VALUE OF ANTIBODIES TO ISLET PROTEIN-TYROSINE PHOSPHATASE-LIKE MOLECULE IN PREDICTING TYPE-1 DIABETES

Islet antigens associated with type 1 diabetes include a recently iden tified protein tyrosine phosphatase-like molecule IA-2, which contains the intracellular fragment IA-2ic. To determine whether combinations of antibodies including those to IA-2 characterize and predict type 1 diabetes, we studied antibodies to IA-2, IA-aic, glutamic acid decarbo xylase (GAD(65)), and islet cell antibodies (ICAs) in 1) 60 newly diag nosed type 1 diabetic patients followed for 1 year, 2) 31 monozygotic twin pairs discordant for type 1 diabetes followed up to 12 years (11 twins developed diabetes), 3) 18 dizygotic twin pairs discordant for t ype 1 diabetes, and 4) normal healthy control subjects. Newly diagnose d type 1 diabetic patients frequently had antibodies to IA-2 (62%), IA -Sic (67%), GAD(65) (77%), and ICAs (85%). The intracellular fragment of IA-2 probably contains the immunodominant epitope as 137 of 143 sam ples with IA-2 antibodies from type 1 diabetic patients also had IA-2i c antibodies. Monozygotic twins were usually discordant for antibody s pecificities. Concordance was higher in monozygotic than matched dizyg otic twins for both antibody combinations (33 vs. 6%, P < 0.05) and th e development of diabetes (33 vs. 0%, P < 0.01). In monozygotic twins, all the antibodies were highly predictive of type 1 diabetes (positiv e predictive values all >87%), although antibodies were also detected in twins at low risk of disease. In summary, IA-2 emerges as a major a ntigen associated with type 1 diabetes and distinct from GAD(65). Type 1 diabetes-associated autoimmunity, which is probably induced by envi ronmental factors, does not necessarily herald progression to the dise ase. However, genetic factors may influence the development of combina tions of disease-associated antibodies and the progression to type 1 d iabetes.