MHC CLASS II STRUCTURE STUDIES

特定的MHC II类分子与易感性有关 人类和实验动物中的自身免疫性疾病。MHC II类 人类的HLADQ8和HLADQ2以及NOD小鼠的I-Ag7分子 例如，似乎会增加I型糖尿病的易感性。这个 这些分子的特异性存在于它们的多肽结合部位。 MHC-II类多肽配合物的三维结构 从候选自身抗原中可以提供原子的描述 高危II类分子特有的相互作用。一个详细的 对这些MHC分子的特异性的理解应该提供一个 帮助发现候选抗原表位的背景 并指导这些MHC类选择性阻滞剂的设计 II分子。合成特定的阻滞剂将使 这些MHC分子导致易感性的机制是 在疾病的发生和发展过程中被检查。 这项提议的具体目的是：1)表达可溶性的、人的MHC 第二类分子(人类白细胞抗原-DQ8、人类白细胞抗原-DQ2)与易感性有关 糖尿病，并将候选自身抗原的多肽加载到它们，2)到 多肽结合的人类白细胞抗原-DQ8和人类白细胞抗原-DQ2的结晶和测定 用X射线结晶学研究它们的三维结构，3)使用 用于设计特定配体和文库的结构信息 MHC-II类分子多肽结合部位的非肽配体 增加对糖尿病的易感性，4)检测这些化合物 它们与其II类受体结合的能力，以及5)检查 选择性阻滞剂对自身侵袭性T细胞发育的影响 以及转DQ8或DQ2基因的NOD小鼠的疾病进展 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.