Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated Membranoproliferative GN

Abstract

In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti-C3b IgG, and five patients with anti-FB and anti-C3b IgG. Of these 15 patients, ten were diagnosed with Ig-MPGN. Among those patients with available data, 92% had a nephrotic syndrome, 64% had AKI, and 67% had a documented infection. Patients negative for anti-C3b and anti-FB IgG had much lower rates of infection (17 [25%] patients with C3G and one [10%] patient with Ig-MPGN). After 48 months, four of 15 (26%) positive patients had developed ESRD or died. All 15 patients had high plasma Bb levels, six (40%) patients had low levels of C3, and nine (60%) patients had high levels of soluble C5b9. , IgG purified from patients with anti-FB Abs selectively enhanced C3 convertase activity; IgG from patients with anti-C3b/anti-FB Abs enhanced C3 and C5 cleavage. IgG from patients with anti-C3b Abs stabilized C3bBb and perturbed C3b binding to complement receptor 1 but did not perturb binding to factor H. In conclusion, the prevalence of anti-C3b/anti-FB Abs and alternative pathway activation is similar in Ig-MPGN and C3G, suggesting similar pathogenic mechanisms. Identification of the underlying defect in Ig-MPGN could lead to improved treatment.

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

“…3 Significantly different from double positive patients. 4 Significantly different from C3NeF positive patients. LPV: likely pathogenic variant; C3NeF: C3 nephritic factor; C4NeF: C4 nephritic factor.…”

“…Autoantibodies against complement components occur in a significant proportion of cases with C3G or IC-MPGN, although only a few large-scale studies have analyzed their presence in these conditions. Case reports [4,12,16,21,23,24] and case series studies [2], [5,31,32] described the presence of nephritic factors and other complement autoantibodies, but still, approximately 30 to 60% of the C3G cases remain without identified pathogenic factors (autoantibodies to complement components or pathogenic variants of disease-associated complement genes).…”

“…C3G is characterized by more than two magnitude higher C3 staining in immunofluorescence microscopy than any other immune reactant and it is divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), where osmophil dense deposits are present within the basement membrane on electronmicroscopy [3]. Mutations in the genes encoding the regulators or components of the complement system, such as Factor H (CFH), Factor H-related protein 5 (CFHR5), Factor I (CFI), membrane cofactor protein (CD46), thrombomodulin (THBD), or Factor B (CFB) and complement C3 protein (C3) are present in about 30% of C3 glomerulopathy patients [4][5][6][7][8], whereas acquired factors (autoantibodies) may be identified as well in a significant subgroup (40-80%)of these cases [9][10][11]. The latter include several different autoantibodies that can be detected in the patients' sera such as anti-Factor H, anti-C3b, anti-Factor B [4,[12][13][14][15][16] and C3-or C4 nephritic factors which are present mostly in patients with complement-mediated renal diseases.…”

Update on C3 Glomerulopathy: A Complement-Mediated Disease

“…In addition, NeFs against the classic/lectin pathway C3 convertase (known as C4NeFs) have also been described [20]. Other autoantibodies include anti-FH, anti-FB, and anti-C3b [31]. However, while the pathogenic role of NeFs in C3G is well established, still there are some uncertainties concerning the best diagnostic methods for their detection, their correlation with the clinical course of the disease, and the most effective therapy to target the production of these autoantibodies [20].…”

Immunological features of patients affected by Barraquer-Simons syndrome

“…Their study revealed that they prevented the spontaneous dissociation of the C3 convertase of the AP and increased its normal half-life, thus causing systemic complement activation in the patient [30]. Additional patients with anti-FB and anti-C3b autoantibodies have since been reported in C3G and Ig-Associated Membranoproliferative Glomerulonephritis cohorts supporting their pathological role in the dysregulation of the AP [31,32]. Therefore, further studies are needed in order to clarify if anti-FB and anti-C3b autoantibodies have a primary mechanistic role in the pathology of the lipodystrophy or if they rather secondarily arise as a consequence of the increase in circulating complement proteins produced due to unabated complement activation in the presence of C3NeF.…”