Activated STING in a vascular and pulmonary syndrome

Y. Liu, A. A. Jesus, B. Marrero, D. Yang, S. E. Ramsey, G. A. Montealegre Sanchez, K. Tenbrock, H. Wittkowski, O. Y. Jones, H. S. Kuehn, C. C R Lee, M. A. DiMattia, E. W. Cowen, B. Gonzalez, I. Palmer, J. J. DiGiovanna, A. Biancotto, H. Kim, W. L. Tsai, A. M. Trier & 32 others Y. Huang, D. L. Stone, S. Hill, H. J. Kim, C. St Hilaire, S. Gurprasad, N. Plass, D. Chapelle, I. Horkayne-Szakaly, D. Foell, A. Barysenka, F. Candotti, S. M. Holland, J. D. Hughes, H. Mehmet, A. C. Issekutz, M. Raffeld, J. McElwee, J. R. Fontana, Caterina P. Minniti, S. Moir, D. L. Kastner, M. Gadina, A. C. Steven, P. T. Wingfield, S. R. Brooks, S. D. Rosenzweig, T. A. Fleisher, Z. Deng, M. Boehm, A. S. Paller, R. Goldbach-Mansky

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)507-518
Number of pages12
JournalNew England Journal of Medicine
Volume371
Issue number6
DOIs
StatePublished - Aug 7 2014
Externally publishedYes

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Interferons
Blood Vessels
Lung
Genes
STAT1 Transcription Factor
Janus Kinases
Blood Cells
Endothelial Cells
Fibroblasts
Phosphorylation
Lymphocytes
Inflammation
Mutation
Interleukin-1
Exons
Interleukin-6
Pneumonia
Up-Regulation
Tumor Necrosis Factor-alpha
Apoptosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Liu, Y., Jesus, A. A., Marrero, B., Yang, D., Ramsey, S. E., Montealegre Sanchez, G. A., ... Goldbach-Mansky, R. (2014). Activated STING in a vascular and pulmonary syndrome. New England Journal of Medicine, 371(6), 507-518. https://doi.org/10.1056/NEJMoa1312625

Activated STING in a vascular and pulmonary syndrome. / Liu, Y.; Jesus, A. A.; Marrero, B.; Yang, D.; Ramsey, S. E.; Montealegre Sanchez, G. A.; 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.; St Hilaire, C.; 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, Caterina 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.

In: New England Journal of Medicine, Vol. 371, No. 6, 07.08.2014, p. 507-518.

Research output: Contribution to journalArticle

Liu, Y, Jesus, AA, Marrero, B, Yang, D, Ramsey, SE, Montealegre Sanchez, GA, Tenbrock, K, Wittkowski, H, Jones, OY, Kuehn, HS, Lee, CCR, DiMattia, MA, Cowen, EW, Gonzalez, B, Palmer, I, DiGiovanna, JJ, Biancotto, A, Kim, H, Tsai, WL, Trier, AM, Huang, Y, Stone, DL, Hill, S, Kim, HJ, St Hilaire, C, Gurprasad, S, Plass, N, Chapelle, D, Horkayne-Szakaly, I, Foell, D, Barysenka, A, Candotti, F, Holland, SM, Hughes, JD, Mehmet, H, Issekutz, AC, Raffeld, M, McElwee, J, Fontana, JR, Minniti, CP, Moir, S, Kastner, DL, Gadina, M, Steven, AC, Wingfield, PT, Brooks, SR, Rosenzweig, SD, Fleisher, TA, Deng, Z, Boehm, M, Paller, AS & Goldbach-Mansky, R 2014, 'Activated STING in a vascular and pulmonary syndrome', New England Journal of Medicine, vol. 371, no. 6, pp. 507-518. https://doi.org/10.1056/NEJMoa1312625
Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA et al. Activated STING in a vascular and pulmonary syndrome. New England Journal of Medicine. 2014 Aug 7;371(6):507-518. https://doi.org/10.1056/NEJMoa1312625
Liu, Y. ; Jesus, A. A. ; Marrero, B. ; Yang, D. ; Ramsey, S. E. ; Montealegre Sanchez, G. A. ; 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. ; St Hilaire, C. ; 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, Caterina 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. / Activated STING in a vascular and pulmonary syndrome. In: New England Journal of Medicine. 2014 ; Vol. 371, No. 6. pp. 507-518.
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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.",
author = "Y. Liu and Jesus, {A. A.} and B. Marrero and D. Yang and Ramsey, {S. E.} and {Montealegre Sanchez}, {G. A.} and K. Tenbrock and H. Wittkowski and Jones, {O. Y.} and Kuehn, {H. S.} and Lee, {C. C R} and DiMattia, {M. A.} and Cowen, {E. W.} and B. Gonzalez and I. Palmer and DiGiovanna, {J. J.} and A. Biancotto and H. Kim and Tsai, {W. L.} and Trier, {A. M.} and Y. Huang and Stone, {D. L.} and S. Hill and Kim, {H. J.} and {St Hilaire}, C. and S. Gurprasad and N. Plass and D. Chapelle and I. Horkayne-Szakaly and D. Foell and A. Barysenka and F. Candotti and Holland, {S. M.} and Hughes, {J. D.} and H. Mehmet and Issekutz, {A. C.} and M. Raffeld and J. McElwee and Fontana, {J. R.} and Minniti, {Caterina P.} and S. Moir and Kastner, {D. L.} and M. Gadina and Steven, {A. C.} and Wingfield, {P. T.} and Brooks, {S. R.} and Rosenzweig, {S. D.} and Fleisher, {T. A.} and Z. Deng and M. Boehm and Paller, {A. S.} and R. Goldbach-Mansky",
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TY - JOUR

T1 - Activated STING in a vascular and pulmonary syndrome

AU - Liu, Y.

AU - Jesus, A. A.

AU - Marrero, B.

AU - Yang, D.

AU - Ramsey, S. E.

AU - Montealegre Sanchez, G. A.

AU - Tenbrock, K.

AU - Wittkowski, H.

AU - Jones, O. Y.

AU - Kuehn, H. S.

AU - Lee, C. C R

AU - DiMattia, M. A.

AU - Cowen, E. W.

AU - Gonzalez, B.

AU - Palmer, I.

AU - DiGiovanna, J. J.

AU - Biancotto, A.

AU - Kim, H.

AU - Tsai, W. L.

AU - Trier, A. M.

AU - Huang, Y.

AU - Stone, D. L.

AU - Hill, S.

AU - Kim, H. J.

AU - St Hilaire, C.

AU - Gurprasad, S.

AU - Plass, N.

AU - Chapelle, D.

AU - Horkayne-Szakaly, I.

AU - Foell, D.

AU - Barysenka, A.

AU - Candotti, F.

AU - Holland, S. M.

AU - Hughes, J. D.

AU - Mehmet, H.

AU - Issekutz, A. C.

AU - Raffeld, M.

AU - McElwee, J.

AU - Fontana, J. R.

AU - Minniti, Caterina P.

AU - Moir, S.

AU - Kastner, D. L.

AU - Gadina, M.

AU - Steven, A. C.

AU - Wingfield, P. T.

AU - Brooks, S. R.

AU - Rosenzweig, S. D.

AU - Fleisher, T. A.

AU - Deng, Z.

AU - Boehm, M.

AU - Paller, A. S.

AU - Goldbach-Mansky, R.

PY - 2014/8/7

Y1 - 2014/8/7

N2 - 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.

AB - 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.

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