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The innate sensor STING is critical for innate immune activation, but its role in adaptive immunity is unknown. By studying pathogenic mutations in STING found in patients, Cerboni et al. show that active STING inhibits proliferation in T lymphocytes.

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Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.

Capsule summary 55This article demonstrates that JAK inhibition represents a highly promising and well-tolerated 56 therapy for STING-associated vasculopathy, and which may also be relevant to the treatment 57 of other type I interferonopathies. 58 59Key words: Stimulator of Interferon genes, TMEM173, Janus kinase 1/2 inhibitor, type I 60 interferonopathy, interstitial lung disease, vasculopathy. 61 To the Editor: 62Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) 63 underlie a novel type I interferonopathy, 1 termed SAVI (STING-associated vasculopathy with 64 onset in infancy). 2,3 This disease is associated with high childhood morbidity and mortality. 65 STING is a central component of DNA sensing that leads to the induction of type I 66 interferons (IFN), which in turn drives the expression of IFN-stimulated genes (ISGs) through 67 the engagement of a common receptor and subsequent activation of Janus kinase 1 (JAK1) 68 and tyrosine kinase 2 (TYK2). 69We describe, for the first time, the use and efficacy of ruxolitinib, a selective oral JAK1/2 70 inhibitor, in three children with TMEM173-activating mutations over 6 to 18 months of 71 follow-up. The patients, aged between 5 and 12 years, exhibited the phenotypic variability 72 associated with TMEM173-activating mutations, 2,3,4 with lung disease and systemic 73 inflammation being the major features in P1 and P3, whilst in P2 skin involvement was most 74 prominent (Fig 1 and see Supplemental Text, Fig E3, and Table E1 in the Online Repository). 75There was minimal response to a broad spectrum of immunosuppressive therapies including 76 steroids, methotrexate and anti-CD20 monoclonal antibodies. 77 78An increased expression of ISGs, a so-called type I IFN signature, 5 was observed in all three 79 patients (see Fig E1, A in the Online Repository). Increased levels of STAT1 phosphorylation 80 were recorded in patient T lymphocytes (P1, P2, P3), T cultured lymphoblasts (P1) and 81 primary fibroblasts (P3) compared to controls (see Fig E2, A in the Online Repository). Liu et 82 al. demonstrated that, in vitro, three JAK1 inhibitors (ruxolitinib, tofacitinib and baricitinib) 83 were able to block the constitutive phosphorylation of STAT1 in lymphocytes from 84 TMEM173-mutated patients, 2 and we saw that exposure to ruxolitinib inhibited the 85 constitutive phosphorylation of STAT1 and decreased the expression of IL-6 and 3 ISGs 86 tested in T lymphoblasts from P1 (see Fig E2, B, C in the Online Repository). Considering the 87 severity of the phenotype and the poor response to conventional immunosuppressive 88 therapies, we hypothesized that JAK1 inhibition would block IFN signaling in the context of 89 activating mutations in TMEM173. 90 91We observed a marked positive effect on all aspects of the phenotype in all three treated 92 children. There was a general improvement in patient-reported well-being, a reduction of 93 febrile episodes, an almost complete resolution of the associated cutaneous lesions and a 94 major impr...

We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.

This observational report describes a new case of SAVI, a recently defined monogenic inflammatory phenotype, that exemplifies an emerging group of disorders related to primary upregulation of type I interferon signaling.

STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.