Contributors: Institut de Biologie du Développement de Marseille (IBDM); Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS); Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)); École Pratique des Hautes Études (EPHE); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); Laboratoire d'Immunologie et Immunopathologie CHU Poitiers (CNRS URA 1172); Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers La Milétrie )-Centre National de la Recherche Scientifique (CNRS); Service d'immunologie HEGP, Paris; Hôpital Européen Georges Pompidou APHP (HEGP); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO); Service de Néphrologie-transplantation-dialyse Bordeaux; CHU Bordeaux; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Service de Néphrologie Rouen; CHU Rouen; Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN); Normandie Université (NU); Vascular research center of Marseille (VRCM); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre Hospitalier Universitaire de Toulouse (CHU Toulouse); CHU Tenon AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers La Milétrie ); Laboratoire d’immunologie Hôpital Européen Georges Pompidou - APHP; KIDNEEDS research grant 2015, Fondation du rein (FRM, Prix 2012 FDR), Association pour l'Information et la Recherche dans les maladies Rénales génétiques (AIRG France), Fondation Pour La Recherche Medicale (FDM 20130727355), Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales (SC, VF-B); ANR-17-CE18-0015,VINP,monopDNA-Nanoparticules Virus-Inspirées pour transfert de gènes.(2017); European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012)
نبذة مختصرة : International audience ; C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of "monoclonal gammopathy of renal significance." However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of Chauvet et al. C3 Glomerulopathy and Monoclonal Gammopathy complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy.
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