Sophie Chauvet1,2,3, Romain Berthaud3,4, Magali Devriese5, Morgane Mignotet5, Paula Vieira Martins5, Tania Robe-Rybkine1, Maria A Miteva3,6, Aram Gyulkhandanyan7, Amélie Ryckewaert8, Ferielle Louillet9, Elodie Merieau10, Guillaume Mestrallet11, Caroline Rousset-Rouvière12, Eric Thervet2,3, Julien Hogan13, Tim Ulinski14, Bruno O Villoutreix3,15, Lubka Roumenina1, Olivia Boyer3,4,16, Véronique Frémeaux-Bacchi17,5,3. 1. Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France. 2. Departments of Nephrology and. 3. Paris University, Paris, France. 4. Department of Pediatric Nephrology, AP-HP, Necker Hospital - Sick Children, Paris, France. 5. Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France. 6. INSERM U1268 Medicinal Chemistry and Translational Research, Cibles Thérapeutiques et Conception du Médicament UMR8038 Centre National de la Recherche Scientifique (CNRS), Paris, France. 7. University of Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, INSERM UMR S973, Paris, France. 8. Department of Nephrology, Rennes Hospital, Rennes, France. 9. Department of Pediatric Nephrology, Rouen Hospital, Rouen, France. 10. Department of Pediatric Nephrology, Tours Hospital, Tours, France. 11. Department of Pediatry, Villefranche sur Soane Hospital, Villefranche sur Soane, France. 12. Department of Pediatric Nephrology, Timone Hospital, Marseille, France. 13. Department of Pediatric Nephrology, AP-HP, Robert Debré Hospital, Paris, France. 14. Department of Pediatric Nephrology, AP-HP, Trousseau Hospital, Paris, France. 15. Laboratory of cristallography and biological Nuclear magnetic resonance, UMR 8015 CNRS, Paris, France; and. 16. Reference Center for Hereditary Kidney and Childhood Diseases (MARHEA), Imagine Institute, Paris, France. 17. Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France; veronique.fremeaux-bacchi@aphp.fr.
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.
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.
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