Activated STING in a vascular and pulmonary syndrome

Details

Serval ID
serval:BIB_0F81943EEA19
Type
Article: article from journal or magazin.
Collection
Publications
Title
Activated STING in a vascular and pulmonary syndrome
Journal
N Engl J Med
Author(s)
Liu Y., Jesus A. A., Marrero B., Yang D., Ramsey S. E., Sanchez G. A. M., Tenbrock K., Wittkowski H., Jones O. Y., Kuehn H. S., Lee C. R., DiMattia M. A., Cowen E. W., Gonzalez B., Palmer I., DiGiovanna J. J., Biancotto A., Kim H., Tsai W. L., Trier A. M., Huang Y., Stone D. L., Hill S., Kim H. J., Hilaire C. S., Gurprasad S., Plass N., Chapelle D., Horkayne-Szakaly I., Foell D., Barysenka A., Candotti F., Holland S. M., Hughes J. D., Mehmet H., Issekutz A. C., Raffeld M., McElwee J., Fontana J. R., Minniti C. P., Moir S., Kastner D. L., Gadina M., Steven A. C., Wingfield P. T., Brooks S. R., Rosenzweig S. D., Fleisher T. A., Deng Z., Boehm M., Paller A. S., Goldbach-Mansky R.
ISSN
1533-4406 (Electronic)
ISSN-L
0028-4793
Publication state
Published
Issued date
2014
Volume
371
Number
6
Pages
507-518
Language
english
Notes
Liu, Y
Jesus, A A
Marrero, B
Yang, D
Ramsey, S E
Sanchez, G A Montealegre
Tenbrock, K
Wittkowski, H
Jones, O Y
Kuehn, H S
Lee, C-C R
DiMattia, M A
Cowen, E W
Gonzalez, B
Palmer, I
DiGiovanna, J J
Biancotto, A
Kim, H
Tsai, W L
Trier, A M
Huang, Y
Stone, D L
Hill, S
Kim, H J
Hilaire, C St
Gurprasad, S
Plass, N
Chapelle, D
Horkayne-Szakaly, I
Foell, D
Barysenka, A
Candotti, F
Holland, S M
Hughes, J D
Mehmet, H
Issekutz, A C
Raffeld, M
McElwee, J
Fontana, J R
Minniti, C P
Moir, S
Kastner, D L
Gadina, M
Steven, A C
Wingfield, P T
Brooks, S R
Rosenzweig, S D
Fleisher, T A
Deng, Z
Boehm, M
Paller, A S
Goldbach-Mansky, R
eng
ZIA AR041138-11/Intramural NIH HHS/
Research Support, N.I.H., Intramural
N Engl J Med. 2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625. Epub 2014 Jul 16.
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-beta, 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.).
Keywords
Age of Onset, Cytokines/genetics/metabolism, Female, Fibroblasts/metabolism, Genes, Dominant, Humans, Infant, Infant, Newborn, Inflammation/*genetics/metabolism, Interferon-gamma/genetics/metabolism, Janus Kinases/antagonists & inhibitors, Lung Diseases/genetics, Male, Membrane Proteins/*genetics, *Mutation, Pedigree, Phosphorylation, STAT1 Transcription Factor/metabolism, Sequence Analysis, DNA, Skin Diseases, Vascular/*genetics/metabolism, Syndrome, Transcription, Genetic, Up-Regulation
Pubmed
Create date
01/11/2017 10:29
Last modification date
20/08/2019 12:36
Usage data