The polymorphisms of T cell-specific TBX21 gene may contribute to the susceptibility of chronic immune thrombocytopenia in Chinese population
Introduction
Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease, characterized by transient or persistent decrease of the platelet count and increased risk of bleeding [1]. Although auto-reactive B lymphocytes secreting auto-antibodies against platelet glycoproteins are considered to play crucial roles in platelets destruction by the reticuloendothelial system, dysfunctional cellular immunity as well as the complement-mediated lysis of platelet in ITP patients are also considered important [2], [3], [4]. In addition, abnormal polarization between Th1 cells and Th2 cells in peripheral blood might also play an important role in the pathogenesis [5]. A clear Th1 cytokine polarization of the autoimmune response in patients with chronic ITP has been reported in numerous cytokine profile studies [6], [7]. Correspondingly, Panitas et al. reported that the Th1/Th2 cytokine mRNA ratio correlated inversely with the platelet count [8].
T cell specific T-box transcription factor gene (TBX21, also known as T-bet), located on human chromosome 17q21.32, is a key transcriptional activator inducing helper T cells differentiated to Th1 cells [9]. TBX21 can regulate the fate of Th1 cells through the promotion of Th1 cytokines and the inhibition of Th2 cytokines, so it plays an essential role in Th1/Th2 balance [9], [10], [11]. TBX21-deficient mice showed impaired Th1 differentiation, including defective IFN-γ production primarily in the CD4 and γδ T cells [12], [13], was protected from atherosclerosis [14], autoimmune diabetes [15], and autoimmune myasthenia gravis [16], while displayed failure of infection control [17]. TBX21 contains T-1514C (rs17250932) and T-1993C (rs4794067) polymorphisms in the promoter region, and the two polymorphisms are associated with the production of IL-4 and IFN-gamma by lymphocytes from healthy participants [18], [19]. The two polymorphisms have been shown to be associated with many diseases recently [20], [21], [22], [23], [24], [25].
Since the pathogenesis of acute and chronic ITP are different, and the Th1 polarization has been reported mainly in chronic primary ITP [7], [8], [26], in this study, we investigated the relationship between the distribution of TBX21 (T-1993C and T-1514) polymorphisms and the susceptibility of chronic primary ITP.
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Subjects
The total subjects comprised 275 Chinese primary ITP patients attending our outpatient clinic consecutively, and 261 ethnically matched controls without the history of ITP and other autoimmune disorders. All patients met the diagnostic criteria of chronic ITP as previously described [27]. The controls were randomly selected from our voluntary employees of our hospital, with the disease-free status ascertained by their self-reported questionnaire and previous medical records. All patients were
Results
In this study, we detected two SNPs of TBX21 T-1514C (rs17250932) and T-1993C (rs4794067) among 275 ITP patients and 261 healthy controls by PCR-RFLP (Table 2). The genotyping by PCR-RFLP analysis was confirmed by DNA sequencing analysis. Genotypic frequencies in controls and patients were in Hardy–Weinberg equilibrium (p > 0.05).
Both frequencies of -1993T allele and T/T genotype were significantly elevated in patients when compared with controls (Table 3). However, in our study, there were no
Discussion
The T-box transcription factor T-bet is a member of the T-box transcription factor family. TBX21 plays a critical role both in the development and maintenance of Th1 cells [30], and has been proved to be a positive transcriptional regulator of IFN-γ production in CD4+ T cells [30] and effector CD8+ T cells [31]. Generally, the up-regulated expression of TBX21 is associated with many autoimmune diseases both in human and animals [32], such as autoimmune myasthenia gravis [16], systemic lupus
Acknowledgments
This work was supported in part by grants of National Natural Science Foundation of China (81070397, 81270581), Ministry of Science and Technology (2011ZX09302-007-04), Ministry of Health (201202017) and Tianjin Municipal Science and Technology Commission (10JCZDJC19700 and 12JCQNJC08000).
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2017, Autoimmunity ReviewsCitation Excerpt :As in other AID, specific genetic backgrounds have been reported to be associated with ITP (Table 1). The major histocompatibility complex (MHC) [12–15], Fcγ receptors (FcγR) [16–21], transcription factors [22], chemokines [23], pro-inflammatory cytokines [24–29] or anti-inflammatory cytokines [27,30,31] together with their receptors [27,28,32] display polymorphisms that are often observed in ITP cohorts, or specifically during the chronic course of the disease. Polymorphisms of regulator proteins such as the phosphatase PTPN22 are also overrepresented in ITP patients [33–35].
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Association of the rs17250932, rs4794067, and rs2240017 polymorphism in the TBX21 gene with autoimmune diseases: A meta-analysis
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Donglei Zhang and Xian Zhang contributed equally to this manuscript.