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?
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