MHC-Linked Susceptibility to Type 1 Diabetes

Abstract

The MHC represents the most important susceptibility locus for type 1 diabetes, and the MHC class II alleles that encode DQ8 and DQ2 in humans and I-A(g7) in NOD mice represent critical elements. Even though these genetic facts have been known for a number of years, the biochemical and structural features of these MHC class II molecules have only been elucidated recently. We expressed DQ8 and I-A(g7) as soluble proteins and observed significant structural and functional similarities between these human and murine MHC molecules. It had been postulated that I-A(g7) and DQ8 are poor peptide binders, based on the observation that the subunits dissociate in the presence of SDS, a denaturing detergent. We observed that both DQ8 and I-A(g7) form stable, long-lived complexes with a number of different peptides, indicating that they are not unstable in the absence of detergent. DQ8 and I-A(g7) were found to bind similar sets of peptides, which included peptides that had been identified as immunodominant T cell epitopes of insulin and GAD 65 in NOD mice. The insulin B (9-23) peptide formed long-lived complexes with DQ8 and was thus chosen for crystallization of the complex. No defect in the peptide binding groove was evident in the crystal structure and the insulin peptide was deeply anchored in the binding site. The structure demonstrated significant similarities between DQ8 and I-A(g7), indicating that similar antigen presentation events are relevant in the NOD mouse model and the human disease.