The antiviral 2 ',5 '-oligoadenylate synthetase is persistently activated in type 1 diabetes

Type 1 diabetes results from autoimmune destruction of the pancreatic beta- cells. Although viruses have been implicated as etiologic factors, specific pathogenic mechanisms have not been identified. Recently, increased attent ion has focused on the role of the innate antiviral defense system in direc ting adaptive immune responses. In this context, the pathogenesis of type 1 diabetes may involve an aberrant response to endogenous or exogenous virus es or their products. The family of 2',5' oligoadenylate synthetases (2',5' AS) are IFN-alpha-inducible, RNA-dependent effector molecules in the antiv iral defense system. We show that lymphocytic 2',5' AS activity is signific antly increased in type 1 diabetes, both in recent-onset and in longstandin g type 1 diabetes, and in diabetic: twins from monozygotic twin pairs. The activity of 2',5' AS was not elevated in patients with type 2 diabetes or m ultiple sclerosis thus excluding hyperglycemia or autoimmunity per se as in ducing upregulation of enzyme activity. In recent-onset diabetic patients, lymphocyte levels of protein kinase p68 and MxA, two other IFN-alpha-induci ble antiviral proteins, were similar to control levels. These data suggest that the increased 2',5' AS activity may reflect an aberrant response to vi ruses or RNA molecules originating from exogenous or endogenous sources. (C ) 2000 Academic Press.