a complex that interacts with C8 and C9 to produce the membrane attack complex (C5b, 6, 7, 8, 9) which causes cytolysis

Lectin pathway:
-mannan-binding lectin (MBL), also known as mannose-binding protein binds to the surface of microbes bearing mannan
-this activates proteases associated with MBL that cleave C2 and C4 components of complement and activate the classic pathway

Alternative pathway:
-many unrelated cell surface substances (bacterial lipopolysaccharides, fungal cell walls and viral envelopes) can initiate the process by binding to C3 (H2O) and factor B
-this complex is cleaved by a protease, factor D to produce C3b, Bb which acts as a C3 convertase to generate more C3b


Biologic effects of complement:
1. Opsonization - presence of C3b
2. Chemotaxis - C5a and C5, 6, 7 complex attract neutrophils while C5a also enhances adhesion of neutrophils to endothelium
3. Anaphylatoxin - C3a, C4a and C5a cause degranulation of mast cells with release of mediators, such as histamine, leading to increase in vascular permeability and smooth muscle contraction (bronchospasm)
4. Cytolysis - C5b, 6, 7, 8, 9 complex (membrane attack complex) leads to killing or lysis of many types of cells such as erythrocytes, bacteria and tumor cells, results in disruption of the membrane and entry of water and electrolytes into the cell
5. Enhancement of antibody production - binding of c3b to its receptors on the surface of activated B cells greatly enhances antibody production.