Complement System

Complement System


The complement system comprises an integrated network of proteins that forms part of the innate immune system. The three complement activation pathways (classical, lectin and alternative) activate C3 and generate C3b, feed into the amplification loop before activating the terminal pathway.


The complement system discriminates between foreign and host surfaces via proteins that are critical to complement activation and complement regulation.


Component C3 (C3) and Factor B play an important role in complement activation. Activated C3 in the form of C3b binds FB to form the C3 convertase of the alternative pathway (C3bBb). This cleaves more C3 into C3b to complete an amplification loop.


Regulators of C3bBb are present on the surface of host cells and in the fluid phase. Complement Factor H (FH) and complement Factor I (FI) regulate the alternative pathway in the fluid phase. membrane-bound regulators include membrane co-factor protein (CD46, MCP) decay accelerating factor (DAF, CD55) and complement receptor 1 (CR1, CD35).


The formation of C5 convertase (C3bBbC3b) results in the cleavage of the complement component C5 and activates the terminal pathway. Eculizumab, the only licensed complement inhibitor approved for clinical use, binds C5 and prevents its cleavage by C3bBbC3b.


A family of FH-related (FHR) proteins also play a role in complement regulation. Three of these, FHR1, FHR2 and FHR5 exist in homo- and hetero-dimeric form. As dimers, these FHR proteins compete with the ability of FH to regulate complement on cell surfaces.


 Summary of complement pathways