Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype

Background: C3 nephritic factors, i.e. autoantibodies that stabilize the C3 convertase of the alternative pathway are the most frequent acquired abnormality in C3 glomerulopathy and primary immunoglobulin-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 (68%) patients with low C3 levels and 8/8 (100%) patients with normal C3 levels were positive for C3 nephritic factors by haemolytic 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 9 with a double-function, 6 only enhancing the C3bBb formation, and 3 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 sC5b-9 levels. The stabilization of C3bBb did not correlate with C3 or sC5b-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 to 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.