Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes

The major histocompatibility complex (MHC) is the most important susceptibi lity locus for type I diabetes in humans and NOD mice. NOD mice express a s ingle MHC class II molecule (I-A(g7)) which carries a unique beta chain seq uence. In humans, DQ alleles that encode DQ8 and DQ2 confer the highest ris k for the disease. Soluble DQ8 and I-A(g7) were used to directly compare th e binding specificity of these MHC molecules. Peptides from three islet ant igens - insulin, GAD 65 and HSP 60 - bound to both CQ8 and I-A(g7). These p eptides included epitopes that are immunodominant in NOD mice, namely insul in (9-23), GAD (206-220) and HSP 60 (441-460). All of these peptide sequenc es are highly conserved between the human and murine antigens. The binding specificity of DQ8 and I-A(g7) was similar, but not identical, since two pe ptides eluted from splenocytes of NOD mice did not bind to DQ8. DQ8 formed long-lived complexes with the majority of these peptides, indicating that D Q8 is not a poor peptide binder. These results demonstrate functional simil arities between human and murine MHC class II molecules that confer suscept ibility to type I diabetes.