Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2017; 23(48): 8500-8511
Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8500
Influence of TBX21 T-1993C variant on autoimmune hepatitis development by Yin-Yang 1 binding
Wei Sun, Hong-Yan Wu, Song Chen
Wei Sun, Song Chen, Institute of Infectious Diseases, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
Hong-Yan Wu, Nuclear Medicine Department, the First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
Author contributions: Sun W and Wu HY contributed equally to this work; Chen S designed the research study and wrote the paper; Sun W collected and analyzed the data; Wu HY performed the research; all authors have read and approved the final version to be published
Supported by National Natural Science Foundation of China, No. 30972595.
Institutional review board statement: All liver biopsy specimens and blood samples from the patients were taken after informed consent and ethical permission was obtained for participation in the study.
Conflict-of-interest statement: We declare that there are no conflicts of interest related to this study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Song Chen, MD, Chief Doctor, Professor, Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Zhengjie, Shapingba District, Chongqing 400038, China. cs196@medmail.com.cn
Telephone: +86-23-65461319 Fax: +86-23-65461319
Received: June 28, 2017
Peer-review started: July 30, 2017
First decision: August 30, 2017
Revised: October 15, 2017
Accepted: November 8, 2017
Article in press: November 8, 2017
Published online: December 28, 2017
Processing time: 152 Days and 8.5 Hours
Abstract
AIM

To investigated the mechanism of the association between the TBX21 T-1993C promoter polymorphism and autoimmune hepatitis type 1 (AIH-1) development.

METHODS

In vivo, In vivo, and reporter analyses were performed to determine the function of transcription factors binding to the T-1993C element of the TBX21 promoter in human CD4+ T and B cell lines. Flow cytometry and quantitative real-time PCR were used to analyze T-box transcription factor (T-bet) and interferon-γ (IFN-γ) expressions in CD4+ T cells, B cells and monocytes from the peripheral blood of AIH-1 patients including 5-1993TC and 15-1993TT genotype carriers, and healthy controls including 10-1993TC and 25-1993TT genotype carriers. Furthermore, a range of biochemical indices was measured simultaneously in the blood of AIH-1 patients.

RESULTS

TBX21-1993C allele created a strong Yin-Yang 1 (YY1)-binding site and decreased transcriptional activity of TBX21 promoter in human CD4+ T and B cells. Higher levels of T-bet and IFN-γ were detected in the circulating CD4+ T cells and B cells of AIH-1 patients carrying the TBX21-1993 TT genotype compared with the patients carrying the -1993 TC genotype and controls with the -1993 TC genotype. T-bet expression levels of circulating T cells and B cells were positively correlated with AIH-1 disease activity. Knockdown of YY1 with siRNA caused increased expression of T-bet and IFN-γ in peripheral blood mononuclear cells in AIH-1 patients.

CONCLUSION

The repression of TBX21 expression by high-affinity binding of YY1 to the -1993C allele may contribute to a decreased development of AIH-1 via suppression of type 1 immunity.

Keywords: TBX21; Single nucleotide polymorphism; Yin-Yang 1; T helper cells; B cells; Autoimmune hepatitis

Core tip: The -1993C allele in the TBX21 gene (encoding T-bet) promoter has been shown to associated with protection against autoimmune hepatitis type 1 (AIH-1), but the underlying mechanisms are unknown. We found that the TBX21-1993C allele created a strong Yin-Yang 1 (YY1)-binding site and decreased T-bet expression. Reduced T-bet and IFN-γ expression of circulating CD4+ T cells and B cells existed in the individuals carrying the -1993C allele compared with those without the -1993C allele and played a protective role in AIH-1 development. The repression of T-bet expression by high-affinity binding of YY1 to the -1993C allele may contribute to a decreased development of AIH-1 via the suppression of type 1 immunity.