Research on the molecular basis for genetic control of immune response in human

为了阐明遗传控制外来抗原免疫应答和自身免疫性疾病易感性的分子基础，我们对人类白细胞抗原基因的结构和功能进行了研究。对人类白细胞抗原I、II类基因和多肽转运蛋白基因在人类白细胞抗原区域的详细结构分析表明，人类白细胞抗原基因具有显著的多态性。为确定自身免疫性疾病(包括类风湿性关节炎、胰岛素依赖型糖尿病、Graves病、桥本甲状腺炎、系统性红斑狼疮、混合性结缔组织病、白塞病、大动脉炎和亚急性甲状腺炎)的易感性和/或抵抗力，建立了基于聚合酶链式反应的HLA-DNA分型方法。每种自身免疫性疾病都与不同基因座上的特定等位基因有很强的相关性。其中一个突出的发现是，Graves病的易感性与人类白细胞抗原A2和人类白细胞抗原DPB1**0501密切相关，这说明了人类白细胞抗原基因座在自身免疫性疾病中的不同功能参与。对外来抗原的免疫低反应性与人类白细胞抗原B、DQ等位基因密切相关。为了建立一个体内模型来研究每个人类白细胞抗原基因的功能，我们构建了携带人类白细胞抗原-DRA、-DQA或-DQB基因的转基因小鼠。在这些转基因小鼠中发现，人类白细胞抗原基因改变了小鼠的T细胞谱系，并且这些转基因小鼠对与相应的人类白细胞抗原分子结合的抗原肽产生了免疫应答。这些实验为人类白细胞抗原基因是等位基因特异性IR基因提供了直接证据。此外，通过使用这些转基因小鼠，发现链球菌来源的蛋白具有DQ特异的超抗原性。

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.