Patients with stimulator of interferon genes (STI N G)-associated vasculopathy with onset in infancy (SAVI) develop systemic inflammation characterized by vasculopathy, interstitial lung disease, ulcerative skin lesions, and premature death. Autosomal dominant mutations in STI N G are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)- stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STI N G N153S knock-in mice as a model of SAVI. These mice spontaneously developed inflammation within the lung, hypercytokinemia, T cell cytopenia, skin ulcerations, and premature death. Cytometry by time-of-flight (CyTO F) analysis revealed that the STI N G N153S mutation caused myeloid cell expansion, T cell cytopenia, and dysregulation of immune cell signaling. Unexpectedly, we observed only mild up-regulation of ISGs in STI N G N153S fibroblasts and splenocytes and STI N G N154S SAVI patient fibroblasts. STI N G N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STI N G N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice.
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