TET2-mediated upregulation of 5-hydroxymethylcytosine in LRRC39 promoter promotes Th1 response in association with downregulated Treg response in Vogt-Koyanagi-Harada disease

Bibliographische Detailangaben
Veröffentlicht in:	Clinical immunology (Orlando, Fla.). - 1999. - 250(2023) vom: 01. Mai, Seite 109323
1. Verfasser:	Zhang, Wanyun (VerfasserIn)
Weitere Verfasser:	Chen, Zhijun, Yi, Kun, Su, Guannan, Liu, Yaning, Deng, Yang, Zhang, Yinan, Cao, Qingfeng, Pu, Yanlin, Luo, Xiang, Lai, Yujie, Yang, Peizeng
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2023
Zugriff auf das übergeordnete Werk:	Clinical immunology (Orlando, Fla.)
Schlagworte:	Journal Article Research Support, Non-U.S. Gov't 5-hmC Autoimmune disease LRRC39 TET2 Transcriptomics VKH disease 5-hydroxymethylcytosine 1123-95-1 mehr... Dioxygenases EC 1.13.11.- DNA-Binding Proteins Forkhead Transcription Factors Interleukin-17 RNA, Messenger TET2 protein, human LRRC39 protein, human

Beschreibung
Zusammenfassung:	Copyright © 2023 Elsevier Inc. All rights reserved. DNA 5-Hydroxymethylcytosine (5-hmC), an oxidative reaction mediated by the ten-eleven translocation (TET) family, has been reported to play an essential role in the progression of auto-inflammatory and autoimmune diseases. By far, little is known about the effect of DNA 5-hmC and the TET family on the development of Vogt-Koyanagi-Harada (VKH) disease. In this study, we discovered that the global DNA 5-hmC level and the TET activity were elevated in association with the up-regulated expression of TET2 at both mRNA and protein levels in CD4+T cells from active VKH patients compared to healthy controls. Integrated analysis of DNA 5-hmC pattern and transcription profile of CD4+ T cells revealed that 6 candidate target genes were involved in the development of VKH disease. The promoter 5-hmC and mRNA levels of leucine rich repeat containing 39 (LRRC39) were verified to be elevated in active VKH patients. Functional experiments showed that TET2 could up-regulate LRRC39 mRNA expression by increasing the promoter 5-hmC level of LRRC39 in CD4+ T cells from active VKH patients. Up-regulated LRRC39 expression could increase the frequencies of IFN-γ+ and IL-17+ CD4+ T cells as well as the secretions of IFN-γ and IL-17 in association with the decreased frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the reduced production of IL-10. Additionally, restoration of LRRC39 rescued TET2-silencing-mediated reduced frequency of IFN-γ+ CD4+ T cells and increased frequency of CD4+CD25+FOXP3+ Treg cells. Collectively, our study reveals a novel axis, the TET2-5-hmC-LRRC39-Th1/Treg responses axis, in the pathogenesis of VKH and provides a potential target for further investigation into the epigenetic therapy of this disease
Beschreibung:	Date Completed 01.05.2023 Date Revised 07.05.2023 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-7035
DOI:	10.1016/j.clim.2023.109323