44 - Complement System in Disease

Abstract

“Complement” is an ancient innate immune system. Initially, it was likely designed to handle cellular debris and invasion by pathogens, even in single cell organisms. In host defense, its two major functions are mediated by opsonization and membrane perturbation (including the lysis of gram negative bacteria and enveloped viruses). In parallel, small protein fragments (anaphylatoxins) are liberated that engage receptors to promote the inflammatory response. Through these activities, the complement system also serves as nature’s adjuvant to trigger the adaptive immune system. The three pathways evolved to work in seconds to protect the circulation from infections. In evolution, lectins and then antibodies became more rapid and specific triggers of their respective pathways. Complete deficiency of a complement system activating component predisposes to recurrent bacterial infections (particularly pneumococcal for early and meningococcal for late pathway) and autoimmunity, namely systemic lupus erythematosus. If a regulator is deficient secondary due to a rare genetic mutation, there is too much activation for a given degree of injury predisposing to paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and age-related macular degeneration. Therapeutic agents, particularly monoclonal antibodies to components of each of the three major pathways, are in development. A monoclonal antibody to C5 is Food and Drug Administration approved to treat PNH and aHUS. The complement system’s role in the pathophysiology of many chronic inflammatory conditions and in autoantibody-mediated diseases remains to be defined.