title: Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome.
abstract: Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1. Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts. A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n=13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homo- or heterozygous for the CFHR1 gene (n=6) was heterogeneous. No significant changes apart from total antibody titer were observed during follow-up in each patient. Fine epitope mapping with recombinant FH SCR19-20 containing single amino acid mutations showed significantly reduced binding in 6 out of 14 patients. In most cases, autoantibody binding to residues 1183-1189 and 1210-1215 was impaired, revealing a major common autoantibody epitope. Avidities showed variations between patients, but in most cases the avidity index did not change upon time. Most autoantibodies were IgG3, and all but three presented only with kappa or with lambda light chains. Although the pathogenic role of anti-FH autoantibodies in aHUS is well established, this study shows autoantibody heterogeneity among patients, but no significant variation in their characteristics over time in each patient. The presence of a single light chain in 16 out of 19 patients and the limited number of recognized epitopes suggest a restricted autoantibody response in most patients.
authors.affiliation: Immunology Unit, University Hospital "La Paz"-IdiPAZ, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 754, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Nozal
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 754, Madrid, Spain; Complement Research Group, Research Unit, University Hospital "La Paz"-IdiPAZ, Madrid, Spain.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Bernabéu-Herrero
authors.affiliation: MTA-ELTE Immunology Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Barbara
authors.initials: B
authors.lastname: Uzonyi
authors.affiliation: Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Szilágyi
authors.affiliation: Department of Bacteriology and Immunology and Research Programs Unit, Immunobiology, University of Helsinki and Helsinki University Hospital, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Hyvärinen
authors.affiliation: Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
authors.affiliation: Department of Bacteriology and Immunology and Research Programs Unit, Immunobiology, University of Helsinki and Helsinki University Hospital, Finland.
authors.forename: T Sakari
authors.initials: TS
authors.lastname: Jokiranta
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 754, Madrid, Spain; Complement Research Group, Research Unit, University Hospital "La Paz"-IdiPAZ, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.affiliation: Immunology Unit, University Hospital "La Paz"-IdiPAZ, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Unit 754, Madrid, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
authors.affiliation: MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary. Electronic address: mihaly.jozsi@gmx.net.
authors.forename: Mihály
authors.initials: M
authors.lastname: Józsi
mesh_terms: D000328:Adult; D000915:Antibody Affinity / Q000276:immunology; D065766:Atypical Hemolytic Uremic Syndrome / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D017242:Complement Factor H / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007223:Infant; D008297:Male
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017242:Complement Factor H
keywords: Atypical hemolytic uremic syndrome; Autoantibody; Autoimmunity; Avidity; Epitope mapping; Factor H