Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype

Key Points Dysregulation of the C3bBb convertase is a key factor in the pathogenesis of C3 glomerulopathy and primary Ig-mediated membranoproliferative GN. IgG-driven increase of the C3bBb convertase formation was correlated with C3 consumption. IgG antibodies that promote the formation and the stabilization of the C3bBb convertase were associated with the severity of C3 glomerulopathy. Background C3 nephritic factors, that is, autoantibodies that stabilize the C3 convertase of the alternative pathway are the most frequent acquired abnormality in C3 glomerulopathy and primary Ig-mediated membranoproliferative GN (Ig-MPGN). Methods Our study included 27 patients with C3 glomerulopathy ( n =21) or Ig-MPGN ( n =6), of whom 78% were children at disease onset. At the time of sampling, 13/19 patients (68%) with low C3 levels and 8/8 patients (100%) with normal C3 levels were positive for C3 nephritic factors by hemolytic assay. Using novel Luminex assays, we performed a screening for IgG that recognize and affect the formation and/or the stabilization of the alternative pathway C3 convertase (C3bBb). Results Using Luminex assays, an increase in C3bBb formation and/or stabilization was observed in the presence of IgG from 18/27 patients, including nine with a double-function, six only enhancing the C3bBb formation, and three that exclusively stabilized C3bBb. All patients presenting a formation and stabilization function had a low C3 level versus 55% without this double-function. The level of C3bBb formation correlated to the plasmatic C3 but not soluble C5b-9 levels. The stabilization of C3bBb did not correlate with C3 or soluble C5b-9 levels. At the last follow-up, 5/27 patients (19%) reached kidney failure after a median delay of 87 (52–119) months. The patients positive for double-function anti-C3bBb antibodies had a 5-year kidney survival of 70% compared with 100% in those negative ( P = 0.02). Conclusions Our findings highlight the association of the dual function of C3bBb formation and stabilization with severe C3 consumption and poor kidney survival in C3 glomerulopathy and Ig-MPGN.