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Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice

Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularit...

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Autores principales: O’Sullivan, Brendan J., Yekollu, Suman, Ruscher, Roland, Mehdi, Ahmed M., Maradana, Muralidhara Rao, Chidgey, Ann P., Thomas, Ranjeny
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972300/
https://www.ncbi.nlm.nih.gov/pubmed/29872433
http://dx.doi.org/10.3389/fimmu.2018.01092
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author O’Sullivan, Brendan J.
Yekollu, Suman
Ruscher, Roland
Mehdi, Ahmed M.
Maradana, Muralidhara Rao
Chidgey, Ann P.
Thomas, Ranjeny
author_facet O’Sullivan, Brendan J.
Yekollu, Suman
Ruscher, Roland
Mehdi, Ahmed M.
Maradana, Muralidhara Rao
Chidgey, Ann P.
Thomas, Ranjeny
author_sort O’Sullivan, Brendan J.
collection PubMed
description Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB(−/−) mice, which have spontaneous multiorgan autoimmune disease. RelB(−/−) thymi were organized, with medullary structures containing AIRE(−) mTECs, DCs, and CD4(+) thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB(−/−) thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB(+) DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation.
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spelling pubmed-59723002018-06-05 Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice O’Sullivan, Brendan J. Yekollu, Suman Ruscher, Roland Mehdi, Ahmed M. Maradana, Muralidhara Rao Chidgey, Ann P. Thomas, Ranjeny Front Immunol Immunology Polymorphisms impacting thymic function may decrease peripheral tolerance and hasten autoimmune disease. The NF-κB transcription factor subunit, RelB, is essential for the development and differentiation of medullary thymic epithelial cells (mTECs): RelB-deficient mice have reduced thymic cellularity and markedly fewer mTECs, lacking AIRE. The precise mechanism of this mTEC reduction in the absence of RelB is unclear. To address this, we studied mTECs and dendritic cells (DCs), which critically regulate negative selection, and thymic regulatory T-cells (tTreg) in RelB(−/−) mice, which have spontaneous multiorgan autoimmune disease. RelB(−/−) thymi were organized, with medullary structures containing AIRE(−) mTECs, DCs, and CD4(+) thymocytes, but fewer tTreg. Granulocytes infiltrated the RelB(−/−) thymic cortex, capsule, and medulla, producing inflammatory thymic medullary atrophy, which could be treated by granulocyte depletion or RelB(+) DC immunotherapy, with concomitant recovery of mTEC and tTreg numbers. These data indicate that central tolerance defects may be accelerated by autoimmune thymic inflammation where impaired RelB signaling impairs the medullary niche, and may be reversible by therapies enhancing peripheral Treg or suppressing inflammation. Frontiers Media S.A. 2018-05-22 /pmc/articles/PMC5972300/ /pubmed/29872433 http://dx.doi.org/10.3389/fimmu.2018.01092 Text en Copyright © 2018 O’Sullivan, Yekollu, Ruscher, Mehdi, Maradana, Chidgey and Thomas. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
O’Sullivan, Brendan J.
Yekollu, Suman
Ruscher, Roland
Mehdi, Ahmed M.
Maradana, Muralidhara Rao
Chidgey, Ann P.
Thomas, Ranjeny
Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title_full Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title_fullStr Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title_full_unstemmed Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title_short Autoimmune-Mediated Thymic Atrophy Is Accelerated but Reversible in RelB-Deficient Mice
title_sort autoimmune-mediated thymic atrophy is accelerated but reversible in relb-deficient mice
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972300/
https://www.ncbi.nlm.nih.gov/pubmed/29872433
http://dx.doi.org/10.3389/fimmu.2018.01092
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