Influence of TBX21 T-1993C variant on autoimmune hepatitis development by Yin-Yang 1 binding

Abstract

AIMTo investigated the mechanism of the association between the TBX21 T-1993C promoter polymorphism and autoimmune hepatitis type 1 (AIH-1) development.METHODSIn 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.RESULTSTBX21-1993C 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.CONCLUSIONThe 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.

TBX21-1993T/C polymorphism association with Th1 and Th17 response at periapex and with periapical lesions development risk

“…However, in the view of the complexity inherent to genetic association case‐control studies, after the identification of positive genetic association of TBX21‐1993 with the risk of developing apical periodontitis, we next evaluated whether the impact of such genetic variants on the lesions outcome could be derived from a Th1‐polarizing effect in the lesions environment. Our results demonstrate that the TBX21‐1993 C allele was associated with decreased Tbet and IFNg mRNA expression in the periapical lesions, in accordance with the classic description of Tbet essential role in IFNg transcription, as well with the reports of decreased transcriptional activity of the Tbx21 promoter associated with TBX21‐1993C allele . It is important to mention that a previous study described the association between TBX21‐1993 and Tbet expression, but not with IFN‐g transcriptional level, in periodontal lesions .…”

“…Interestingly, our results demonstrate that T allele/TT genotype significantly prevail in the tertiles with IFNg dominance (i.e., higher IFN/IL17 ratio), whereas the fractions characterized by higher IL-17 levels (i.e., lower IFN/IL17 ratio) presented a similar TT and TC/CC genotype frequency. Notably, the predisposition to a lower Th1 response due TBX21-1993 C allele was confirmed in vitro, where CD4 T cells from C carries produced lower IFNg levels upon stimulation, in accordance with previous in vivo studies 27. Importantly, T cells derived from TBX21-1993 T allele carriers were found to produce higher IFNg levels even under nonpolarizing conditions, as well under suboptimal polarizing conditions, reinforcing the influence of TBX21 variants on Th1-phenotype acquisition and function.…”

“…Our results demonstrate that the TBX21-1993 C allele was associated with decreased Tbet and IFNg mRNA expression in the periapical lesions, in accordance with the classic description of Tbet essential role in IFNg transcription, 10 as well with the reports of decreased transcriptional activity of the Tbx21 promoter associated with TBX21-1993C allele. 27 It is important to mention that a previous study described the association between TBX21-1993 and Tbet expression, but not with IFN-g transcriptional level, in periodontal lesions. 13 While apical and marginal periodontitis share some immunopathological features, it is possible that the more complex, diverse, and virulent microbiota characteristically associated with chronic periodontitis 13 may overcome the genetic influence over IFNg expression observed in periapical lesions.…”

Pathogenesis of autoimmune hepatitis

“…Gene mutations other than HLA are also related to AIH susceptibility or progression: Fas-670a/g and Fas-1377g/a polymorphisms[ 5 ], VDR[ 6 ], and GATA-2[ 7 ] are closely related to the onset of AIH. The high-affinity combination of y1 and -1993 c alleles inhibits expression of tbx21, which may inhibit the occurrence of AIH I by inhibiting the type 1 immune response[ 8 ]. The haplotypes of the rs7582694-c and rs7574865-t alleles in the stat4 allele are related to the increased risk of AIH I, while the rs2476601 in the ptpn22 allele is related to reduced risk of AIH I[ 9 ].…”

Human papillomavirus and herpes simplex virus infections in patients with mucocutaneous lesions can be linked to host TBX-21 gene polymorphism

“…14 It is responsible for switching the T-cell precursors towards IFN-γ producing cells like NK cells 15 and CD8 T-cells. 16 Polymorphism in TBX21 genes linked to a wide range of immunity mediated outcomes such as rheumatoid arthritis, 1 7 asthma, 1 8 autoimmune hepatitis, 19 , and susceptibility to viral infections. 15 TBX21 gene is located on human chromosome 17 with several regions that have allelic variations, including rs17244587 G>A locus.…”