Anti-Factor B Antibodies and Acute Postinfectious GN in Children

Abstract

Background The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis. Methods This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia. Results All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity in vitro, confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity. Conclusions These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy. Significance Statement Acute postinfectious GN, the leading cause of acute nephritis in children, associates with transient complement activation of undetermined mechanism. Its clinical features overlap considerably with those of C3 glomerulopathy, a severe chronic condition. In this retrospective study, the authors demonstrated that in more than 90% of children with acute postinfectious GN, complement overactivation results from activation of the alternative pathway of the complement system, driven by transient presence of autoantibodies targeting factor B, a component of the alternative C3 convertase. They also identified crucial antibody binding sites on factor B, including one correlated to disease severity at onset. The presence of anti-factor B antibodies was highly specific to acute postinfectious GN, suggesting that screening for these antibodies might help clinicians distinguish the disorder during its acute phase from C3 glomerulopathy. Visual Abstract