C5a is a protein fragment released from complement component C5. C5a is an extremely potent proinflammatory mediator, as well as a potent chemotactic factor for neutrophils and other leukocytes. It causes histamine release, increases in vascular permeability, induces several cytokines production from leukocytes, enhances neutrophil-endothelial cell adhesion, and augments the humoral and cell-mediated immune response. C5a is quickly metabolised by carboxypeptidases, forming the less potent C5adesArg. Acting via a classical G protein-coupled receptor, CD88, C5a and C5adesArg exert a number of effects essential to the innate immune response, while their actions at the more recently discovered non-G protein-coupled receptor, C5L2 (or GPR77), remain unclear. The widespread expression of C5a receptors throughout the body allows C5a to elicit a broad range of effects. Thus, C5a has been found to be a significant pathogenic driver in a number of immuno-inflammatory diseases, making C5a inhibition an attractive therapeutic strategy. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accordingly, the anaphylatoxin C5a is implicated in a variety of diseases such as rheumatoid arthritis, systemic lupus erythematosus, reperfusion injury, Alzheimer's disease, and sepsis.
Complement is defined as key part of innate immunity and as the first line of defense in the fight against invading pathogens. Complement 3 (C3) is the most abundant component of the complement cascade and the convergent point for all three major complement activation pathways: namely classical, alternative and mannose-binding lectin pathways. Complement activation leads to the formation of the C3 convertase, which cleaves C3 into the key effector molecules, C3a (anaphylatoxin) and C3b (opsonin) which then drive microbe removal. By binding to C3a receptor (C3aR), C3a exhibits potent anaphylatoxin activity, including increased vascular permeability, triggering degranulation of mast cells, inflammation, and activating leukocytes.
Complement component C8 is a constituent of the membrane attack complex, C8 alpha, C8 beta and C8G. C8G is a secreted protein and comsists a disulfide-linked C8 alpha-gamma heterodimer and a non-covalently associated C8 beta chain. C8 alpha and C8 beta play an important role in complement-mediated bacterial killing together.C8 is involved in the formation of Membrane Attack Complex on bacterial cell membranes. C8 binds to the C5B-7 complex, forming the C5B-8 complex. C5-B8 binds C9 and acts as a catalyst in the polymerization of C9. The gamma subunit seems to be able to bind retinol. Patients lacking C8 are susceptible to certain bacterial infections.
Complement Factor B (CFB) belongs to the peptidase S1 family of enzymes. It is expressed by hepatocytes and macrophages and localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. CFB which is a component of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb. The active subunit Bb is a serine protease which associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation.
Complement factor H, also known as H factor 1, and CFH, is a sialic acid containing glycoprotein that plays an integral role in the regulation of the complement-mediated immune system that is involved in microbial defense, immune complex processing, and programmed cell death. Factor H protects host cells from injury resulting from unrestrained complement activation. CFH regulates complement activation on self cells by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3 convertase, C3bBb. CFH protects self cells from complement activation but not bacteria/viruses. Due to the central role that CFH plays in the regulation of complement, there are many clinical implications arrising from aberrant CFH activity. Mutations in the Factor H gene are associated with severe and diverse diseases including the rare renal disorders hemolytic uremic syndrome (HUS) and membranoproliferative glomerulonephritis (MPGN) also termed dense deposit disease (DDD), membranoproliferative glomuleronephritis type II or dense deposit disease, as well as the more frequent retinal disease age related macular degeneration (AMD). In addition to its complement regulatory activities, factor H has multiple physiological activities and 1) acts as an extracellular matrix component, 2) binds to cellular receptors of the integrin type, and 3) interacts with a wide selection of ligands, such as the C-reactive protein, thrombospondin, bone sialoprotein, osteopontin, and heparin.
Complement Factor H (CFH) is a secreted protein which is a member of the regulators of complement activation family and is a complement control protein. It is expressed by the liver and secreted in plasma. Its principal function is to regulate the Alternative Pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses, because it binds to glycosaminoglycans (GAGs) that are generally present on host cells but not, normally, on pathogen surfaces.
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