Abstract
A spectrum of human autoinflammatory conditions result from defects in cytosolic nucleic acid clearance or overexpression of the nucleic acid sensor STING. These patients often develop severely debilitating lesions and invariably show robust IFN signatures that have been attributed to the cGAS/STING signaling cascade and type I IFN. However, murine models that recapitulate major features of these syndromes have now shown that autoinflammation is more likely to depend on type II IFN/IFNgamma or type III IFN/IFNlambda, and further revealed a critical role for Th1 cells in tissue damage and the persistence of inflammation. These studies provide important insights about the types of IFNs, and the interplay of the innate and adaptive immune systems mediated by these IFNs, that can initiate and maintain the corresponding human diseases. They further point to type II/III IFNs and effector T cells as targets for more effective therapeutic strategies in the treatment of these patient populations.