What is the Classical Complement Pathway?

Recognition and Activation Phase:

The classical pathway is the major effector function of the complement system in humoral immune response. Either IgG or IgM antibody bound to antigen triggers the classical pathway. Binding of antibody to antigen exposes “Fc region”- the binding and activating site for the first complement component CI.

When at least two Fc regions of antigen bound antibodies are exposed, the Clq sub components of CI get activated and bind to the exposed sites initiating the cascade of complement activation reactions. Clq is a hexameric molecule comprised of “stalks” and “knobs”. It undergoes a conformational change after binding with Fc region.

The protruding knobs of the Clq molecule bind to exposed Fc sites of antigen-bound antibody, and initiates activation of the remaining sub components of CI, followed by the cascade of remaining activation reactions. Pairs of activated Clr and Cls molecules associate with one another, to make a shape of figure-8.

This figure-8 fits over the knobs of the Clq molecule to make a complete, intact CI molecule. Activated Cls are responsible for the cleavage of the next two components C4 and C2 involved in the reactions.

(Remember, the numbers indicate the order in which the components were discovered, not the order in which they activate in the cascade). C4 is cleaved into two unequal fragments C4a and C4b. The larger C4b molecule attaches to the target membrane nearby while the small C4a molecule floats away.

The free surface of deposited C4b is available to interact with the next complement component C2. Activated Cls again cleave the C2 molecule into two fragments C2a and C2b. C2b fragment binds with the CI, C4b complex and C2b fragment floats away.

C4b2b is also known as the C3 convertase, because its role is to convert the next complement component. The C3 convertase of the classical pathway splits C3 into two fragments, C3a and C3b. The convertase has the ability to cleave multiple C3 molecules, forming plenty of C3a and C3b fragments. The C3a fragments float away and have a role in inducing an inflammatory response.

The C3b binds to the C4b2b to form C4b2b3b complex or C5 convertase. Like the C3 convertase C5 convertase catalyzes the cleavage of number of C5 complement component molecules into C5a and C5b before it reverts to inactivity. C5a floats away and contributes to inflammation while the C5b fragment binds to the cell surface on which the antigen is present.

This binding of C5b to the cell surface is the initial step in the formation of the membrane attack complex (MAC). The period of activation reactions, up to the conversion of inactive C5 into active form are considered as enzymatic phase of complement system. C5a is a powerful chemo attractant of neutrophils and monocytes.

The attack phase

Attachment of C5b to the membrane leads to uncovering of binding sites on C6 and C7.

The C6 and C7 components with active sites join C5b on cell membrane resulting in the formation of membrane bound C5b67 complex. This trimolecular membrane bound complex initiates binding of C8 to the cell membrane along with them.

The C5b678 complex acts as a receptor for a variable number of membrane- disrupting C9 molecules. The resultant C5b678 and poly-C9 complex is known as “membrane attack complex.”(MAC).

The MAC polymerizes membrane constituents and creates a Trans membrane channel of about 1000A in diameter. The Tran’s membrane pore or lesion results lysis of the target cell.