title: Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome.
abstract: Complement is a major innate immune surveillance system. One of its most important regulators is the plasma protein factor H (FH). FH inactivation by mutations or by autoantibodies is associated with a thrombotic microangiopathy disease, atypical hemolytic uremic syndrome. In this study, we report the characterization of blood samples from 19 anti-FH Ab-positive atypical hemolytic uremic syndrome patients collected at the acute phase of the disease. Analyses of the functional consequences and epitope mapping, using both fluid phase and solid phase approaches, were performed. The anti-FH Abs perturbed FH-mediated cell protection (100%), inhibited FH interaction with C3 (46%), and caused C3 consumption (47%). The Abs were directed against multiple FH epitopes located at the N and C termini. In all tested patients, high titers of FH-containing circulating immune complexes were detected. The circulating immune complex titers correlated with the disease stage better than did the Ab titers. Our results show that anti-FH autoantibodies induce neutralization of FH at acute phase of the disease, leading to an overall impairment of several functions of FH, extending the role of autoantibodies beyond the impairment of the direct cell surface protection.
authors.affiliation: INSERM Unité Mixte de Recherche en Santé 872, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Blanc
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Yahya
authors.initials: Y
authors.lastname: Ashraf
authors.forename: Satu
authors.initials: S
authors.lastname: Hyvärinen
authors.forename: Sidharth Kumar
authors.initials: SK
authors.lastname: Sethi
authors.forename: Bruno
authors.initials: B
authors.lastname: Ranchin
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Ashima
authors.initials: A
authors.lastname: Gulati
authors.forename: Arvind
authors.initials: A
authors.lastname: Bagga
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.forename: T Sakari
authors.initials: TS
authors.lastname: Jokiranta
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Dragon-Durey
mesh_terms: D000208:Acute Disease; D000328:Adult; D001323:Autoantibodies / Q000502:physiology*; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D002648:Child; D003176:Complement C3 / Q000378:metabolism; D017242:Complement Factor H / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D009500:Neutralization Tests / Q000379:methods; D011485:Protein Binding / Q000276:immunology
chemical_list: D001323:Autoantibodies; D003176:Complement C3; D017242:Complement Factor H