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Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that thes...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577851/ https://www.ncbi.nlm.nih.gov/pubmed/26371186 http://dx.doi.org/10.1084/jem.20150585 |
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author | Kolhatkar, Nikita S. Brahmandam, Archana Thouvenel, Christopher D. Becker-Herman, Shirly Jacobs, Holly M. Schwartz, Marc A. Allenspach, Eric J. Khim, Socheath Panigrahi, Anil K. Luning Prak, Eline T. Thrasher, Adrian J. Notarangelo, Luigi D. Candotti, Fabio Torgerson, Troy R. Sanz, Ignacio Rawlings, David J. |
author_facet | Kolhatkar, Nikita S. Brahmandam, Archana Thouvenel, Christopher D. Becker-Herman, Shirly Jacobs, Holly M. Schwartz, Marc A. Allenspach, Eric J. Khim, Socheath Panigrahi, Anil K. Luning Prak, Eline T. Thrasher, Adrian J. Notarangelo, Luigi D. Candotti, Fabio Torgerson, Troy R. Sanz, Ignacio Rawlings, David J. |
author_sort | Kolhatkar, Nikita S. |
collection | PubMed |
description | Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell–intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells. |
format | Online Article Text |
id | pubmed-4577851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45778512016-03-21 Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome Kolhatkar, Nikita S. Brahmandam, Archana Thouvenel, Christopher D. Becker-Herman, Shirly Jacobs, Holly M. Schwartz, Marc A. Allenspach, Eric J. Khim, Socheath Panigrahi, Anil K. Luning Prak, Eline T. Thrasher, Adrian J. Notarangelo, Luigi D. Candotti, Fabio Torgerson, Troy R. Sanz, Ignacio Rawlings, David J. J Exp Med Article Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell–intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells. The Rockefeller University Press 2015-09-21 /pmc/articles/PMC4577851/ /pubmed/26371186 http://dx.doi.org/10.1084/jem.20150585 Text en © 2015 Kolhatkar 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 | Article Kolhatkar, Nikita S. Brahmandam, Archana Thouvenel, Christopher D. Becker-Herman, Shirly Jacobs, Holly M. Schwartz, Marc A. Allenspach, Eric J. Khim, Socheath Panigrahi, Anil K. Luning Prak, Eline T. Thrasher, Adrian J. Notarangelo, Luigi D. Candotti, Fabio Torgerson, Troy R. Sanz, Ignacio Rawlings, David J. Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title | Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title_full | Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title_fullStr | Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title_full_unstemmed | Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title_short | Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome |
title_sort | altered bcr and tlr signals promote enhanced positive selection of autoreactive transitional b cells in wiskott-aldrich syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577851/ https://www.ncbi.nlm.nih.gov/pubmed/26371186 http://dx.doi.org/10.1084/jem.20150585 |
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