A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins

In human type 1 diabetes (T1D) and in its murine model, the major histocomp atibility complex (MHC) class II molecules, human leukocyte antigens (HLA)- DQ and -DR and their murine orthologues, IA and IE, are the major genetic d eterminants. In this report, we have ranked HLA class IA molecule-associate d Ti D risk in a two-sided gradient from very high to very low. Very low ri sk corresponded to dominant protection from T1D. We predicted the protein s tructure of DO by using the published crystal structures of different allot ypes of the murine orthologue of DO, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. L ikewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecul es. We also found striking interisotypic conservation between protective DO , IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in dise ase susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.