The Role of Complement in Inflammatory Diseases From Behind the Scenes into the Spotlight

Abstract

Our understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a "complement" to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity.

Candidate inhibitors of porcine complement

“…C4b2a cleaves C3 to C3a and C3b and forms the C5 convertase The main function of the complement system is to detect and kill microorganisms, as well as maintain homeostasis through clearance of apoptotic cells and cell debris, and tissue regeneration (65)(66)(67)(68). Opsonization by C3b leading to phagocytosis is the most important mechanism, but for some pathogens like Neisseria-species, killing by direct lysis by the MAC is equally important (69).…”

Cancer and the Complement Cascade

“…This latter property is a recognized pathogenic factor in a wide spectrum of chronic inflammatory diseases, including rheumatoid arthritis (13), glomerulonephritis (14), atherosclerosis (15), asthma (16,17), and multiple sclerosis (18). Thus, it is not surprising that evidence for complement-mediated disease pathogenesis has centered primarily on dysfunctional immunity caused by the absence, alteration, or overactivity of complement proteins (19)(20)(21). The relationship grows even more complex with the growing body of evidence suggesting that complement proteins mediate cellular turnover, growth, and regeneration, including bone marrow stem cell engraftment, bone and cartilage development, neurogenesis, synaptogenesis, white matter healing, and regeneration of the liver, limb, and lens (22)(23)(24).…”

Anti-factor B autoantibody in dense deposit disease

“…The complement system, which consists of ~35 proteins, is a rapidly activated protein cascade that plays an important role in host defense against infections and in inflammatory processes (Walport 2001;Markiewski and Lambris, 2007). Complement can be activated via three major pathways, of which the alternative pathway shows a continuous low-level activation in plasma.…”