TBX21基因启动子rSNP功能鉴定及其与Th1/Th2分化关系的研究
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摘要
T-bet是Th1特异性转录调节因子,属T-box蛋白家族成员。T-bet上调IFN-γ转录和IL-12Rβ2表达,提高T细胞对IL-12信号传递的敏感性,从而促进初始Th细胞分化为Th1细胞[1]。目前已发现在人体CD4+ T细胞、NK细胞、CD8+效应T细胞中表达T-bet,且与宿主炎症反应、抗病原体免疫应答关系密切[2, 3]。对孪生子研究还发现,宿主遗传因素对TBX21基因(其编码T-bet)表达及其调控的Th1细胞分化起主要作用;Th2应答不受遗传因素影响,而受T-bet诱导的Th1应答所调控[4]。
人类基因组中存在广泛的多态性,基因组序列的差异构成了不同个体与群体对疾病的易感性、对药物与环境因子不同反应的遗传基础。单核苷酸多态性(single nucleotide polymorphism,SNP)是人类基因组中分布广泛、密度高、易于批量检测且相对稳定的第三代遗传标记,在复杂疾病的基因定位、关联分析、个体和群体对环境致病因子与药物的易感性研究中得到广泛应用[5]。
启动子核苷酸序列的遗传变异可导致一些复杂遗传疾病关联基因表达量的改变。宿主遗传因素决定的IFN-γ水平降低可促进机体免疫耐受形成。对TBX21基因外显子和启动子的扫描显示,T-1993C SNP为日本人和高加索人群中最常见多态。T-1993C多态性与日本人和高加索人群的哮喘发病有关[6],且体外功能实验证实T-1993C多态性可影响TBX21基因的转录活性[7]。我们对中国人群的TBX21基因SNP分析显示,T-1993C多态性与慢性HBV感染[8]、自身免疫性肝炎和系统性红斑狼疮关联[9]。这些免疫性疾病发生可能与免疫耐受的缺失或免疫反应受到抑制的分子遗传机制有关。
遗传关联研究不能说明TBX21基因功能是直接受T-1993C多态性影响,还是受与T-1993C SNP连锁不平衡的其他多态性位点影响。为更好地弄清T-bet表达的调控机制及其关联的自身免疫性疾病、变应性和感染性疾病的宿主易感性,本研究采用电泳迁移率分析(electrophoretic mobility shift assay, EMSA)、染色质免疫沉淀分析(chromatin immunoprecipitation, ChIP),证实-1993位点的等位特异性顺式调控作用;同时,以健康体检者外周血为研究对象,采用流式细胞检测技术观察-1993位点T/C等位变异对正常人群CD4+ T淋巴细胞TBX21表达量(蛋白水平)及Th1/Th2应答的影响,以期深入认识TBX21基因调节性SNP(regulatory SNP,rSNP)在感染性疾病、自身免疫性疾病及变应性疾病中的作用。
1.转录因子YY1与TBX21基因-1993T/C位点区域结合的确定
生物信息分析显示,TBX21基因启动子-2211至-1712区域包含一个转录因子YY1结合的保守序列,T-1993C SNP相邻YY1结合的保守序列(AAATGG)。采用-1993T和-1993C等位寡核苷酸探针进行竞争抑制实验显示,YY1与T和C等位均特异性结合,但其与C等位亲和力明显高于T等位。T、C等位探针交叉抑制实验进一步证实,同等浓度时C等位可以将T等位结合条带完全抑制,而T等位却不能将C等位结合条带完全抑制; YY1冷探针可以将T、C等位结合的慢迁移率结合带完全抑制,而突变YY1冷探针则不能抑制慢迁移率结合带。采用YY1抗体进行超漂移实验证实,与T和C等位结合的慢迁移率条带包含转录因子YY1。同时,我们利用人CD4+ T淋巴细胞株jurkat进行ChIP分析,进一步确定YY1与TBX21基因启动子区包含-1993位点序列发生结合。
2.重庆人群TBX21基因T-1993C多态性的分布状况
我们对收集的370例健康献血员的全血标本基因组DNA进行PCR-限制性内切酶长度多态分析,结果显示:370例标本中,-1993TT基因型为279例(76%), -1993TC基因型为86例(23%), -1993CC基因型为5例(1%),-1993T/C等位频率为13%。
3. -1993T/C基因型与TBX21表达量和CD4+ T细胞应答的关系
在-1993位点分型标本中,我们随机选取17例,其中,TT基因型和TC基因型各7例,CC基因型3例。再次采集全血,采用五色流式细胞检测技术对T-bet、IFN-γ及IL-4水平进行检测,结果显示,T-bet和IFN-γ的表达量从TT→TC→CC基因型呈递减趋势,而IL-4表达量则呈递增趋势,且不同基因型个体的各种因子之间存在显著差异(P<0.05)。
结论:
TBX21基因启动子-1993位点区域与转录因子YY1特异性结合,后者与C等位结合量明显大于T等位;TBX21-1993TT纯合子人群的CD4+ T细胞T-bet表达量明显高于-1993CC纯合子人群,前者外周血主要表现Th1细胞应答,后者则表现Th2应答。转录因子YY1对TBX21基因表达的负性调控作用,直接影响初始Th细胞分化为Th1细胞。
T-bet is a Th1-specific transcription factor and a member of T-box protein family. T-bet upregulates IFN-γtranscription and IL-12Rβ2 expression, enhances the sensitivity of IL-12 signal to T cell, thereby promoting the initial Th cells differentiating into Th1 cells. T-bet expression has been found in human CD4 + T cells, NK cells, CD8 + T cells, and is closely related with the host inflammatory response and anti-pathogen immune response. Twins study also found that host genetic factors play a major role in TBX21 gene (which encode T-bet) expression and Th1 cells differentiation regulated by T-bet; Th2 response is not influenced by genetic factors,but regulated by Th1 responses induced by T-bet.
There is a wide range of human genome polymorphism. Differences in genome sequences of different individuals and groups constitute the susceptibility to disease, drugs and environmental factors on the genetic basis of different responses. Single nucleotide polymorphisms (single nucleotide polymorphism, SNP) is widely distributed in the human genome, high density, easy-to-volume and relatively stable detection of the third generation of genetic markers. It has been widely used in complex disease gene mapping, association analysis, individual and groups of Environmental factors and disease susceptibility to the drug.
Genetic variation of Promoter sequences can lead to changes in gene expression associated with complex genetic diseases. the lower IFN-γlevel Determined by host genetic factors can promote the formation of immune tolerance. The scan Of TBX21 exons and promoter shows T-1993C SNP is the most common polymorphism for the Japanese and Caucasian populations. T-1993C polymorphism was associated with the pathogenesis of asthma in Japanese and Caucasian populations. Functional experiments in vitro confirmed that T-1993C polymorphism can affect the transcription activity of TBX21 gene. Analysis of TBX21 gene SNP of our Chinese population indicate T-1993C polymorphism was associated with chronic HBV infection, autoimmune hepatitis and systemic lupus erythematosus.These autoimmune diseases may be resulted from a molecular genetic mechanism related with the absence of immune tolerance or a suppressed immune response .
Genetic association studies can not explain whether TBX21 gene function is directly affected by the T-1993C polymorphism, or the other which has a linkage disequilibrium relationship with the T-1993C polymorphism. To better understand the regulatory mechanism of T-bet expression and its associated host susceptibility of autoimmune diseases, allergic and infectious diseases, in this study, electrophoretic mobility shift analysis (electrophoretic mobility shift assay, EMSA), Chromatin immunoprecipitation analysis (chromatin immunoprecipitation, ChIP) was applied to confirm -1993 site-specific cis-allelic effect; at the same time, we analyzed the peripheral blood of healthy objects by flow cytometry to observe the affection of the -1993 site T / C allele variation on TBX21 expression (protein level) of CD4 + T lymphocytes and the Th1/Th2 response in the normal population and expected a in-depth understanding of the role of TBX21 gene regulatory SNP (regulatory SNP, rSNP) in infectious diseases, autoimmune Disease and allergic diseases.
Results:
1. Determination of YY1 protein binding to the region around the -1993 site of TBX21 gene.
Bioinformatics analysis showed that, -2211 to -1712 region of TBX21 gene promoter contains a conserved transcription factor YY1 binding sequence, T-1993C SNP adjacent to the conserved YY1 binding sequence (AAATGG). Competitive inhibition experiments with-1993T and-1993C allele oligonucleotide probe showed that, YY1 can specifically bind to T and C allele probe, but its affinity with the C allele was significantly higher than the T allele. T, C allele probe cross-inhibition experiments further confirmed that the same concentration of T allele binding bands can be completely inhibited by the C allele, while the T allele is not able to completely inhibit the C allele binding bands; YY1 cold probe can completely inhibit the slow mobility band of T, C allele, while the mutant cold probe YY1 can not. Super shift experiment with YY1 antibody confirmed that the slow mobility band of the T allele and the C allele contains the transcription factor YY1. We use human CD4 + T lymphocyte lines jurkat for ChIP analysis, further defining YY1 binding to sequences containing -1993 site in the TBX21 gene promoter region.
2. Distribution of TBX21 gene T-1993C polymorphism in Chongqing populationWe collected whole blood samples of 370 healthy blood donors for genomic DNA extraction,then analyzed its genotype by RFLP(restriction fragment length polymorphism. The result showed: of 370 samples,0.76(279 ? 370) for TT homozygotes, 0.23 (86 ? 370) for TC heterozygotes, 0.01 (5 ? 370) for CC homozygotes and 0.13 for T-1993C allele frequency.
3.The relationship between -1993T / C genotype and TBX21 expression、the response of CD4 + T cells .
We randomly selected 17 cases in genotyped samples, of which, 7 cases are for each TT genotype and TC genotype, 3 cases for CC genotype. We collected their whole blood again, detected the level of T-bet, IFN-γand IL-4 by five-color flow cytometry .the results indicate that T-bet and IFN-γexpression showed an order of TT〉TC〉CC, while IL-4 was just opposite, and there were a significant difference in different genotypes (P <0.05).
Conclusion:
Transcription factor YY1 specifically bind to TBX21 gene promoter at -1993 position, which combined with the C allele was significantly greater than the T allele; T-bet expression in CD4 + T cell of TBX21-1993TT homozygous population was significantly higher than -1993CC homozygous population, with the former mainly expressing Th1 cell responses in peripheral blood, while the latter mainly Th2 response. the negative regulation of transcription factor YY1 on TBX21 gene expression directly affect the initial Th cells differentiation into Th1 cells.
人类基因组中存在广泛的多态性,基因组序列的差异构成了不同个体与群体对疾病的易感性、对药物与环境因子不同反应的遗传基础。单核苷酸多态性(single nucleotide polymorphism,SNP)是人类基因组中分布广泛、密度高、易于批量检测且相对稳定的第三代遗传标记,在复杂疾病的基因定位、关联分析、个体和群体对环境致病因子与药物的易感性研究中得到广泛应用[5]。
启动子核苷酸序列的遗传变异可导致一些复杂遗传疾病关联基因表达量的改变。宿主遗传因素决定的IFN-γ水平降低可促进机体免疫耐受形成。对TBX21基因外显子和启动子的扫描显示,T-1993C SNP为日本人和高加索人群中最常见多态。T-1993C多态性与日本人和高加索人群的哮喘发病有关[6],且体外功能实验证实T-1993C多态性可影响TBX21基因的转录活性[7]。我们对中国人群的TBX21基因SNP分析显示,T-1993C多态性与慢性HBV感染[8]、自身免疫性肝炎和系统性红斑狼疮关联[9]。这些免疫性疾病发生可能与免疫耐受的缺失或免疫反应受到抑制的分子遗传机制有关。
遗传关联研究不能说明TBX21基因功能是直接受T-1993C多态性影响,还是受与T-1993C SNP连锁不平衡的其他多态性位点影响。为更好地弄清T-bet表达的调控机制及其关联的自身免疫性疾病、变应性和感染性疾病的宿主易感性,本研究采用电泳迁移率分析(electrophoretic mobility shift assay, EMSA)、染色质免疫沉淀分析(chromatin immunoprecipitation, ChIP),证实-1993位点的等位特异性顺式调控作用;同时,以健康体检者外周血为研究对象,采用流式细胞检测技术观察-1993位点T/C等位变异对正常人群CD4+ T淋巴细胞TBX21表达量(蛋白水平)及Th1/Th2应答的影响,以期深入认识TBX21基因调节性SNP(regulatory SNP,rSNP)在感染性疾病、自身免疫性疾病及变应性疾病中的作用。
1.转录因子YY1与TBX21基因-1993T/C位点区域结合的确定
生物信息分析显示,TBX21基因启动子-2211至-1712区域包含一个转录因子YY1结合的保守序列,T-1993C SNP相邻YY1结合的保守序列(AAATGG)。采用-1993T和-1993C等位寡核苷酸探针进行竞争抑制实验显示,YY1与T和C等位均特异性结合,但其与C等位亲和力明显高于T等位。T、C等位探针交叉抑制实验进一步证实,同等浓度时C等位可以将T等位结合条带完全抑制,而T等位却不能将C等位结合条带完全抑制; YY1冷探针可以将T、C等位结合的慢迁移率结合带完全抑制,而突变YY1冷探针则不能抑制慢迁移率结合带。采用YY1抗体进行超漂移实验证实,与T和C等位结合的慢迁移率条带包含转录因子YY1。同时,我们利用人CD4+ T淋巴细胞株jurkat进行ChIP分析,进一步确定YY1与TBX21基因启动子区包含-1993位点序列发生结合。
2.重庆人群TBX21基因T-1993C多态性的分布状况
我们对收集的370例健康献血员的全血标本基因组DNA进行PCR-限制性内切酶长度多态分析,结果显示:370例标本中,-1993TT基因型为279例(76%), -1993TC基因型为86例(23%), -1993CC基因型为5例(1%),-1993T/C等位频率为13%。
3. -1993T/C基因型与TBX21表达量和CD4+ T细胞应答的关系
在-1993位点分型标本中,我们随机选取17例,其中,TT基因型和TC基因型各7例,CC基因型3例。再次采集全血,采用五色流式细胞检测技术对T-bet、IFN-γ及IL-4水平进行检测,结果显示,T-bet和IFN-γ的表达量从TT→TC→CC基因型呈递减趋势,而IL-4表达量则呈递增趋势,且不同基因型个体的各种因子之间存在显著差异(P<0.05)。
结论:
TBX21基因启动子-1993位点区域与转录因子YY1特异性结合,后者与C等位结合量明显大于T等位;TBX21-1993TT纯合子人群的CD4+ T细胞T-bet表达量明显高于-1993CC纯合子人群,前者外周血主要表现Th1细胞应答,后者则表现Th2应答。转录因子YY1对TBX21基因表达的负性调控作用,直接影响初始Th细胞分化为Th1细胞。
T-bet is a Th1-specific transcription factor and a member of T-box protein family. T-bet upregulates IFN-γtranscription and IL-12Rβ2 expression, enhances the sensitivity of IL-12 signal to T cell, thereby promoting the initial Th cells differentiating into Th1 cells. T-bet expression has been found in human CD4 + T cells, NK cells, CD8 + T cells, and is closely related with the host inflammatory response and anti-pathogen immune response. Twins study also found that host genetic factors play a major role in TBX21 gene (which encode T-bet) expression and Th1 cells differentiation regulated by T-bet; Th2 response is not influenced by genetic factors,but regulated by Th1 responses induced by T-bet.
There is a wide range of human genome polymorphism. Differences in genome sequences of different individuals and groups constitute the susceptibility to disease, drugs and environmental factors on the genetic basis of different responses. Single nucleotide polymorphisms (single nucleotide polymorphism, SNP) is widely distributed in the human genome, high density, easy-to-volume and relatively stable detection of the third generation of genetic markers. It has been widely used in complex disease gene mapping, association analysis, individual and groups of Environmental factors and disease susceptibility to the drug.
Genetic variation of Promoter sequences can lead to changes in gene expression associated with complex genetic diseases. the lower IFN-γlevel Determined by host genetic factors can promote the formation of immune tolerance. The scan Of TBX21 exons and promoter shows T-1993C SNP is the most common polymorphism for the Japanese and Caucasian populations. T-1993C polymorphism was associated with the pathogenesis of asthma in Japanese and Caucasian populations. Functional experiments in vitro confirmed that T-1993C polymorphism can affect the transcription activity of TBX21 gene. Analysis of TBX21 gene SNP of our Chinese population indicate T-1993C polymorphism was associated with chronic HBV infection, autoimmune hepatitis and systemic lupus erythematosus.These autoimmune diseases may be resulted from a molecular genetic mechanism related with the absence of immune tolerance or a suppressed immune response .
Genetic association studies can not explain whether TBX21 gene function is directly affected by the T-1993C polymorphism, or the other which has a linkage disequilibrium relationship with the T-1993C polymorphism. To better understand the regulatory mechanism of T-bet expression and its associated host susceptibility of autoimmune diseases, allergic and infectious diseases, in this study, electrophoretic mobility shift analysis (electrophoretic mobility shift assay, EMSA), Chromatin immunoprecipitation analysis (chromatin immunoprecipitation, ChIP) was applied to confirm -1993 site-specific cis-allelic effect; at the same time, we analyzed the peripheral blood of healthy objects by flow cytometry to observe the affection of the -1993 site T / C allele variation on TBX21 expression (protein level) of CD4 + T lymphocytes and the Th1/Th2 response in the normal population and expected a in-depth understanding of the role of TBX21 gene regulatory SNP (regulatory SNP, rSNP) in infectious diseases, autoimmune Disease and allergic diseases.
Results:
1. Determination of YY1 protein binding to the region around the -1993 site of TBX21 gene.
Bioinformatics analysis showed that, -2211 to -1712 region of TBX21 gene promoter contains a conserved transcription factor YY1 binding sequence, T-1993C SNP adjacent to the conserved YY1 binding sequence (AAATGG). Competitive inhibition experiments with-1993T and-1993C allele oligonucleotide probe showed that, YY1 can specifically bind to T and C allele probe, but its affinity with the C allele was significantly higher than the T allele. T, C allele probe cross-inhibition experiments further confirmed that the same concentration of T allele binding bands can be completely inhibited by the C allele, while the T allele is not able to completely inhibit the C allele binding bands; YY1 cold probe can completely inhibit the slow mobility band of T, C allele, while the mutant cold probe YY1 can not. Super shift experiment with YY1 antibody confirmed that the slow mobility band of the T allele and the C allele contains the transcription factor YY1. We use human CD4 + T lymphocyte lines jurkat for ChIP analysis, further defining YY1 binding to sequences containing -1993 site in the TBX21 gene promoter region.
2. Distribution of TBX21 gene T-1993C polymorphism in Chongqing populationWe collected whole blood samples of 370 healthy blood donors for genomic DNA extraction,then analyzed its genotype by RFLP(restriction fragment length polymorphism. The result showed: of 370 samples,0.76(279 ? 370) for TT homozygotes, 0.23 (86 ? 370) for TC heterozygotes, 0.01 (5 ? 370) for CC homozygotes and 0.13 for T-1993C allele frequency.
3.The relationship between -1993T / C genotype and TBX21 expression、the response of CD4 + T cells .
We randomly selected 17 cases in genotyped samples, of which, 7 cases are for each TT genotype and TC genotype, 3 cases for CC genotype. We collected their whole blood again, detected the level of T-bet, IFN-γand IL-4 by five-color flow cytometry .the results indicate that T-bet and IFN-γexpression showed an order of TT〉TC〉CC, while IL-4 was just opposite, and there were a significant difference in different genotypes (P <0.05).
Conclusion:
Transcription factor YY1 specifically bind to TBX21 gene promoter at -1993 position, which combined with the C allele was significantly greater than the T allele; T-bet expression in CD4 + T cell of TBX21-1993TT homozygous population was significantly higher than -1993CC homozygous population, with the former mainly expressing Th1 cell responses in peripheral blood, while the latter mainly Th2 response. the negative regulation of transcription factor YY1 on TBX21 gene expression directly affect the initial Th cells differentiation into Th1 cells.
引文
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23. Park IK, Letterio JJ, Gorham JD. TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent. Mol Immunol 2007;44(13):3283-3290.
24.欧阳为明,王宏芳,蕴汪, et al. CD226和911C3特异性抗体对NK292细胞杀伤作用的影响.中国免疫学杂志2002;18.
25. Ye J, Cippitelli M, Dorman L, et al. The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. Mol Cell Biol 1996;16(9):4744-4753.
26. Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991;19(9):2499.
27. Huang Y, Yang H, Borg BB, et al. A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection. Proc Natl Acad Sci U S A 2007;104(3):985-990.
28.张伟,明镇寰.转录因子YY1的作用机制.生命的化学2000;20(5).
29. Chen B, Chrambach A. Estimation of polymerization efficiency in the formation of polyacrylamide gel, using continuous optical scanning during polymerization. J Biochem Biophys Methods 1979;1(2):105-116.
30. Sikes ML, Bradshaw JM, Ivory WT, et al. A streamlined method for rapid and sensitive chromatin immunoprecipitation. J Immunol Methods 2009;344(1):58-63.
31.赵静,周韧.单核苷酸多态性及其数据库的应用.国际病理科学与临床杂志2006;26(2):152-155.
32. Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999;22(3):231-238.
33. Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 1999;56(4):247-258.
34. Cameron L, Webster RB, Strempel JM, et al. Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation. J Immunol 2006;177(12):8633-8642.
35. Soutto M, Zhang F, Enerson B, et al. A minimal IFN-gamma promoter confers Th1 selective expression. J Immunol 2002;169(8):4205-4212.
36. Shrivastava A, Calame K. An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res 1994;22(24):5151-5155.
37. Li JR, Li JG, Deng GH, et al. A Common Promoter Variant of TBX21 is Associated with Allele Specific Binding to Yin-Yang 1 and Reduced Gene Expression. Scand J Immunol 2011;73(5):449-458.
38. D A, CS L, J B, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. Clin Immunol 2003;23(3):147-161.
39. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today 1991;12(8):256-257.
40.焦志军,王文红,辛利军. PMA+ Ion和PHA用于流式细胞术检测Thl/Th2细胞的结果比较.中国免疫学杂志2006;22:558-559.
41. Komanduri KV, Viswanathan MN, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998;4(8):953-956.
42. Zhu K, Ye J, Wu M, et al. Expression of Th1 and Th2 cytokine-associated transcription factors, T-bet and GATA-3, in peripheral blood mononuclear cells and skin lesions of patients with psoriasis vulgaris. Arch Dermatol Res 2010;302(7):517-523.
43. AC M, AS H, FA H, et al. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 2002;3(7):652-658.
44. Tang Y, Desierto MJ, Chen J, et al. The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure. Blood 2010;115(3):541-548.
1. Romagnani S. Human Th1 and Th2 subsets: doubt no more. Immunol Today 1991;12(8):256-257.
2.李娜,杨海澜. Th1 /Th2型细胞的免疫调节机制与妊娠期高血压疾病.中国妇幼保健2010;25(4):577-579.
3. H K, HJ L, T M. Friend of GATA3 is exp ressed in native Th cells and functions as a rep ressor of GATA32mediated Th2 cell development. J Immunol 2002;168(9):4583-4545.
4. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100(6):655-669.
5. Hwang SS, Kim YU, Lee W, et al. Differential expression of nuclear receptors in T helper cells. J Microbiol Biotechnol 2009;19(2):208-214.
6. Bowen H, Kelly A, Lee T, et al. Control of cytokine gene transcription in Th1 and Th2 cells. Clin Exp Allergy 2008;38(9):1422-1431.
7. Gamper CJ, Agoston AT, Nelson WG, et al. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol 2009;183(4):2267-2276.
8. Guan H, Nagarkatti PS, Nagarkatti M. Role of CD44 in the differentiation of Th1 and Th2 cells: CD44-deficiency enhances the development of Th2 effectors in response to sheep RBC and chicken ovalbumin. J Immunol 2009;183(1):172-180.
9. Amsen D, Antov A, Flavell RA. The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 2009;9(2):116-124.
10. Finotto S. T-cell regulation in asthmatic diseases. Chem Immunol Allergy 2008;94:83-92.
11. Hausding M, Sauer K, Maxeiner JH, et al. Transgenic models in allergic responses. Curr Drug Targets 2008;9(6):503-510.
12. Liu GL, Shi JH, Lin YG, et al. [T-bet gene modified dendritic cells abrogate and reverse the airway inflammation in allergic asthma: experiment with mice]. Zhonghua Yi Xue Za Zhi 2009;89(8):519-523.
13. Ishimaru N, Yamada A, Kohashi M, et al. Development of inflammatory bowel disease in Long-Evans Cinnamon rats based on CD4+CD25+Foxp3+ regulatory T cell dysfunction. J Immunol 2008;180(10):6997-7008.
14. Di Sabatino A, Rovedatti L, Kaur R, et al. Targeting gut T cell Ca2+ release-activated Ca2+ channels inhibits T cell cytokine production and T-box transcription factor T-bet in inflammatory bowel disease. J Immunol 2009;183(5):3454-3462.
15. Bettelli E, Sullivan B, Szabo SJ, et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 2004;200(1):79-87.
16. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity 2004;21(5):719-731.
17. Nath N, Giri S, Prasad R, et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 2004;172(2):1273-1286.
18. t Hart BA, Bauer J, Brok HP, et al. Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme. J Neuroimmunol 2005;168(1-2):1-12.
19. Steinman L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999;24(3):511-514.
20. Wang J, Fathman JW, Lugo-Villarino G, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest 2006;116(2):414-421.
21. Hultgren OH, Verdrengh M, Tarkowski A. T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis. Microbes Infect 2004;6(6):529-535.
22. Chae SC, Shim SC, Chung HT. Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis. Exp Mol Med 2009;41(1):33-41.
23.党倩丽,陆学东,张小艳.慢性荨麻疹患者血清IL-4、IFN-γ及IgE水平观察.临床皮肤科杂志2000;29(4):208 - 209.
24. Sasaki Y, Ihara K, Matsuura N, et al. Identification of a novel type 1 diabetes susceptibility gene, T-bet. Hum Genet 2004;115(3):177-184.
25. Esensten JH, Lee MR, Glimcher LH, et al. T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function. J Immunol 2009;183(1):75-82.
26. You Y, Zhao W, Chen S, et al. Association of TBX21 gene haplotypes in a Chinese population with systemic lupus erythematosus. Scand J Rheumatol 2010;39(3):254-258.
27. Charlton B, Lafferty KJ. The Th1/Th2 balance in autoimmunity. Curr Opin Immunol 1995;7(6):793-798.
28. Chen S, Zhao W, Tan W, et al. Association of TBX21 T-1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers. Hepatol Res 2009;39(7):716-723.
29.邱谷风,王锁英,王胜军, et al. T-bet、GATA3及相关因子的表达与胃癌及转移的相关性研究.中国免疫学杂志2007;23(9):798-802.
30. Svensson A, Nordstrom I, Sun JB, et al. Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol 2005;174(10):6266-6273.
31. Svensson A, Bergin AM, Lowhagen GB, et al. A 3'-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans. J Gen Virol 2008;89(Pt 9):2262-2268.
32. Szegedi A, Aleksza M, Gonda A, et al. Elevated rate of Thelper1 (T(H)1) lymphocytes and serum IFN-gamma levels in psoriatic patients. Immunol Lett 2003;86(3):277-280.
33. Tamauchi H, Terashima M, Ito M, et al. Evidence of GATA-3-dependent Th2 commitment during the in vivo immune response. Int Immunol 2004;16(1):179-187.
34.吴苗,朱可建,周燕, et al.寻常性银屑病患者皮损中T-bet和GATA-3的表达.中国皮肤性病学杂志2009;23(3):135-137.
35. Apetrei C, Marx PA, Smith SM. The evolution of HIV and its consequences. Infect Dis Clin North Am 2004;18(2):369-394.
36. Kulkarni A, Ravi DS, Singh K, et al. HIV-1 Tat modulates T-bet expression and induces Th1 type of immune response. Biochem Biophys Res Commun 2005;329(2):706-712.
37.任少敏,张春霞,李维才.急性特发性血小板减少性紫癜儿童T-bet和GATA3的表达.中国当代儿科杂志2010;12(1):29-31.
38. Ren SM, Zhang CX, Li WC. [Expression of T-bet and GATA3 in children with acute idiopathic thrombocytopenic purpura]. Zhongguo Dang Dai Er Ke Za Zhi 2010;12(1):29-31.
39. Peng SL, Townsend MJ, Hecht JL, et al. T-bet regulates metastasis rate in a murine model of primary prostate cancer. Cancer Res 2004;64(2):452-455.
40. Werneck MB, Lugo-Villarino G, Hwang ES, et al. T-bet plays a key role in NK-mediated control of melanoma metastatic disease. J Immunol 2008;180(12):8004-8010.
41. Zhu JX, Shan LY, Li LH, et al. [Expression of T cell-specific transcription factors T-bet and GATA-3 in recurrent aphthous ulcerations]. Zhonghua Kou Qiang Yi Xue Za Zhi 2006;41(8):494-497.
42.朱金晓,单莉英,李莉华, et al.转录因子T-bet/GATA-3在复发性口疮患者免疫失衡中的作用.南京医科大学学报2006;26(9):777-780.
43. Chen DY, Shi YW, Hua Y. [Expression of transcription factor T-bet and GATA-3 in peripheral blood mononuclear cells and its correlation with immune status in esophageal cancer patients]. Zhonghua Zhong Liu Za Zhi 2009;31(3):189-191.
44.时亚伟,陈德玉,俊刘, et al.转录因子T-bet , GATA23对食管癌患者免疫状态的影响.江苏大学学报2008;18(2):156-158.
45. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006;116(11):2843-2854.
46. Liu R, Hao J, Dayao CS, et al. T-bet deficiency decreases susceptibility to experimental myasthenia gravis. Exp Neurol 2009;220(2):366-373.
2. Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 2002;295(5553):338-342.
3. Frisullo G, Iorio R, Plantone D, et al. CD4+T-bet+, CD4+pSTAT3+and CD8+T-bet+T cells accumulate in peripheral blood during NZB treatment. Mult Scler 2010.
4. Hohler T, Reuss E, Adams P, et al. A genetic basis for IFN-gamma production and T-bet expression in humans. J Immunol 2005;175(8):5457-5462.
5.胡培丽,岳秉飞.单核苷酸多态性的研究进展.实验动物科学与管理2006;23(1):36-38.
6. Akahoshi M, Obara K, Hirota T, et al. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet 2005;117(1):16-26.
7. Suttner K, Rosenstiel P, Depner M, et al. TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants. J Allergy Clin Immunol 2009;123(5):1062-1068, 1068 e1061-1068.
8. Chen S, Zhao W, Tan W, et al. Association of TBX21 T-1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers. Hepatol Res 2009;39(7):716-723.
9. You Y, Zhao W, Chen S, et al. Association of TBX21 gene haplotypes in a Chinese population with systemic lupus erythematosus. Scand J Rheumatol 2010;39(3):254-258.
10. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100(6):655-669.
11. Finotto S, Neurath MF, Glickman JN, et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 2002;295(5553):336-338.
12. Neurath MF, Weigmann B, Finotto S, et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J Exp Med 2002;195(9):1129-1143.
13. Sullivan BM, Juedes A, Szabo SJ, et al. Antigen-driven effector CD8 T cell function regulated by T-bet. Proc Natl Acad Sci U S A 2003;100(26):15818-15823.
14. Juedes AE, Rodrigo E, Togher L, et al. T-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes. J Exp Med 2004;199(8):1153-1162.
15. Townsend MJ, Weinmann AS, Matsuda JL, et al. T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 2004;20(4):477-494.
16. Pearce EL, Mullen AC, Martins GA, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 2003;302(5647):1041-1043.
17. Bettelli E, Sullivan B, Szabo SJ, et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 2004;200(1):79-87.
18. Svensson A, Nordstrom I, Sun JB, et al. Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol 2005;174(10):6266-6273.
19. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264(5162):1152-1156.
20. Rosenwasser LJ, Klemm DJ, Dresback JK, et al. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 1995;25 Suppl 2:74-78; discussion 95-76.
21. Svensson A, Bergin AM, Lowhagen GB, et al. A 3'-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans. J Gen Virol 2008;89(Pt 9):2262-2268.
22. Yu J, Wei M, Boyd Z, et al. Transcriptional control of human T-BET expression: the role of Sp1. Eur J Immunol 2007;37(9):2549-2561.
23. Park IK, Letterio JJ, Gorham JD. TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent. Mol Immunol 2007;44(13):3283-3290.
24.欧阳为明,王宏芳,蕴汪, et al. CD226和911C3特异性抗体对NK292细胞杀伤作用的影响.中国免疫学杂志2002;18.
25. Ye J, Cippitelli M, Dorman L, et al. The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. Mol Cell Biol 1996;16(9):4744-4753.
26. Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991;19(9):2499.
27. Huang Y, Yang H, Borg BB, et al. A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection. Proc Natl Acad Sci U S A 2007;104(3):985-990.
28.张伟,明镇寰.转录因子YY1的作用机制.生命的化学2000;20(5).
29. Chen B, Chrambach A. Estimation of polymerization efficiency in the formation of polyacrylamide gel, using continuous optical scanning during polymerization. J Biochem Biophys Methods 1979;1(2):105-116.
30. Sikes ML, Bradshaw JM, Ivory WT, et al. A streamlined method for rapid and sensitive chromatin immunoprecipitation. J Immunol Methods 2009;344(1):58-63.
31.赵静,周韧.单核苷酸多态性及其数据库的应用.国际病理科学与临床杂志2006;26(2):152-155.
32. Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999;22(3):231-238.
33. Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 1999;56(4):247-258.
34. Cameron L, Webster RB, Strempel JM, et al. Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation. J Immunol 2006;177(12):8633-8642.
35. Soutto M, Zhang F, Enerson B, et al. A minimal IFN-gamma promoter confers Th1 selective expression. J Immunol 2002;169(8):4205-4212.
36. Shrivastava A, Calame K. An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res 1994;22(24):5151-5155.
37. Li JR, Li JG, Deng GH, et al. A Common Promoter Variant of TBX21 is Associated with Allele Specific Binding to Yin-Yang 1 and Reduced Gene Expression. Scand J Immunol 2011;73(5):449-458.
38. D A, CS L, J B, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. Clin Immunol 2003;23(3):147-161.
39. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today 1991;12(8):256-257.
40.焦志军,王文红,辛利军. PMA+ Ion和PHA用于流式细胞术检测Thl/Th2细胞的结果比较.中国免疫学杂志2006;22:558-559.
41. Komanduri KV, Viswanathan MN, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998;4(8):953-956.
42. Zhu K, Ye J, Wu M, et al. Expression of Th1 and Th2 cytokine-associated transcription factors, T-bet and GATA-3, in peripheral blood mononuclear cells and skin lesions of patients with psoriasis vulgaris. Arch Dermatol Res 2010;302(7):517-523.
43. AC M, AS H, FA H, et al. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 2002;3(7):652-658.
44. Tang Y, Desierto MJ, Chen J, et al. The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure. Blood 2010;115(3):541-548.
1. Romagnani S. Human Th1 and Th2 subsets: doubt no more. Immunol Today 1991;12(8):256-257.
2.李娜,杨海澜. Th1 /Th2型细胞的免疫调节机制与妊娠期高血压疾病.中国妇幼保健2010;25(4):577-579.
3. H K, HJ L, T M. Friend of GATA3 is exp ressed in native Th cells and functions as a rep ressor of GATA32mediated Th2 cell development. J Immunol 2002;168(9):4583-4545.
4. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100(6):655-669.
5. Hwang SS, Kim YU, Lee W, et al. Differential expression of nuclear receptors in T helper cells. J Microbiol Biotechnol 2009;19(2):208-214.
6. Bowen H, Kelly A, Lee T, et al. Control of cytokine gene transcription in Th1 and Th2 cells. Clin Exp Allergy 2008;38(9):1422-1431.
7. Gamper CJ, Agoston AT, Nelson WG, et al. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol 2009;183(4):2267-2276.
8. Guan H, Nagarkatti PS, Nagarkatti M. Role of CD44 in the differentiation of Th1 and Th2 cells: CD44-deficiency enhances the development of Th2 effectors in response to sheep RBC and chicken ovalbumin. J Immunol 2009;183(1):172-180.
9. Amsen D, Antov A, Flavell RA. The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 2009;9(2):116-124.
10. Finotto S. T-cell regulation in asthmatic diseases. Chem Immunol Allergy 2008;94:83-92.
11. Hausding M, Sauer K, Maxeiner JH, et al. Transgenic models in allergic responses. Curr Drug Targets 2008;9(6):503-510.
12. Liu GL, Shi JH, Lin YG, et al. [T-bet gene modified dendritic cells abrogate and reverse the airway inflammation in allergic asthma: experiment with mice]. Zhonghua Yi Xue Za Zhi 2009;89(8):519-523.
13. Ishimaru N, Yamada A, Kohashi M, et al. Development of inflammatory bowel disease in Long-Evans Cinnamon rats based on CD4+CD25+Foxp3+ regulatory T cell dysfunction. J Immunol 2008;180(10):6997-7008.
14. Di Sabatino A, Rovedatti L, Kaur R, et al. Targeting gut T cell Ca2+ release-activated Ca2+ channels inhibits T cell cytokine production and T-box transcription factor T-bet in inflammatory bowel disease. J Immunol 2009;183(5):3454-3462.
15. Bettelli E, Sullivan B, Szabo SJ, et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 2004;200(1):79-87.
16. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity 2004;21(5):719-731.
17. Nath N, Giri S, Prasad R, et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 2004;172(2):1273-1286.
18. t Hart BA, Bauer J, Brok HP, et al. Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme. J Neuroimmunol 2005;168(1-2):1-12.
19. Steinman L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999;24(3):511-514.
20. Wang J, Fathman JW, Lugo-Villarino G, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest 2006;116(2):414-421.
21. Hultgren OH, Verdrengh M, Tarkowski A. T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis. Microbes Infect 2004;6(6):529-535.
22. Chae SC, Shim SC, Chung HT. Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis. Exp Mol Med 2009;41(1):33-41.
23.党倩丽,陆学东,张小艳.慢性荨麻疹患者血清IL-4、IFN-γ及IgE水平观察.临床皮肤科杂志2000;29(4):208 - 209.
24. Sasaki Y, Ihara K, Matsuura N, et al. Identification of a novel type 1 diabetes susceptibility gene, T-bet. Hum Genet 2004;115(3):177-184.
25. Esensten JH, Lee MR, Glimcher LH, et al. T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function. J Immunol 2009;183(1):75-82.
26. You Y, Zhao W, Chen S, et al. Association of TBX21 gene haplotypes in a Chinese population with systemic lupus erythematosus. Scand J Rheumatol 2010;39(3):254-258.
27. Charlton B, Lafferty KJ. The Th1/Th2 balance in autoimmunity. Curr Opin Immunol 1995;7(6):793-798.
28. Chen S, Zhao W, Tan W, et al. Association of TBX21 T-1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers. Hepatol Res 2009;39(7):716-723.
29.邱谷风,王锁英,王胜军, et al. T-bet、GATA3及相关因子的表达与胃癌及转移的相关性研究.中国免疫学杂志2007;23(9):798-802.
30. Svensson A, Nordstrom I, Sun JB, et al. Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol 2005;174(10):6266-6273.
31. Svensson A, Bergin AM, Lowhagen GB, et al. A 3'-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans. J Gen Virol 2008;89(Pt 9):2262-2268.
32. Szegedi A, Aleksza M, Gonda A, et al. Elevated rate of Thelper1 (T(H)1) lymphocytes and serum IFN-gamma levels in psoriatic patients. Immunol Lett 2003;86(3):277-280.
33. Tamauchi H, Terashima M, Ito M, et al. Evidence of GATA-3-dependent Th2 commitment during the in vivo immune response. Int Immunol 2004;16(1):179-187.
34.吴苗,朱可建,周燕, et al.寻常性银屑病患者皮损中T-bet和GATA-3的表达.中国皮肤性病学杂志2009;23(3):135-137.
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