Molecular biology of IDDM

The clinical onset of insulin-dependent diabetes is associated with several autoimmune phenomena including islet cell antibodies, glutamic acid decarboxylase (the GAD65 isoform) autoantibodies (GAD65Ab) as well as insulin autoantibodies. The molecular cloning of these autoantigens has permitted the development of precise and reproducible antibody immunoassays to identify marker-positive patients and control subjects. Among patients with new-onset diabetes about 70% were GAD65Ab positive compared to 1.5% among control subjects while 46% of patients had IAA compared to 1% among control subjects. The autoreactive sites or epitopes of GAD65 and insulin remain to be determined. The disease association with HLA on chromosome 6 may help to define the epitope specificity of the autoimmune reaction. Recent data suggest that 95% of new-onset IDDM children (0-15 years of age) are positive for either DQ2, DQ8 or both compared to about 50% of healthy control subjects. HLA-DQ6 is negatively associated with the disease. Both HLA-DQ2 and DQ8 therefore seem to be necessary, but not sufficent for diabetes. Molecular modelling suggests comparable physicochemical properties of DQ2 and DQ8 but are widely different from DQ6. In 1984, the conclusion was that molecular cloning of the genes for the autoantigens, antibodies, T-cell receptors, as well as HLA class I and II molecules associated with diabetes are essential for analysing the components which control the development of pancreatic beta-cell autoimmunity. In 1994, autoantigens and HLA molecules have been cloned and recombinant reagents developed to be used in experiments aimed at testing whether it will be possible to predict IDDM. Our understanding of immune autoreactivity is, however, still inadequate and remains a major challenge to future Minkowski Award hopefuls.