title: The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease.
abstract: Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against complement factor H (CFH). It is unknown why nearly all patients with autoimmune aHUS lack CFHR1 (CFH-related protein-1). These patients have autoantibodies against CFH domains 19 and 20 (CFH19-20), which are nearly identical to CFHR1 domains 4 and 5 (CFHR14-5). Here, binding site mapping of autoantibodies from 17 patients using mutant CFH19-20 constructs revealed an autoantibody epitope cluster within a loop on domain 20, next to the two buried residues that are different in CFH19-20 and CFHR14-5. The crystal structure of CFHR14-5 revealed a difference in conformation of the autoantigenic loop in the C-terminal domains of CFH and CFHR1, explaining the variation in binding of autoantibodies from some aHUS patients to CFH19-20 and CFHR14-5. The autoantigenic loop on CFH seems to be generally flexible, as its conformation in previously published structures of CFH19-20 bound to the microbial protein OspE and a sialic acid glycan is somewhat altered. Cumulatively, our data suggest that association of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between CFHR1 and the autoantigenic CFH epitope, suggesting a novel explanation for CFHR1 deficiency in the pathogenesis of autoimmune aHUS.
authors: From the Department of Bacteriology and Immunology, Medicum, and Immunobiology Research Program Unit, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki, Finland, the Institute of Biotechnology and arnab.bhattacharjee@helsinki.fi.
authors: Arnab
authors: A
authors: Bhattacharjee
authors: the Junior Research Group for Cellular Immunobiology, Leibniz Institute for Natural Product, Research and Infection Biology-Hans Knöll Institute, 07745 Jena, Germany.
authors: Stefanie
authors: S
authors: Reuter
authors: the Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, 1125 Budapest, Hungary, and.
authors: Eszter
authors: E
authors: Trojnár
authors: the Institute of Biotechnology and Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, 00014 University of Helsinki, Finland.
authors: Robert
authors: R
authors: Kolodziejczyk
authors: the Junior Research Group for Cellular Immunobiology, Leibniz Institute for Natural Product, Research and Infection Biology-Hans Knöll Institute, 07745 Jena, Germany.
authors: Harald
authors: H
authors: Seeberger
authors: From the Department of Bacteriology and Immunology, Medicum, and Immunobiology Research Program Unit, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki, Finland.
authors: Satu
authors: S
authors: Hyvärinen
authors: the MTA-ELTE Immunology Research Group and.
authors: Barbara
authors: B
authors: Uzonyi
authors: the Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, 1125 Budapest, Hungary, and.
authors: Ágnes
authors: Á
authors: Szilágyi
authors: the Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, 1125 Budapest, Hungary, and.
authors: Zoltán
authors: Z
authors: Prohászka
authors: the Institute of Biotechnology and Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, 00014 University of Helsinki, Finland.
authors: Adrian
authors: A
authors: Goldman
authors: the Junior Research Group for Cellular Immunobiology, Leibniz Institute for Natural Product, Research and Infection Biology-Hans Knöll Institute, 07745 Jena, Germany, MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary mihaly.jozsi@gmx.net.
authors: Mihály
authors: M
authors: Józsi
authors: From the Department of Bacteriology and Immunology, Medicum, and Immunobiology Research Program Unit, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki, Finland.
authors: T Sakari
authors: TS
authors: Jokiranta
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D003180:Complement C3b Inactivator Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary
chemical_list: D001323:Autoantibodies; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D000939:Epitopes; D010446:Peptide Fragments; D017242:Complement Factor H
keywords: Atypical Hemolytic Uremic Syndrome; Autoimmune Disease; Autoimmunity; Complement Regulation; Immunoglobulin G (IgG); Immunology; Structure-Function Study; Thrombotic Microangiopathy; X-ray Crystallography