Rodero et al. report the direct quantification of IFNα protein in monogenic interferonopathies, autoimmunity, and infectious disease states, made possible by the combination of digital ELISA and high-affinity autoantibodies isolated from APECED patients, revealing differential levels and cellular sources dependent on underlying pathology.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER–Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.

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These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

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...

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.

PurposeIncreased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases.Design, Setting, and ParticipantsA cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data.ResultsNine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90–18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99–17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51–21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427–1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493–1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491–3.74).Conclusions and RelevanceAn assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0359-1) contains supplementary material, which is available to authorized users.