Complement

Complement is the name for a repertoire of blood plasma proteins that circulate around the body in an inactive state, waiting to be triggered into action by an invading pathogen. There are 3 possible outcomes once complement signaling has been triggered:

• Phagocytosis

• Inflammation

• Attack of the pathogen's membrane

During a complement response, an invading pathogen becomes coated in various complement-involved proteins. This signals to immune cells like macrophages that whatever lies beneath the protein coating must be destroyed (leading to phagocytosis). The signaling cascade of complement comprises a series of proenzymes ('zymogens') becoming cleaved and activated, then going on to cleave and activate more zymogen signaling molecules. The non-enzymatic cleavage produces of complement activation also serve as signalling molecules in their own right, serving to recruit more immune cells to the location of activation (leading to inflammation) The products of Complement proteins can also eliminate pathogens in their own right by creating pores in the membranes of invading pathogenic cells (leading to membrane attack). IgM is the best at initiating a complement response.

Classical Pathway

This pathway is initiated usually by an antibody binding to a pathogen and then the proximal complement protein, C1, binding on top. C1 can also bind the pathogen directly. IgM is the most effective antibody for initiating a classical complement response.

Alternative Pathway

This pathway skips a few steps of the classical pathway and is initiated by the spontaneous cleavage of a later stage complement protein called C3. This leads to the formation of the critical complement enzyme C3b convertase which then progresses the immune signaling cascade. Antibodies are not required for this pathway to be triggered.

Lectin Pathway

This pathway is initiated by molecules called lectins and ficolins that can bind to sugars on the outside of bacteria.

Outcomes of complement activation

All pathways ultimately led to the activation of the C3b convertase enzyme which is responsible for the production of two molecules: C3b and C3a. C3a acts as a signaling beacon to call more cells to the area which leads to the classical signs of inflammation in the area (redness, swelling, pain and localized heat). C3b binds to the surface of the pathogen, marking it for destruction (phagocytosis) or allowing the formation of a membrane attack complex (MAC) that porates the pathogen's membrane, eliminates the cell.