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. 2020 Dec 15:11:607211.
doi: 10.3389/fimmu.2020.607211. eCollection 2020.

Factor H Autoantibodies and Complement-Mediated Diseases

Yuzhou Zhang  1 , Nicolo Ghiringhelli Borsa  1 , Dingwu Shao  1 , Arthur Dopler  2 , Michael B Jones  1 , Nicole C Meyer  1 , Gabriella R Pitcher  1 , Amanda O Taylor  1 , Carla M Nester  1 , Christoph Q Schmidt  2 , Richard J H Smith  1
Affiliations

Factor H Autoantibodies and Complement-Mediated Diseases

Yuzhou Zhang et al. Front Immunol. .

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.

Keywords: C3 glomerulopathy; atypical hemolytic uremic syndrome; autoantibodies; complement; factor H; monoclonal gammopathy of renal significance.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
FH autoantibodies (FHAAs) and key biomarkers at the age-of-onset of disease in patients with aHUS and C3G. Patient with M- proteins are in red. (A) Age; (B) FHAA titers in aHUS and C3G; (C) FHAAs (C3G and aHUS) with and without FHR1; (D) FH levels; (E) C3 levels; (F) C4 levels. Solid lines: medians. Dashed lines: normal cutoff based on results from 300 healthy individuals. *P < 0.05 and ****P < 0.0001 by Mann-Whitney U test.
Figure 2
Figure 2
Epitopes of factor H autoantibodies (FHAAs) targeting domains on factor H (FH). Recombinant FH fragments (SCRs) and the mini FH construct are shown above a schematic of FH. Below are shown the epitope mapping results for aHUS (n=49) and C3G (n=19) patients (solid lines = positive FHAA results, dash lines = negative FHAA results).
See this image and copyright information in PMC

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