Autoantibodies to complement components in C3 glomerulopathy and atypical hemolytic uremic syndrome

Abstract

The alternative pathway of complement is implicated in the pathogenesis of several renal diseases, such as atypical hemolytic uremic syndrome, dense deposit disease and other forms of C3 glomerulopathy. The underlying complement defects include genetic and/or acquired factors, the latter in the form of autoantibodies. Because the autoimmune forms require a specific treatment, in part different from that of the genetic forms, it is important to detect the autoantibodies as soon as possible and understand their characteristics. In this overview, we summarize the types of anti-complement autoantibodies detected in such diseases, i.e. autoantibodies to factor H, factor I, C3b, factor B and those against the C3 convertases (C3 nephritic factor and C4 nephritic factor). We draw attention to newly described autoantibodies and their characteristics, and highlight similarities and differences in the autoimmune forms of these diseases.

Functional Characterization of Autoantibodies against Complement Component C3 in Patients with Lupus Nephritis

“…The antibodies of the patient JTH recognized primarily C3 and C3b, suggesting the presence of a conformational epitope, located in the C3b portion, lost after the cleavage of C3b. No patient was positive for anti-C3d antibodies, similar to the patients with SLE (13), DDD (7), and aHUS (26). Interestingly, the plasma of only one of the two DDD patients recognized C3c, and neither were positive for iC3b (7), contrary to the aHUS patient, whose antibodies recognized iC3b.…”

“…Using an ELISA-based approach, anti-C3 autoantibodies were found only rarely in other diseases, including in 2 of 20 and 1 of 18 patients with rheumatoid arthritis in two different cohorts (12,14), in two isolated patients with DDD (7), and one isolated patient with atypical hemolytic uremic syndrome (aHUS) (26), and no patient was positive in a cohort of primary biliary cirrhosis (14). Early studies performed by an agglutination technique (27,28) detected the presence of immunoconglutinins, which turned out to be anti-C3 and/or anti-C4 autoantibodies, in patients with acute nephritis (29), with nephrotic syndrome (16,17), in cases with ulcerative colitis, and in Crohn disease patients (15).…”

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

“…FH autoantibodies have also been identified in patients with C3G, (Blanc et al 2015;Goodship et al 2012;Jozsi et al 2014;Nozal et al 2012). In this disease, autoantibodies show a binding preference for the N-terminal complement regulatory domains of FH (SCRs1-4) and they do not associate with CFHR1 deletion.…”

Complementopathies

“…While many patients with aHUS will have identifiable genetic susceptibility factors, approximately 10 percent of patients have detectable autoantibodies against CFH or other complement components [79]. In some cases, these may represent acquired autoimmune forms of aHUS, but in other cases, autoantibodies have been found in conjunction with alterations in complement genes.…”