Cargando…

Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms

Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed...

Descripción completa

Detalles Bibliográficos
Autores principales: Raposo, Bruno, Dobritzsch, Doreen, Ge, Changrong, Ekman, Diana, Xu, Bingze, Lindh, Ingrid, Förster, Michael, Uysal, Hüseyin, Nandakumar, Kutty Selva, Schneider, Gunter, Holmdahl, Rikard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949579/
https://www.ncbi.nlm.nih.gov/pubmed/24534192
http://dx.doi.org/10.1084/jem.20130968
_version_ 1782306913275346944
author Raposo, Bruno
Dobritzsch, Doreen
Ge, Changrong
Ekman, Diana
Xu, Bingze
Lindh, Ingrid
Förster, Michael
Uysal, Hüseyin
Nandakumar, Kutty Selva
Schneider, Gunter
Holmdahl, Rikard
author_facet Raposo, Bruno
Dobritzsch, Doreen
Ge, Changrong
Ekman, Diana
Xu, Bingze
Lindh, Ingrid
Förster, Michael
Uysal, Hüseyin
Nandakumar, Kutty Selva
Schneider, Gunter
Holmdahl, Rikard
author_sort Raposo, Bruno
collection PubMed
description Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (V(H)) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific V(H) alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.
format Online
Article
Text
id pubmed-3949579
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-39495792014-09-10 Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms Raposo, Bruno Dobritzsch, Doreen Ge, Changrong Ekman, Diana Xu, Bingze Lindh, Ingrid Förster, Michael Uysal, Hüseyin Nandakumar, Kutty Selva Schneider, Gunter Holmdahl, Rikard J Exp Med Brief Definitive Report Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (V(H)) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific V(H) alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases. The Rockefeller University Press 2014-03-10 /pmc/articles/PMC3949579/ /pubmed/24534192 http://dx.doi.org/10.1084/jem.20130968 Text en © 2014 Raposo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Raposo, Bruno
Dobritzsch, Doreen
Ge, Changrong
Ekman, Diana
Xu, Bingze
Lindh, Ingrid
Förster, Michael
Uysal, Hüseyin
Nandakumar, Kutty Selva
Schneider, Gunter
Holmdahl, Rikard
Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title_full Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title_fullStr Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title_full_unstemmed Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title_short Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
title_sort epitope-specific antibody response is controlled by immunoglobulin v(h) polymorphisms
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949579/
https://www.ncbi.nlm.nih.gov/pubmed/24534192
http://dx.doi.org/10.1084/jem.20130968
work_keys_str_mv AT raposobruno epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT dobritzschdoreen epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT gechangrong epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT ekmandiana epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT xubingze epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT lindhingrid epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT forstermichael epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT uysalhuseyin epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT nandakumarkuttyselva epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT schneidergunter epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms
AT holmdahlrikard epitopespecificantibodyresponseiscontrolledbyimmunoglobulinvhpolymorphisms