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Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance
B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA(+) RA c...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934703/ https://www.ncbi.nlm.nih.gov/pubmed/31882654 http://dx.doi.org/10.1038/s41598-019-56279-0 |
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author | Wang, Yan Lloyd, Katy A. Melas, Ioannis Zhou, Diana Thyagarajan, Radha Lindqvist, Joakim Hansson, Monika Svärd, Anna Mathsson-Alm, Linda Kastbom, Alf Lundberg, Karin Klareskog, Lars Catrina, Anca I. Rapecki, Stephen Malmström, Vivianne Grönwall, Caroline |
author_facet | Wang, Yan Lloyd, Katy A. Melas, Ioannis Zhou, Diana Thyagarajan, Radha Lindqvist, Joakim Hansson, Monika Svärd, Anna Mathsson-Alm, Linda Kastbom, Alf Lundberg, Karin Klareskog, Lars Catrina, Anca I. Rapecki, Stephen Malmström, Vivianne Grönwall, Caroline |
author_sort | Wang, Yan |
collection | PubMed |
description | B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA(+) RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM(+) B cells and CD11c in IgA(+) memory. Moreover, both IgA(+) and IgG(+) double negative (IgD(−) CD27(−)) CD11c(+) B cells were increased in ACPA(+) RA, and there was a trend for elevation in a CXCR5/CCR6(high) transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p < 0.0001). Furthermore, both ACPA(+) and ACPA(−) RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM(+) B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG(+) B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA. |
format | Online Article Text |
id | pubmed-6934703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69347032019-12-30 Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance Wang, Yan Lloyd, Katy A. Melas, Ioannis Zhou, Diana Thyagarajan, Radha Lindqvist, Joakim Hansson, Monika Svärd, Anna Mathsson-Alm, Linda Kastbom, Alf Lundberg, Karin Klareskog, Lars Catrina, Anca I. Rapecki, Stephen Malmström, Vivianne Grönwall, Caroline Sci Rep Article B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA(+) RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM(+) B cells and CD11c in IgA(+) memory. Moreover, both IgA(+) and IgG(+) double negative (IgD(−) CD27(−)) CD11c(+) B cells were increased in ACPA(+) RA, and there was a trend for elevation in a CXCR5/CCR6(high) transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p < 0.0001). Furthermore, both ACPA(+) and ACPA(−) RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM(+) B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG(+) B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA. Nature Publishing Group UK 2019-12-27 /pmc/articles/PMC6934703/ /pubmed/31882654 http://dx.doi.org/10.1038/s41598-019-56279-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wang, Yan Lloyd, Katy A. Melas, Ioannis Zhou, Diana Thyagarajan, Radha Lindqvist, Joakim Hansson, Monika Svärd, Anna Mathsson-Alm, Linda Kastbom, Alf Lundberg, Karin Klareskog, Lars Catrina, Anca I. Rapecki, Stephen Malmström, Vivianne Grönwall, Caroline Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title | Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title_full | Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title_fullStr | Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title_full_unstemmed | Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title_short | Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance |
title_sort | rheumatoid arthritis patients display b-cell dysregulation already in the naïve repertoire consistent with defects in b-cell tolerance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934703/ https://www.ncbi.nlm.nih.gov/pubmed/31882654 http://dx.doi.org/10.1038/s41598-019-56279-0 |
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