Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Abstract

Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway–mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

The role of the alternative pathway of complement activation in glomerular diseases

“…C3Nef frequently coexists with anti-CFH, possibly having a synergistic effect on AP dysregulation in plasma. In a single report, anti-CFH was also associated with monoclonal Ig (35% cases in the small group of 17 patients), which is in line with previous reports of monoclonal Ig pathogenic involvement in C3G [82,83,99].…”

“…In MPGN I patients, Servais et al reported low AP proteins levels, such as C3, CFB, CFH, and CFI (in 46.3, 34.1, 4.9, and 7.3% of cases, respectively) and the prevalence of the C3NeF (in 53.6% cases), what suggested the AP activation [62]. In the other studies, anti-C3b, anti-CFB, and anti-CFH antibodies have been found in Ig-MPGN patients (Table 2) [95,99]. Recent reports have also shown that genetic abnormalities of the AP proteins may be present in immune-complex GN ( Table 1).…”

“…Various autoantibodies have different mechanisms of AP dysregulation. The anti-CFH antibody is directed precisely to the N-terminal end of CFH (SCR 1-4), resulting in the loss of CFH regulation in plasma [95,99]. C3Nef frequently coexists with anti-CFH, possibly having a synergistic effect on AP dysregulation in plasma.…”

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

“…There were no changes in isotype or light chain of the FH autoantibodies over time. Blanc et al described that a restriction of light chains in FH autoantibody positive patients was found in C3 glomerulopathy (C3G), in association with monoclonal gammopathy, but not in autoimmune aHUS (Blanc et al 2015).…”

“…Recently, Blanc et al studied FH:autoantibody complexes in the presence of various NaCl concentrations (Blanc et al 2015), but a detailed analysis regarding the avidity profiles and avidity indexes of the FH autoantibodies in serial samples of aHUS patients is currently lacking.…”