The Antiviral 2′,5′-Oligoadenylate Synthetase Is Persistently Activated in Type 1 Diabetes

Type 1 diabetes results from autoimmune destruction of the pancreatic β-cells. Although viruses have been implicated as etiologic factors, specific pathogenic mechanisms have not been identified. Recently, increased attention has focused on the role of the innate antiviral defense system in directing adaptive immune responses. In this context, the pathogenesis of type 1 diabetes may involve an aberrant response to endogenous or exogenous viruses or their products. The family of 2′,5′ oligoadenylate synthetases (2′,5′ AS) are IFN-α-inducible, RNA-dependent effector molecules in the antiviral defense system. We show that lymphocytic 2′,5′ AS activity is significantly increased in type 1 diabetes, both in recent-onset and in long-standing 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 multiple sclerosis thus excluding hyperglycemia or autoimmunity per se as inducing upregulation of enzyme activity. In recent-onset diabetic patients, lymphocyte levels of protein kinase p68 and MxA, two other IFN-α-inducible antiviral proteins, were similar to control levels. These data suggest that the increased 2′,5′ AS activity may reflect an aberrant response to viruses or RNA molecules originating from exogenous or endogenous sources.