Regulation of ectopic expression of HLA class II genes.

HLA II 类基因异位表达的调节。

• 批准号: 01480192
• 负责人: KIMURA Akinori
• 金额: $ 4.35万
• 依托单位: Medical Institute of Bioregulation, Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01480192/
• 关键词: HLA; Polymorphisms; Promoter region; Expression; Transcription factor; 発現調節; TNF; IFN; トランスジェニックマウス; DNAタイピング; 自己免疫疾患; HLAクラスII遺伝子; 転写調節; サイトカイン; 核蛋白

To decipher the molecular mechanism of the association between HLA and autoinsune diseases, we have investigated the polymorphisms of HLA class I and class 11 genes in the coding and promoter regions. The highly polymorphic second exons of HLA-B. DRB1. DRBS, DRB4. DRB5. DRB6. DQA1. DQB1. DPAI. and DPBI genes were analyzed by the PCR-SSOP and PCR-SSCP methods. and 27, 51, 3.1.4.3.9.14.8. and 36 alleles. respectively. were defined. In addition, cytoplasmic exons of HLA-DRA and DQBL genes were found to be polymorphic, as well 9 allelic differences in the promoter region of the DQAL gene were identified. These polymorphisms were analysed in healthy individuals antipatients with several autoimmune diseases including IDDM. RA, Graves' disease. Behcet's disease, Takayasu arteritis, Hashim to hyroiditis. SLE. mixed connective tissue disease, and specific alleles were identified to be strongly associated with each disease. Moreover, the regulation of the HLA class 11 genes, especially their inductions by cytokinesis such as interferons and TNFs were investigated in detail. and it was found that the HLA-DQAL gene was differently regulated from the other class 11 genes by means of expressivity and inducibility via a DQAL gene-specific positive transcription factor NF-TRS. The binding sites of NF-TRS is overlapping with that of another transcription factor NF-Y and the polymorphism at the sites was found to affect the binding affinity for these factors. suggesting that the expression of the HLA-DQAL gene is allele-specific and may play a role in immune regulation and in developing the autoimmune diseases.

为了揭示HLA与自身免疫性疾病相关的分子机制，我们对HLA Ⅰ类和11类基因编码区和启动子区的多态性进行了研究。HLA-B的第二外显子高度多态性。DRB 1。DRB4. DRB 5。DRB 6。DQA 1. DQB 1. DPAI。采用PCR-SSOP和PCR-SSCP方法分析DPBI基因。和27、51、3.1.4.3.9.14.8。和36个等位基因。分别被定义。此外，HLA-DQBL基因和HLA-DQAL基因的胞质外显子被发现是多态性的，以及在DQAL基因的启动子区的9个等位基因的差异被确定。这些多态性在健康个体和包括IDDM在内的几种自身免疫性疾病患者中进行了分析。RA，Graves病。白塞氏病、大动脉炎、哈希姆氏至甲状腺炎。SLE。混合性结缔组织病，并且特定的等位基因被确定与每种疾病密切相关。此外，HLA 11类基因的调控，特别是它们的诱导胞质分裂，如干扰素和肿瘤坏死因子进行了详细的研究。并发现HLA-DQAL基因通过DQAL基因特异性正转录因子NF-TRS的表达和诱导作用受到与其它11类基因不同的调控。NF-TRS的结合位点与另一种转录因子NF-Y的结合位点重叠，发现位点的多态性影响这些因子的结合亲和力。提示HLA-DQAL基因的表达具有等位基因特异性，可能在免疫调节和自身免疫性疾病的发生发展中起作用。

项目成果

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Sasazuki, T.、Urabe, K.、Harada, F.、Iwanaga, T.、Kimura, A.：“6 号染色体 HLA III 类区域内基因的结构分析。”

Kimura, A., Sasazuki, T.: "Epitope analysis of workshop panels : combined study of oligotyping and serological typing" "HLA 1991 Vol. I". Oxford University Press.

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Fukui,Y.,Esaki,Y.,Yasunami,M.,Kimura,K.,Hirokawa,K.,Nishimura,Y.,Sasazuki,T.: "T cell repertoire and selfーtolerance in the transgenic mice with HLAーDRA on X chromosome.in"HLA 1991 Vol.II"eds.Sasazuki,T.,Aizawa,M.,Tsuji,K." Oxford University Press,Oxford,

Fukui, Y.、Esaki, Y.、Yasunami, M.、Kimura, K.、Hirokawa, K.、Nishimura, Y.、Sasazuki, T.：“HLA-转基因小鼠的 T 细胞库和自身耐受性X 染色体上的 DRA。载于“HLA 1991 Vol.II”eds.Sasazuki,T.,Aizawa,M.,Tsuji,K.”牛津大学出版社，牛津，

Tsuchiya,K.,Kondo,M.,Kimura,A.,Nishimura,Y.,and Sasazuki,T.: "DRB1 and/or DQB1 locus control susceptibility and DRB1 controls resistance to RA.in"HLA 1991 Vol.II"eds.Sasazuki,T.,Aizawa,M.,Tsuji,K." Oxford University Press,Oxford, (1992)

Tsuchiya,K.、Kondo,M.、Kimura,A.、Nishimura,Y. 和 Sasazuki,T.：“HLA 1991 Vol.II 中的 DRB1 和/或 DQB1 位点控制易感性，DRB1 控制对 RA 的耐药性”

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