Over the last several years our laboratory has isolated, cloned, sequenced, expressed and determined the chromosomal localization of mouse and human IA-2 and IA-2 beta, both of which have turned out to be major autoantigens in insulin-dependent diabetes mellitus (IDDM). The genomic structure of these molecules also has been determined and the 5' upstream regions sequenced and shown to possess promoter activity. Sequence analysis revealed that IA-2 and IA-2 beta are members of the protein tyrosine phosphatase (PTP) family, but lack enzyme activity because of the presence of two amino acid substitutions in the highly conserved catalytic domain. Correction of these substitutions by site-directed mutagenesis resulted in the restoration of enzyme activity. Detailed molecular and cellular biology studies have provided information on the processing and post-translational modification and antigenic determinants of IA-2. Our very recent studies have uncovered homologs of IA-2 and IA-2 beta in C. elegans and Drosophila. These and other findings argue that IA-2 and IA-2 beta belong to a new subgroup of the PTP super family. Perhaps the most important outcome from these studies is that autoantibodies to IA-2 and IA-2 beta appear years before the development of clinically apparent IDDM and, therefore, can serve as predictive markers for this disease. In collaboration with colleagues in the United States and England, we demonstrated this in three separate clinical studies. The first, with identical twins, showed that 90% of non-diabetic co-twins (of diabetic probands) that eventually went on to develop IDDM had autoantibodies to IA-2 five years or more years before the appearance of clinical disease. In contrast, none of the non-diabetic co-twins (of diabetic probands) that failed to develop IDDM displayed autoantibodies to IA-2 at any time during the five-to-ten years of follow-up. The second study involved approximately 10,000 school children who were followed for up to 10 years for the presence of autoantibodies. Eleven of these children went on to develop diabetes and ten of them were found to have autoantibodies to IA-2 years before they developed IDDM. The third study involved close to 15,000 first degree relatives of IDDM patients who were followed prospectively. Of those who went on to develop IDDM, over half showed autoantibodies to IA-2 years before they developed clinical disease. Even more striking was the observation that in individuals who had autoantibodies to both IA-2 and glutamic acid decarboxylase (GAD), another major IDDM autoantigen, the likelihood of coming down with IDDM was approximately 50% at five years and was even higher at 10 years. In the general population it is estimated that nearly one in 300 individuals will at some time during their life develop IDDM. Thus, 30,000 children would have to be admitted to a clinical trial in order to study the efficacy of therapeutic intervention on the 100 children likely to develop IDDM. Now by screening populations for IA-2 and GAD, as few as 200 double-positive children (i.e., autoantibodies to both IA-2 and GAD) are all that are needed to obtain significant results, since 50% of these children are likely to come down with IDDM within 5 years. Similar observations now have been made in a number of other laboratories around the world and screening for double-positive individuals is being widely used to study the pathogenesis of IDDM and to determine who to admit into therapeutic intervention trials.
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