Reduced expression of the MDA5 Gene IFIH1 prevents autoimmune diabetes

Abstract

Although it is widely accepted that type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin-producing β-cells in the pancreas, little is known about the events leading to islet autoimmunity. Epidemiological and genetic data have associated virus infections and antiviral type I interferon (IFN-I) response genes with T1D. Genetic variants in the T1D risk locus interferon induced with helicase C domain 1 (IFIH1) have been identified by genome-wide association studies to confer resistance to T1D and result in the reduction in expression of the intracellular RNA virus sensor known as melanoma differentiation-associated protein 5 (MDA5). Here, we translate the reduction in IFIH1 gene expression that results in protection from T1D. Our functional studies demonstrate that mice heterozygous at the Ifih1 gene express less than half the level of MDA5 protein, which leads to a unique antiviral IFN-I signature and adaptive response after virus infection that protects from T1D. IFIH1 heterozygous mice have a regulatory rather than effector T-cell response at the site of autoimmunity, supporting IFIH1 expression as an essential regulator of the diabetogenic T-cell response and providing a potential mechanism for patients carrying IFIH1 protective polymorphisms.