Question

Name the three pathways of complement activation, and describe similarities, differences and major outcomes.

Answer 1

Complement:

• Complements are a group of proteins normally found in serum in an inactive form, but when activated they augment the immune responses.
• It constitutes about 5% of normal serum proteins
• They are antigen nonspecific: Their level does not increase following either infection or vaccination.
• It is species nonspecific.
• It is heat-labile (56°C for 30 minutes).
• It binds to the Fc region of antibody IgM.
• The site of synthesis of Complements: mainly by the liver, also in GIT, macrophage, and spleen.

Complement Pathways:

There are three pathways of complement activation.

1. Classical pathway: This is an Ab dependent pathway, triggered by the Ag-Ab complex.

2. Alternative pathway: This is an Ab independent pathway, triggered by the antigen directly.

3. Lectin pathway resembles the classical pathway, but it is Ab independent.

There are four main stages in the activation of any of the complement pathways:

1. Initiation of the pathway

2. Formation of C3 convertase

3. Formation of C5 convertase

4. Formation of membrane attack complex (MAC)

Complement activation :

All the complement proteins are synthesized in their active form and are activated by proteolysis.

Complements have two unequal fragments: large fragments and small fragments. The larger fragments are designated as 'b' and the smaller fragments are designated as 'a'. An exception is 'C2a' which is a larger fragment. The larger fragment participates in the cascade reaction of the complement pathway and the smaller fragment diffuses away to mediate the other functions.

Cascade reaction:

The fragments of complements interact in a sequential manner which results in the formation of the complex.

Similarities and differences:

• All three pathways differ from each other in their initiation until the formation of C3 convertase.
• Then, the remaining stages are identical in all the pathways.

• Complement pathways: similarities and differences

• Classical pathway:

Initially, there is binding of C1 to the antigen-antibody complex. Later, there is the formation of C3 convertase. Then, there is formation of C5 convertase of the classical pathway. Finally, there is the formation of the Membrane Attack Complex. It destroys the target cell by attacking the cell membrane. This process is called complement-mediated cytotoxicity.

• Alternative pathway :

It is initiated by various cell surface constituents (bacterial endotoxin). The first complement component involved is free C3 in the serum. The formation of C3 convertase involves the binding of factor B to C3b. Then, the remaining two steps of complement activation are the same as that of the classical pathway.

• Lectin pathway :

It is initiated when the mannose-binding lectin (MBL) binds to mannose residue on the microbial surface. After binding to MBL, another host protein called MBL- associated serine protease forms a complex with mannose-binding lectin. Then, there is the formation of C3 convertase. The remaining steps of complement activation are similar to that of the classical pathway.

Major outcomes:

• Target cell lysis: MAC (membrane attack complex) makes pores or channels in the target cell membrane.
• Inflammatory response: Complement by-products such as C3a, C4a and C5a act as anaphylatoxins and chemotactic agents
• Opsonization: C3b and C4b act as major opsonins.
• It removes the immune complexes from blood to the spleen (by C3b)
• Viral neutralization