Abstract
Factor H (FH), a member of the regulators-of-complement-activation (RCA) family of proteins, circulates in human plasma at concentrations of 180–420 mg/L where it controls the alternative pathway (AP) of complement in the fluid phase and on cell surfaces. When the regulatory function of FH is impaired, complement-mediated tissue injury and inflammation occur, leading to diseases such as atypical hemolytic uremic syndrome (a thrombotic microangiopathy or TMA), C3 glomerulopathy (C3G) and monoclonal gammopathy of renal significance (MGRS). A pathophysiological cause of compromised FH function is the development of autoantibodies to various domains of the FH protein. FH autoantibodies (FHAAs) are identified in 10.9% of patients with aHUS, 3.2% of patients with C3G, and rarely in patients with MGRS. The phenotypic variability of FHAA-mediated disease reflects both the complexity of FH and the epitope specificity of FHAA for select regions of the native protein. In this paper, we have characterized FHAA epitopes in a large cohort of patients diagnosed with TMA, C3G or MGRS. We explore the epitopes recognized by FHAAs in these diseases and the association of FHAAs with the genetic deletion of both copies of the CFHR1 gene to show how these disease phenotypes are associated with this diverse spectrum of autoantibodies.
Highlights
Complement factor H (FH), a 155 KDa glycoprotein comprised of 20 short consensus repeat (SCR) domains, circulates in the blood at concentrations of 180–420 mg/L
Multiple epitopes of Factor H (FH) were recognized in six of the 37 FHR1-deficient aHUS patients, including four patients who were co-positive for FH autoantibodies (FHAAs) against N-terminus SCRs and two patients who were copositive for FHAAs against mid-SCRs 8-15
We report a retrospective study of FHAAs in aHUS and C3 glomerulopathy (C3G) patient cohorts from North America
Summary
Complement factor H (FH), a 155 KDa glycoprotein comprised of 20 short consensus repeat (SCR) domains, circulates in the blood at concentrations of 180–420 mg/L It functions as the major regulator of the alternative pathway (AP) of complement in the fluid phase and on cell surfaces. FH protects host surfaces from complement-mediated damage primarily through the two C-terminal SCRs, which recognize and bind to sialic acids, glycosaminoglycans (GAG), heparins, and a site on the C3bcleavage fragment C3d [3, 4] These binding events ensure that the DAA function of FH is targeted to host cell surfaces, thereby protecting these cells from indiscriminate complement amplification that might otherwise be associated with surface deposition of C3b [5]
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