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Complement factor H

  • Author(s): Dinasarapu, Ashok Reddy
  • Chandrasekhar, Anjana
  • Jozsi, Mihaly
  • Subramaniam, Shankar
  • et al.
Abstract

Complement factor H (fH) is a single chain plasma glycoprotein (approximately 150 kDa in size), with 20 domains termed complement control protein (CCP) domains or short consensus repeats (SCR). The complement factor H gene (CFH) is located on chromosome 1q32 in the regulators of complement activation (RCA) gene cluster, adjacent to the genes that code for the Complement factor H-Related Proteins (CFHRs). The RCA cluster includes additional regulators containing SCR domains, such as C4 Binding Protein (C4BP), Complement receptor type 1 (CR1), Complement decay-accelerating factor (DAF), Membrane cofactor protein (MCP). fH and C4BP are fluid-phase (soluble) complement regulators, while the remaining are membrane-bound and all these regulators share similarities in their structure and function. fH prevents the formation of the alternative pathway C3 (C3bBb) and C5 (C3bBb3b) convertases. This inhibitory effect is either by competition with Complement factor B (fB) for C3b binding, by convertase decay acceleration activity or by acting as a cofactor for the Complement factor I (fI)-mediated degradation of C3b. Important targets for fH binding, in the neighborhood of C3b on host cells, are glycosaminoglycans and sialic acid (polyanionic molecules), which increase the affinity of fH for C3b. In addition to C3b and polyanionic molecules, fH also interacts with various endogenous molecules, such as pentraxins, extracellular matrix (ECM) proteins, prion protein, adrenomedullin, DNA, annexin-II and histones, to inhibit complement activation on certain host surfaces such as glomerular basement membrane, the extracellular matrix, and late apoptotic cells. CFH gene mutations and polymorphisms, and auto-antibodies against fH adversely affect regulatory and target recognition functions of fH. Some of the diseases associated with fH dysfunction are atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD; also termed membranoproliferative glomerulonephritis (MPGN) type II) and age-related macular degeneration (AMD). Interestingly, microbes and multicellular pathogens can recruit host fH to their surface in order to protect themselves from complement attack.

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