1. Activated STING in a Vascular and Pulmonary Syndrome
- Author
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Fabio Candotti, Yongmei Liu, Amy S. Paller, G.A. Montealegre Sanchez, Huseyin Mehmet, Raphaela Goldbach-Mansky, Susan Moir, Anna M. Trier, Nicole Plass, S Hill, B Marrero, Mark Raffeld, Iren Horkayne-Szakaly, Sofia Rosenzweig, Ira Palmer, Thomas A. Fleisher, Michael A. DiMattia, Hye Sun Kuehn, Joshua J McElwee, Caterina P. Minniti, A.C. Steven, Steven M. Holland, Chyi-Chia Richard Lee, Manfred Boehm, Stephen R. Brooks, Yhu Chering Huang, Wanxia L. Tsai, Angelique Biancotto, Andrei Barysenka, Jason D. Hughes, Benito Gonzalez, Klaus Tenbrock, Joseph R. Fontana, Deborah L. Stone, Andrew C. Issekutz, Dan Yang, Helmut Wittkowski, Zuoming Deng, Dirk Foell, A Almeida de Jesus, Olcay Y. Jones, C. St. Hilaire, Shakuntala Gurprasad, Suzanne E. Ramsey, Daniel L. Kastner, D. Chapelle, Massimo Gadina, Hanna Kim, Edward W. Cowen, J.J. DiGiovanna, H. Kim, and Paul T. Wingfield
- Subjects
Lung Diseases ,Male ,Transcription, Genetic ,medicine.medical_treatment ,Skin Diseases, Vascular ,Systemic inflammation ,Interferon-gamma ,medicine ,Humans ,Interferon gamma ,STAT1 ,Age of Onset ,Phosphorylation ,Genes, Dominant ,Janus Kinases ,Inflammation ,biology ,business.industry ,Infant, Newborn ,Infant ,Membrane Proteins ,Sequence Analysis, DNA ,Syndrome ,General Medicine ,Fibroblasts ,Pedigree ,Up-Regulation ,Sting ,STAT1 Transcription Factor ,Cytokine ,Mutation ,Immunology ,Cancer research ,STAT protein ,biology.protein ,Cytokines ,Female ,Tumor necrosis factor alpha ,medicine.symptom ,Janus kinase ,business ,medicine.drug - Abstract
BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.)
- Published
- 2014
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