MHC CLASS II STRUCTURE STUDIES

特定的MHC II类分子与以下疾病的易感性有关： 人类和实验动物的自身免疫性疾病。MHC II类 人类中的HLA-DQ 8和HLA-DQ 2分子以及NOD小鼠中的I-Ag 7分子， 例如，似乎赋予I型糖尿病的易感性。的 这些分子的特异性存在于它们的肽结合位点。 MHC Ⅱ类分子与多肽复合物的三维结构 从候选的自身抗原可以提供一个原子的描述， 特定于高风险II类分子的相互作用。详细 了解这些MHC分子的特异性， 用于帮助从候选抗原中发现抗原表位的背景技术 自身抗原，并指导这些MHC类的选择性阻断剂的设计 II分子。特异性阻断剂的合成将允许 这些MHC分子引起易感性的机制是 在疾病的开始和发展中进行检查。 该方案的具体目标是：1）表达可溶性的人MHC II类分子（HLA-DQ 8，HLA-DQ 2）赋予对 糖尿病，并使它们负载来自候选自身抗原的肽，2） 使与肽复合的HLA-DQ 8和HLA-DQ 2结晶并测定 它们的三维结构，3）使用 结构信息来设计特异性配体和 MHC II类分子肽结合位点的非肽配体 赋予对糖尿病的易感性，4）测定这些化合物的 它们与II类受体结合的能力，以及5）检查 选择性阻断剂对自身攻击性T细胞发育的影响 以及对DQ 8或DQ 2转基因NOD小鼠中疾病进展的影响 易感基因

Specific MHC class II molecules are linked to the susceptibility to autoimmune diseases in humans and experimental animals. The MHC class II molecules HLA-DQ8 and HLA-DQ2 in humans and I-Ag7 in NOD mice, for example, appear to confer susceptibility to type I diabetes. The specificity of these molecules is found in their peptide binding sites. The three-dimensional structures of MHC class II complexes with peptides from candidate auto antigens could provide a description of the atomic interactions specific to the high-risk class II molecules. A detailed understanding of the specificity of these MHC molecules should provide a background for helping to discover antigenic epitopes from candidate autoantigens and guide the design of selective blockers of these MHC class II molecules. The synthesis of specific blockers would allow the mechanisms by which these MHC molecules cause susceptibility to be examined in the initiation and progression of disease. The specific aims of this proposal are: 1) to express soluble, human MHC class II molecules (HLA-DQ8, HLA-DQ2) conferring susceptibility to diabetes and to load them with peptides from candidate autoantigens, 2) to crystallize HLA-DQ8 and HLA-DQ2 complexed with peptides and determine their three-dimensional structures by X-ray crystallography, 3) to use structural information to design both specific ligands and libraries of non-peptidic ligands of the peptide binding site of MHC class II molecules conferring susceptibility to diabetes, 4) to assay these compounds for their ability to bind to their class II receptor, and 5) to examine the effect of selective blockers on the development of autoaggressive T cells and on the progression of disease in NOD mice transgenic for DQ8 or DQ2 susceptibility genes.