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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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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 |
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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 |
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