ID: 255: Autoimmunity due to constitutive activation of cytoplasmic viral RNA sensors
MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. Once MDA5 senses replicating viruses, it triggers signal to activate antiviral genes including those of types I and III IFN. Activation of IFN system is critical as antiviral innate immunity and promotes activation of acquired immunity. These immune responses orchestrate eradication of infecting viruses. On the other hand, MDA5 has been implicated in autoimmunity. The mechanisms of how MDA5 contribute to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, IPS-1, indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand, but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. In humans, mutations of MDA5 and RIG-I were found in patients of Aicardi-Goutieres syndrome and Singleton-Merton syndrome. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.