POLYMORPHIC STRUCTURAL FEATURES OF MODELED HLA-DQ MOLECULES SEGREGATEACCORDING TO SUSCEPTIBILITY OR RESISTANCE TO IDDM

The structural features of HLA-DQ alleles which are susceptible and re sistant to insulin-dependent diabetes mellitus (IDDM) have been examin ed using a model of their three-dimensional structure obtained by ener gy minimisation, based on the published structure of HLA-DR1. The mode l shows DQ molecules to have an overall shape nearly identical to that of DR molecules, but with significant differences in the fine structu re: 1) the antigen-binding groove of DQ molecules has a polymorphic fi rst pocket; this pocket can be either amphiphilic or hydrophilic, 2) T he beta 49-56 dimerisation domain of DQ is polymorphic: hydrophobic, o r amphiphilic, or hydrophilic and positively charged, leading to spont aneous or T-cell receptor-induced homodimer formation, or difficulty o f the formation of such dimers, respectively; 3) a prominent Arg-Gly-A sp loop is formed by some DQ alleles (beta 167-169) and probably funct ions in cell adhesion. There are also small differences in the residue s and sequences implicated in CD4 binding (mostly in DQ beta 134-148) but the significance of these differences cannot be evaluated at prese nt. All seven DQ alleles which confer susceptibility to IDDM posses a hydrophilic first pocket in the antigen-binding groove, a hydrophobic or amphiphilic beta 49-56 dimerisation patch that allows for spontaneo us or T-cell receptor-induced dimerisation, and the Arg-Gly-Asp loop. By contrast, in the protective alleles at least one of these three fea tures is absent. This segregation of phenotypes according to susceptib ility or resistance can well explain the model of tighter autoantigen binding by the protective alleles compared to the susceptible alleles, previously proposed for the pathogenesis of IDDM.