NATURAL PEPTIDES SELECTED BY DIABETOGENIC HLA-DQ8

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。导致1型糖尿病（T1DM）发病的最重要的基因是那些编码II类MHC等位基因的基因。特别是，致糖尿病II类MHC分子的生化特征决定了自身抗原肽的结合，最终触发胰岛β细胞反应性T细胞。在人类和非肥胖糖尿病（NOD）小鼠中，与糖尿病相关的II类MHC等位基因的一个显著特征是β链第57位的非天氨酸残基的表达：人类HLA-DQ2和DQ8分子（分别称为DQ2和DQ8）的丙氨酸和NOD II类MHC分子I-Ag7的丝氨酸（5-7）。相比之下，大多数其他II类MHC等位基因在Beta57上表达保守的天冬氨酸，该基因与alpha76上的精氨酸配对，定义肽结合槽的P9口袋。过去的研究分析了由人类致糖尿病II类MHC分子选择的天然加工肽是有限的，并且给出了模糊的结果。在加工过程中自然选择的肽的信息将有助于理解MHC在自身免疫中的作用以及预测潜在的致糖尿病肽。自然加工的多肽代表了CD4 T细胞识别的生理基础：它们代表了APC更愿意选择并向细胞外环境展示的东西。在自身蛋白的加工过程中，DQ8分子结合和选择的天然肽的化学特征是什么？这些自然选择的多肽的结合基序是什么，以及有助于结合和选择的锚定残基是什么？是否存在被DQ8和I-Ag7分子自然选择的肽家族，如果存在，两者之间的结合模式是否相同？

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The single-most important genes responsible for the onset of type 1 diabetes mellitus (T1DM) are those encoding the class II MHC alleles. In particular, the biochemical features of diabetogenic class II MHC molecules determines binding of autoantigenic peptides that ultimately trigger islet Beta cell-reactive T cells. In both humans and non-obese diabetic (NOD) mice, a notable feature of diabetes-related class II MHC alleles is the expression of a non-aspartic acid residue at position 57 of the Beta chain: an alanine for the human HLA-DQ2 and DQ8 molecules (from hereon referred to as DQ2 and DQ8, respectively) and a serine in the case of the NOD class II MHC molecule, I-Ag7 (5-7). In contrast, most other class II MHC alleles express a conserved aspartic acid at Beta57 that pairs with an arginine at alpha76, defining the P9 pocket of the peptide binding groove. Past studies analyzing naturally processed peptides selected by human diabetogenic class II MHC molecules are limited and have given ambiguous results. Information on the peptides naturally selected during processing will help in understanding the role of MHC in autoimmunity as well as in predicting potential diabetogenic peptides. Naturally processed peptides represent the physiological substratum for CD4 T cell recognition: they represent what the APC prefers to select and display to the extracellular milieu. What are the chemical features of the natural peptides bound and selected by DQ8 molecules during the processing of self-proteins? What are the binding motifs of such naturally selected peptides and the anchor residues that contribute towards binding and selection? Are there peptide families that are naturally selected by both DQ8 and I-Ag7 molecules and if so, is the mode of binding identical between the two?