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.

为了破译HLA与自身免疫性疾病之间关联的分子机制，我们研究了HLA I类和HLA 11类基因在编码区和启动子区的多态性。 HLA-B 的高度多态性第二外显子。 DRB1。 DRBS、DRB4。 DRB5。 DRB6。 DQA1. DQB1. DPAI。采用PCR-SSOP和PCR-SSCP方法对DPBI基因进行分析。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-DRA和DQBL基因的细胞质外显子被发现具有多态性，并且在DQAL基因的启动子区域发现了9个等位基因差异。在患有包括 IDDM 在内的多种自身免疫性疾病的健康个体抗患者中对这些多态性进行了分析。 RA，格雷夫斯病。白塞病、大动脉炎、哈希姆甲状腺炎。系统性红斑狼疮。混合结缔组织病，并且确定特定等位基因与每种疾病密切相关。此外，还详细研究了 HLA 11 类基因的调节，特别是干扰素和 TNF 等胞质分裂对它们的诱导。并且发现HLA-DQAL基因通过DQAL基因特异性正转录因子NF-TRS的表达性和诱导性受到与其他11类基因不同的调节。 NF-TRS 的结合位点与另一种转录因子 NF-Y 的结合位点重叠，并且这些位点的多态性被发现影响这些因子的结合亲和力。表明 HLA-DQAL 基因的表达是等位基因特异性的，可能在免疫调节和自身免疫性疾病的发展中发挥作用。

项目成果

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

Kimura, A., Sasazuki, T.：“研讨会小组的表位分析：寡分型和血清学分型的联合研究”“HLA 1991 Vol. I”。

Sasazuki, T., Urabe, K., Harada, F., Iwanaga, T., Kimura, A.: "Structural analysis of the genes within the HLA class III region on chromosome 6." New aspects of the genetics of molecular evolution (Kimura, M., and Takahara, N. EDS.). Academic Press. (1991

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。”

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，

Sasazuki,T.et al: "HLA-linked immune suppression in humans" Immunology,Supplement. 2. 21-24 (1989)

Sasazuki,T.et al：“人类 HLA 相关免疫抑制”免疫学，补充。

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”