HLA-DQ6-mediated protection in IDDM.

Insulin-dependent diabetes mellitus is positively associated with DQ8, DQ2, and DQ6 (DQB1*0604), and negatively associated with DQ6 (DQB1*0602), DQ6 (DQB1*0603), and DQ7 in Swedish caucasians. The protection conferred by DQ6 (DQB1*0602) is stronger in younger individuals and there is decrease in the effect of protection with increasing age. Three-dimensional modeling of the susceptible DQ6 (DQB1*0604) and protective DQ6 (DQB1*0602), which share the same DQA chain (DQA1*0102) but differ in the DQB chain at 6 residues, identifies residue 57 and 70 to be important for protection. Three-dimensional models of the DQ8 molecules were constructed from the coordinates of the DR1 crystal structure and other susceptibility and resistance molecules were made by homology modeling. The positively associated DQ molecules had weakly negative to significantly positive surface electrostatic potentials over the peptide binding and T cell recognition areas, whereas the negatively associated molecules had distinctly more negative areas over the relevant surface. This suggests that the variation in the physicochemical properties such as molecular electrostatic potentials among different DQ molecules are important.