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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
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.
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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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