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Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies...

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Autores principales: Chen, Ziyi, Liu, Yufeng, Hu, Shiqian, Zhang, Meng, Shi, Bingyin, Wang, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074859/
https://www.ncbi.nlm.nih.gov/pubmed/33912135
http://dx.doi.org/10.3389/fendo.2021.632492
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author Chen, Ziyi
Liu, Yufeng
Hu, Shiqian
Zhang, Meng
Shi, Bingyin
Wang, Yue
author_facet Chen, Ziyi
Liu, Yufeng
Hu, Shiqian
Zhang, Meng
Shi, Bingyin
Wang, Yue
author_sort Chen, Ziyi
collection PubMed
description Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future.
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spelling pubmed-80748592021-04-27 Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease Chen, Ziyi Liu, Yufeng Hu, Shiqian Zhang, Meng Shi, Bingyin Wang, Yue Front Endocrinol (Lausanne) Endocrinology Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future. Frontiers Media S.A. 2021-04-12 /pmc/articles/PMC8074859/ /pubmed/33912135 http://dx.doi.org/10.3389/fendo.2021.632492 Text en Copyright © 2021 Chen, Liu, Hu, Zhang, Shi and Wang 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(s) 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 Endocrinology
Chen, Ziyi
Liu, Yufeng
Hu, Shiqian
Zhang, Meng
Shi, Bingyin
Wang, Yue
Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title_full Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title_fullStr Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title_full_unstemmed Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title_short Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease
title_sort decreased treg cell and tcr expansion are involved in long-lasting graves’ disease
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074859/
https://www.ncbi.nlm.nih.gov/pubmed/33912135
http://dx.doi.org/10.3389/fendo.2021.632492
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