MHC LINKED SUSCEPTIBILITY TO AUTOIMMUNITY--STRUCTURE

应用基因芯片在全基因组范围内寻找人类I型糖尿病易感基因 微卫星标记证实了MHC连锁基因是显性的 遗传风险因素人MHC II类基因编码的链 HLA-DQ 8（DQB 1 *0302）和DQ 2（DQB 1 *0201）是高危等位基因。结构 肽结合位点的定义和自- 由这些MHC分子呈递的肽将是至关重要的， 了解导致T细胞丢失的发病机制 对胰岛素依赖型糖尿病的耐受性 该项目的主要目标是：1。来确定晶体 HLA-DQ 8和DQ 2与免疫显性多肽复合物结构 胰岛细胞抗原，2.开发非肽类阻滞剂， 对HLA-DQ 8和DQ 2的肽结合位点具有选择性，3.完成网站 HLA-DQ 8转基因NOD小鼠作为胰岛素依赖型糖尿病动物模型，4.定义HLA- DQ 8限制性胰岛细胞自身抗原的T细胞表位和5.到 表达二价DQ 8/肽复合物作为T细胞受体特异性探针 用于检测和消除致糖尿病T细胞。 该计划的重点是定义分子的共同目标 MHC连锁的胰岛素依赖型糖尿病易感性的机制。该计划项目 将调查人员与结构领域的独特专业知识相结合， 生物学、化学、小鼠遗传学和T细胞免疫学， 整合各自领域的最新进展，以实现这一目标 目标.双周数据俱乐部和系列研讨会将进一步加强这一点 合作和互动研究计划。

A genome-wide search for human type I diabetes susceptibility genes using microsatellite markers confirmed that MHC linked genes are the dominant inherited risk factor. Human MHC class II genes encoding the chains of HLA-DQ8 (DQB1*0302) and DQ2 (DQB1*0201) are high risk alleles. Structural definition of the peptide binding sites and identification of the self- peptides presented by these MHC molecules will be critical for understanding the pathogenetic mechanisms that lead to the loss of T cell tolerance in IDDM. The major goals of this program project are: 1. to determine the crystal structure of HLA-DQ8 and DQ2 complexed with peptides from immunodominant islet cell antigens, 2. to develop non-peptidic blockers that are selective for the peptide binding sites of HLA-DQ8 and DQ2, 3. to generate HLA-DQ8 transgenic NOD mice as an animal model for IDDM, 4. to define HLA- DQ8 restricted T cell epitopes of islet cell autoantigens and 5. to express bivalent DQ8/peptide complexes as T cell receptor specific probes for the detection and depletion of diabetogenic T cells. The program is focused on the common goal of defining the molecular mechanisms of MHC-linked susceptibility to IDDM. The program project combines investigators with unique areas of expertise in structural biology, chemistry, mouse genetics and T cell immunology who will integrate recent advances in their respective fields to accomplish this goal. A biweekly data club and seminar series will further strengthen this collaborative and interactive research program.