Activated STING in a Vascular and Pulmonary Syndrome

作者：Yu Liu, Adriana A. de Jesus, Bernadette Marrero, Dan Yang, Suzanne Ramsey, Gina A. Montealegre Sanchez, Klaus Tenbrock, Helmut Wittkowski, Olcay Y. Jones, Hyesun Kuehn, Chyi‐Chia Richard Lee, Michael A. DiMattia, Edward W. Cowen, B González, Ira Palmer, John J. DiGiovanna, Angélique Biancotto, Hanna Kim, Wen Lin Tsai, Anna M. Trier, Yan Huang, Deborah L. Stone, Suvimol Hill, HyeSoon Kim, Cynthia St. Hilaire, Shakuntala Gurprasad, N Plass, Dawn Chapelle, Iren Horkayne‐Szakaly, Dirk Foell, Andrei Barysenka, Fabio Candotti, Steven M. Holland, Jason D. Hughes, Huseyin Mehmet, Andrew C. Issekutz, M Raffeld, Joshua McElwee, JÉRǑMe Fontana, Caterina P. Minniti, Susan Moir, Daniel L. Kastner, Massimo Gadina, A.C. Steven, Paul T. Wingfield, Stephen R. Brooks, Sergio D. Rosenzweig, Thomas A. Fleisher, Zuoming Deng, Manfred Boehm, Amy S. Paller, Raphaela Goldbach‐Mansky · 发表于：New England Journal of Medicine · 年份：2014 · DOI：10.1056/nejmoa1312625 · 被引用次数：1415 · 研究领域：interferon and immune responses、Cytokine Signaling Pathways and Interactions、Inflammasome and immune disorders

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 sti...