| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Yasuharu Kumamoto University, Gracuate School of Medical Sciences, Department of Neurosci, 医学部, 教授 (10156119)
FUKUI Yoshinori Kyushu University, Medical Institute of Bioregulation, Department of Genetics, A, 生体防御医学研究所, 助手 (60243961)
KAMIKAWAJI Nobuhiro Kyushu University, Medical Institute of Bioregulation, Department of Genetics, A, 生体防御医学研究所, 助手 (90224659)
KIMURA Akinori Kyushu University, Medical Institute of Bioregulation, Department of Genetics, A, 生体防御医学研究所, 助教授 (60161551)
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| Research Abstract |
To decipher the molecular basis for genetic control of immune responsiveness to foreign antigens and that of susceptibility to autoimmune diseases, we have investigated the structure and function of HLA genes. Detailed structural analysis of HLA class I and class II genes and peptide transporter genes in the HLA region has shown remarkable polymorphisms in the HLA genes. PCR-based HLA-DNA typing method was developed to identify the HLA alleles which determine the susceptibility and/or resistance to autoimmune diseases including rheumatoid arthritis, insulin-dependent deabetes mellitus, Graves' disease, Hashimoto's thyroiditis, systemic lupus erythematosus, mixed connective tissue disease, Behcet's disease, Takayasu's arteritis, and subacute thyroiditis. Each autoimmune disease showed strong association with specific alleles in different HLA loci. One of the prominent findings was that the susceptibility to Graves' disease was strongly associated with HLA-A2 and HLA-DPB1**0501, demonstrating the different functional participation of HLA loci in autoimmune diseases. As well, immune low responsiveness to foreign antigens was strongly associated with HLA-B and HLA-DQ alleles. To establish an in vivo model for investigating the function of each HLA gene, we have constructed transgenic mice carrying the HLA-DRA, -DQA, or -DQB gene. It was revealed in these transgenic mice that HLA genes have changed T cell repertoire of mice and that these transgenic mice have acquired immune responsiveness to antigenic peptides binding to the respective HLA molecules. These experiments have provided direct evidence for that the HLA genes are allele-specific Ir genes. In addition, a DQ-specific superantigenicity was found in Streptococcus-derived protein by using these HLA transgenic mice.
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