Type 1 Diabetes Is Not Idiopathic Autoimmunity: Persistent Coxsackievirus B Infection in Genetically Susceptible Pancreatic Islets

Type 1 diabetes has been classified as an autoimmune disease of unknown cause for decades. We propose a unified model that challenges this classification: type 1 diabetes is a persistent enteroviral infection of pancreatic beta cells in individuals with genetically hyperactive viral sensing. The genetic risk is concentrated in IFIH1 (MDA5), a cytoplasmic sensor of double-stranded RNA. The common risk variant rs1990760 produces a hyperactive MDA5 protein. When primary human islets carrying this risk genotype are infected with Coxsackievirus B3, they produce significantly more interferon and ISGs than islets with the protective genotype. The immune system correctly identifies and attacks virus-infected beta cells; the pathology arises from a genetic inability to downregulate the antiviral response. This reclassification has therapeutic implications: antivirals could prevent progression to clinical diabetes in autoantibody-positive children, and beta cell replacement must be combined with viral clearance.