Complement System

The complement system, an enzyme cascade resembling the coagulation system, is built from 48 proteins, 9 different cell membrane proteins and is at work every day, in the healthy individual.

Avacopan  –> the orally administered C5aR inhibitor might reduce inflammatory damage in patients suffering from ANCA-associated vasculitis.

Genetic polymorphisms of C3 or of regulatory proteins can be predisposing for definite diseases, such as haemolytic uremic syndrome, HUS. If complement activation maintains health, its overreaction/persistent activation by autoantigen-antibody complexes leads to inflammatory reaction in those organs that contain much of the reticuloendothelial system (lung, liver, spleen, bone marrow) or where the microvasculature is quite strongly developed (kidney, skin). C5a may prime retinal pigment epithelial cells for inflammasome activation. Crosstalk C –>  growth factor receptors, inflammasomes, metabolic sensors and the Notch system is seen.

The extent of complement overreaction can be measured by exploring the concentration of complement breakdown products, such as C3a and C5a or C3d. Therapeutic downregulation of complement is possible and finds increasing interest of clinicians: TP10, soluble complement receptor 1 is a novel inhibitor for C3 and C5 convertases and eculizumab is a humanized, monoclonal, single-chain antibody fragment that inhibits C5 – both are promising therapeutic options.

Diagnostic procedures are commercially available (e.g. from eurodiagnostica.com).
Trials