Skip to main content

Advertisement

SpringerLink
Log in

STING-Mediated Lung Inflammation and Beyond

  • CME Review
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Mendelian autoinflammatory diseases characterized by constitutive activation of the type I interferon pathway, the so-called type I interferonopathies, constitute a rapidly expanding group of inborn errors of immunity. Among the type I interferonopathies, STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome were described in the last 6 years, both manifesting a major inflammatory lung component associated with significant morbidity and increased mortality. There is striking clinical and histopathological overlap between SAVI and COPA syndrome, although distinct features are also present. Of note, there is a remarkably high frequency of clinical non-penetrance among individuals harboring pathogenic COPA mutations. SAVI is caused by, principally heterozygous, gain-of-function mutations in STING1 (previously referred to as TMEM173) encoding STING, a key adaptor of the interferon signaling pathway induced by DNA. COPA syndrome results from heterozygous dominant-negative mutations in the coatomer protein subunit alpha, forming part of a complex involved in intracellular cargo protein transport between the Golgi and the endoplasmic reticulum (ER). Of importance, a role for COPA in regulating the trafficking of STING, an ER-resident protein which translocates to the Golgi during the process of its activation, was recently defined, thereby possibly explaining some aspects of the phenotypic overlap between SAVI and COPA syndrome. Here, we review the expanding phenotype of these diseases, highlighting common as well as specific features, and recent advances in our understanding of STING biology that have informed therapeutic decision-making in both conditions. Beyond these rare Mendelian disorders, DNA sensing through STING is likely relevant to the pathology of several diseases associated with lung inflammation, including systemic lupus erythematosus, dermatomyositis, environmental toxin exposure, and viral infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

All data are available in the manuscript and the Electronic Supplemental Material (ESM).

References

  1. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24–64.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Uggenti C, Lepelley A, Crow YJ. Self-awareness: nucleic acid-driven inflammation and the type I interferonopathies. Annu Rev Immunol. 2019;37:247–67.

    Article  CAS  PubMed  Google Scholar 

  3. Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91–8.

    Article  CAS  PubMed  Google Scholar 

  4. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med. 2016;213:2527–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Melki I, Frémond M-L. Type I interferonopathies: from a novel concept to targeted therapeutics. Curr Rheumatol Rep. 2020;22:32.

    Article  PubMed  Google Scholar 

  6. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg M-C, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–20.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015;47:654–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rivara S, Ablasser A. COPA silences STING. J Exp Med. 2020;217.

  10. Lepelley A, Martin-Niclós MJ, Le Bihan M, Marsh JA, Uggenti C, Rice GI, et al. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. J Exp Med. 2020;217.

  11. Deng Z, Chong Z, Law CS, Mukai K, Ho FO, Martinu T, et al. A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome. BioRxiv. 2020.

  12. Clarke SLN, Robertson L, Rice GI, Seabra L, Hilliard TN, Crow YJ, et al. Type 1 interferonopathy presenting as juvenile idiopathic arthritis with interstitial lung disease: report of a new phenotype. Pediatr Rheumatol Online J. 2020;18:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Anjani G, Jindal AK, Prithvi A, Kaur A, Rawat A, Sharma M, et al. Deforming polyarthritis in a north Indian family-clinical expansion of STING-associated vasculopathy with onset in infancy (SAVI). J Clin Immunol. 2020.

  14. Frémond M-L, Hadchouel A, Berteloot L, Melki I, Bresson V, Barnabei L, et al. Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients. J Allergy Clin Immunol Pract. 2020.

  15. Tang X, Xu H, Zhou C, Peng Y, Liu H, Liu J, et al. STING-associated vasculopathy with onset in infancy in three children with new clinical aspect and unsatisfactory therapeutic responses to tofacitinib. J Clin Immunol. 2020;40:114–22.

    Article  CAS  PubMed  Google Scholar 

  16. Staels F, Betrains A, Doubel P, Willemsen M, Cleemput V, Vanderschueren S, et al. Adult-onset ANCA-associated vasculitis in SAVI: extension of the phenotypic spectrum. Case Report and Review of the Literature Front Immunol. 2020;11:575219.

    CAS  PubMed  Google Scholar 

  17. Picard C, Thouvenin G, Kannengiesser C, Dubus J-C, Jeremiah N, Rieux-Laucat F, et al. Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 mutation). Chest. 2016;150:e65–71.

    Article  PubMed  Google Scholar 

  18. König N, Fiehn C, Wolf C, Schuster M, Cura Costa E, Tüngler V, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2017;76:468–72.

    Article  PubMed  Google Scholar 

  19. Keskitalo S, Haapaniemi E, Einarsdottir E, Rajamäki K, Heikkilä H, Ilander M, et al. Novel TMEM173 mutation and the role of disease modifying alleles. Front Immunol. 2019;10:2770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li J, An S, Du Z. Familial interstitial lung disease caused by mutation of the STING1 gene. Front Pediatr. 2020;8:543.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lin B, Berard R, Al Rasheed A, Aladba B, Kranzusch PJ, Henderlight M, et al. A novel STING1 variant causes a recessive form of STING-associated vasculopathy with onset in infancy (SAVI). J Allergy Clin Immunol. 2020;146:1204–1208.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Melki I, Rose Y, Uggenti C, Van Eyck L, Frémond M-L, Kitabayashi N, et al. Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. J. Allergy Clin. Immunol. 2017;140:543–552.e5.

    Article  CAS  PubMed  Google Scholar 

  23. Ma W, Goldberg J. Rules for the recognition of dilysine retrieval motifs by coatomer. EMBO J. 2013;32:926–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brandizzi F, Barlowe C. Organization of the ER-Golgi interface for membrane traffic control. Nat Rev Mol Cell Biol. 2013;14:382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gruber C, Bogunovic D. Incomplete penetrance in primary immunodeficiency: a skeleton in the closet. Hum Genet. 2020;139:745–57.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Konno H, Chinn IK, Hong D, Orange JS, Lupski JR, Mendoza A, et al. Pro-inflammation associated with a gain-of-function mutation (R284S) in the innate immune sensor STING. Cell Rep. 2018;23:1112–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Saldanha RG, Balka KR, Davidson S, Wainstein BK, Wong M, Macintosh R, et al. A mutation outside the dimerization domain causing atypical STING-associated vasculopathy with onset in infancy. Front Immunol. 2018;9:1535.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bialas AR, Presumey J, Das A, van der Poel CE, Lapchak PH, Mesin L, et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature. 2017;546:539–43.

    Article  CAS  PubMed  Google Scholar 

  29. Mackenzie KJ, Carroll P, Martin C-A, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548:461–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature. 2018;563:131–6.

    Article  CAS  PubMed  Google Scholar 

  31. Glück S, Guey B, Gulen MF, Wolter K, Kang T-W, Schmacke NA, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017;19:1061–70.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018;561:258–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016;16:566–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hopfner K-P, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21:501–21.

    Article  CAS  PubMed  Google Scholar 

  35. Volkman HE, Cambier S, Gray EE, Stetson DB. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife. 2019;8.

  36. Hertzog J, Rehwinkel J. Regulation and inhibition of the DNA sensor cGAS. EMBO Rep. 2020;e51345.

  37. Ablasser A, Chen ZJ. cGAS in action: expanding roles in immunity and inflammation. Science. 2019;363:eaat8657.

    Article  CAS  PubMed  Google Scholar 

  38. Mukai K, Konno H, Akiba T, Uemura T, Waguri S, Kobayashi T, et al. Activation of STING requires palmitoylation at the Golgi. Nat Commun. 2016;7:11932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ogawa E, Mukai K, Saito K, Arai H, Taguchi T. The binding of TBK1 to STING requires exocytic membrane traffic from the ER. Biochem Biophys Res Commun. 2018;503:138–45.

    Article  CAS  PubMed  Google Scholar 

  40. Gonugunta VK, Sakai T, Pokatayev V, Yang K, Wu J, Dobbs N, et al. Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. 2017;21:3234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gui X, Yang H, Li T, Tan X, Shi P, Li M, et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. 2019;567:262–6.

    Article  CAS  PubMed  Google Scholar 

  42. Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1. J Virol. 2014;88:5328–41.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell. 2017;171:1110–1124.e18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe. 2015;18:157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shang G, Zhang C, Chen ZJ, Bai X-C, Zhang X. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature. 2019;567:389–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ergun SL, Fernandez D, Weiss TM, Li L. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. Cell. 2019;178:290–301.e10.

    Article  CAS  PubMed  Google Scholar 

  47. Arakel EC, Schwappach B. Formation of COPI-coated vesicles at a glance. J. Cell Sci. 2018;131:jcs209890.

    Article  PubMed  Google Scholar 

  48. Warner JD, Irizarry-Caro RA, Bennion BG, Ai TL, Smith AM, Miner CA, et al. STING-associated vasculopathy develops independently of IRF3 in mice. J Exp Med. 2017;214:3279–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bouis D, Kirstetter P, Arbogast F, Lamon D, Delgado V, Jung S, et al. Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice. J. Allergy Clin. Immunol. 2019;143:712–725.e5.

    Article  CAS  PubMed  Google Scholar 

  50. Luksch H, Stinson WA, Platt DJ, Qian W, Kalugotla G, Miner CA, et al. STING-associated lung disease in mice relies on T cells but not type I interferon. J. Allergy Clin. Immunol. 2019;

  51. Motwani M, Pawaria S, Bernier J, Moses S, Henry K, Fang T, et al. Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models. Proc Natl Acad Sci U S A. 2019;116.

  52. Bennion BG, Croft CA, Ai TL, Qian W, Menos AM, Miner CA, et al. STING gain-of-function disrupts lymph node organogenesis and innate lymphoid cell development in mice. Cell Rep. 2020;31:107771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Martin GR, Henare K, Salazar C, Scheidl-Yee T, Eggen LJ, Tailor PP, et al. Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice. Life Sci Alliance. 2019;2:e201800215.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Siedel H, Roers A, Rösen-Wolff A, Luksch H. Type I interferon-independent T cell impairment in a Tmem173 N153S/WT mouse model of STING associated vasculopathy with onset in infancy (SAVI). Clin Immunol. 2020;216:108466.

    Article  CAS  PubMed  Google Scholar 

  55. Bennion BG, Ingle H, Ai TL, Miner CA, Platt DJ, Smith AM, et al. A human gain-of-function STING mutation causes immunodeficiency and gammaherpesvirus-induced pulmonary fibrosis in mice. J Virol. 2019;93.

  56. Cerboni S, Jeremiah N, Gentili M, Gehrmann U, Conrad C, Stolzenberg M-C, et al. Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes. J Exp Med. 2017;214:1769–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Deng Z, Law CS, Ho FO, Wang KM, Jones KD, Shin J-S, et al. A defect in thymic tolerance causes T cell-mediated autoimmunity in a murine model of COPA syndrome. J Immunol. 2020;204:2360–73.

    Article  CAS  PubMed  Google Scholar 

  58. Rodero MP, Decalf J, Bondet V, Hunt D, Rice GI, Werneke S, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med. 2017;214:1547–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rodero MP, Tesser A, Bartok E, Rice GI, Della Mina E, Depp M, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat Commun. 2017;8:2176.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Volpi S, Tsui J, Mariani M, Pastorino C, Caorsi R, Sacco O, et al. Type I interferon pathway activation in COPA syndrome. Clin Immunol. 2018;187:33–6.

    Article  CAS  PubMed  Google Scholar 

  61. Frémond M-L, Legendre M, Fayon M, Clement A, Filhol-Blin E, Richard N, et al. Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage. Thorax. 2020;75:92–5.

    Article  PubMed  Google Scholar 

  62. Mukai K, Ogawa E, Uematsu R, Kuchitsu Y, Uemura T, Waguri S, et al. Homeostatic regulation of STING by Golgi-to-ER membrane traffic. BioRxiv. 2020;

  63. Steiner A, Hrovat Schaale K, Prigione I, De Nardo D, Dagley LF, Yu C-H, et al. Activation of STING due to COPI-deficiency. BioRxiv. 2020;

  64. Sharma S, Campbell AM, Chan J, Schattgen SA, Orlowski GM, Nayar R, et al. Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc Natl Acad Sci U S A. 2015;112:E710–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu J, Dobbs N, Yang K, Yan N. Interferon-independent activities of mammalian STING mediate antiviral response and tumor immune evasion. Immunity. 2020;53:115–126.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yamashiro LH, Wilson SC, Morrison HM, Karalis V, Chung J-YJ, Chen KJ, et al. Interferon-independent STING signaling promotes resistance to HSV-1 in vivo. Nat Commun. 2020;11:3382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tsui JL, Estrada OA, Deng Z, Wang KM, Law CS, Elicker BM, et al. Analysis of pulmonary features and treatment approaches in the COPA syndrome. ERJ Open Research. 2018;4:00017–2018.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Benmerzoug S, Ryffel B, Togbe D, Quesniaux VFJ. Self-DNA sensing in lung inflammatory diseases. Trends Immunol. 2019;40:719–34.

    Article  CAS  PubMed  Google Scholar 

  69. Ma R, Ortiz Serrano TP, Davis J, Prigge AD, Ridge KM. The cGAS-STING pathway: the role of self-DNA sensing in inflammatory lung disease. FASEB J. 2020;34:13156–70.

    Article  CAS  PubMed  Google Scholar 

  70. Benmerzoug S, Rose S, Bounab B, Gosset D, Duneau L, Chenuet P, et al. STING-dependent sensing of self-DNA drives silica-induced lung inflammation. Nat Commun. 2018;9:5226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015;15:760–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bromfield M, McQuillan R, John R, Avila-Casado C. The significance of tubuloreticular inclusions as a marker of systemic stimulation by interferons in a case of focal and segmental glomerulosclerosis associated with cytomegalovirus (CMV) infection. Clin Kidney J. 2014;7:174–8.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Rich SA. Human lupus inclusions and interferon. Science. 1981;213:772–5.

    Article  CAS  PubMed  Google Scholar 

  74. Clarke SLN, Pellowe EJ, de Jesus AA, Goldbach-Mansky R, Hilliard TN, Ramanan AV. Interstitial lung disease caused by STING-associated vasculopathy with onset in infancy. Am J Respir Crit Care Med. 2016;194:639–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zheng S, Lee PY, Wang J, Wang S, Huang Q, Huang Y, et al. Interstitial lung disease and psoriasis in a child with Aicardi-Goutières syndrome. Front Immunol. 2020;11:985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ayrolles A, Ellul P, Renaldo F, Boespflug-Tanguy O, Delorme R, Drunat S, et al. Catatonia in a patient with Aicardi-Goutières syndrome efficiently treated with immunoadsorption. Schizophr Res. 2020;222:484–6.

    Article  PubMed  Google Scholar 

  78. Melki I, Devilliers H, Gitiaux C, Bondet V, Duffy D, Charuel J-L, et al. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling. Rheumatology. 2020;59:1927–37.

    Article  PubMed  Google Scholar 

  79. Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372:1734–47.

    Article  PubMed  Google Scholar 

  80. Pouessel G, Deschildre A, Le Bourgeois M, Cuisset J-M, Catteau B, Karila C, et al. The lung is involved in juvenile dermatomyositis. Pediatr Pulmonol. 2013;48:1016–25.

    Article  PubMed  Google Scholar 

  81. Mira-Avendano IC, Abril A. Pulmonary manifestations of Sjögren syndrome, systemic lupus erythematosus, and mixed connective tissue disease. Rheum Dis Clin N Am. 2015;41:263–77.

    Article  Google Scholar 

  82. Andrade C, Mendonça T, Farinha F, Correia J, Marinho A, Almeida I, et al. Alveolar hemorrhage in systemic lupus erythematosus: a cohort review. Lupus. 2016;25:75–80.

    Article  CAS  PubMed  Google Scholar 

  83. Chaisson NF, Paik J, Orbai A-M, Casciola-Rosen L, Fiorentino D, Danoff S, et al. A novel dermato-pulmonary syndrome associated with MDA-5 antibodies: report of 2 cases and review of the literature. Medicine. 2012;91:220–8.

    Article  PubMed  Google Scholar 

  84. Habermann AC, Gutierrez AJ, Bui LT, Yahn SL, Winters NI, Calvi CL, et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci. Adv. 2020;6:eaba1972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen Y-W, Huang SX, de Carvalho ALRT, Ho S-H, Islam MN, Volpi S, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol. 2017;19:542–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Boulisfane-El Khalifi S, Viel S, Lahoche A, Frémond M-L, Lopez J, Lombard C, et al. COPA syndrome as a cause of lupus nephritis. Kidney Int Rep. 2019;4:1187–9.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Taveira-DaSilva AM, Markello TC, Kleiner DE, Jones AM, Groden C, Macnamara E, et al. Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features. J Med Genet. 2019;56:778–82.

    Article  CAS  PubMed  Google Scholar 

  88. Vece TJ, Watkin LB, Nicholas S, Canter D, Braun MC, Guillerman RP, et al. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. J Clin Immunol. 2016;36:377–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jensson BO, Hansdottir S, Arnadottir GA, Sulem G, Kristjansson RP, Oddsson A, et al. COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA. BMC Med Genet. 2017;18:129.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Mallea JM, Kornafeld A, Khoor A, Erasmus DB. Lung transplantation in a patient with COPA syndrome. Case Rep Transplant. 2020;2020:1–2.

    Article  Google Scholar 

  91. Fischer A, Lee JS, Cottin V. Interstitial lung disease evaluation: detecting connective tissue disease. Respiration. 2015;90:177–84.

    Article  PubMed  Google Scholar 

  92. Hinks A, Marion MC, Cobb J, Comeau ME, Sudman M, Ainsworth HC, et al. Brief report: the genetic profile of rheumatoid factor-positive polyarticular juvenile idiopathic arthritis resembles that of adult rheumatoid arthritis. Arthritis Rheum. 2018;70:957–62.

    Article  CAS  Google Scholar 

  93. Munoz J, Rodière M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 2015;151:872–7.

    Article  PubMed  Google Scholar 

  94. Chia J, Eroglu FK, Özen S, Orhan D, Montealegre-Sanchez G, de Jesus AA, et al. Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. J Am Acad Dermatol. 2016;74:186–9.

    Article  PubMed  Google Scholar 

  95. Banday AZ, Kaur A, Jindal AK, Patra PK, Guleria S, Rawat A. 2020, Splice-site mutation in COPA gene and familial arthritis - a new frontier. Rheumatology

  96. Santiago MB, Galvão V, Ribeiro DS, Santos WD, da Hora PR, Mota AP, et al. Severe Jaccoud’s arthropathy in systemic lupus erythematosus. Rheumatol Int. 2015;35:1773–7.

    Article  CAS  PubMed  Google Scholar 

  97. Wu Y, Zheng J. Jaccoud’s arthropathy and psoriatic arthritis, a rare association. Rheumatol Int. 2010;30:1081–3.

    Article  CAS  PubMed  Google Scholar 

  98. Garg A, Hernandez MD, Sousa AB, Subramanyam L. Martínez de Villarreal L, dos Santos HG, et al. An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J. Clin. Endocrinol. Metab. 2010;95:E58–63.

    Article  PubMed  PubMed Central  Google Scholar 

  99. de Carvalho LM, Ngoumou G, Park JW, Ehmke N, Deigendesch N, Kitabayashi N, et al. Musculoskeletal disease in MDA5-related type I Interferonopathy: a Mendelian mimic of Jaccoud’s arthropathy. Arthritis Rheum. 2017;69:2081–91.

    Article  Google Scholar 

  100. Krutzke S, Rietschel C, Horneff G. Baricitinib in therapy of COPA syndrome in a 15-year-old girl. Eur J Rheumatol. 2019:1–4.

  101. López de Padilla CM, Niewold TB. The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases. Gene. 2016;576:14–21.

    Article  PubMed  Google Scholar 

  102. Ma M, Mazumder S, Kwak H, Adams M, Gregory M. Case report: acute thrombotic microangiopathy in a patient with STING-associated vasculopathy with onset in infancy (SAVI). J Clin Immunol. 2020;40:1111–5.

    Article  PubMed  Google Scholar 

  103. Abid Q, Best Rocha A, Larsen CP, Schulert G, Marsh R, Yasin S, et al. APOL1-associated collapsing focal segmental glomerulosclerosis in a patient with stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI). Am J Kidney Dis. 2020;75:287–90.

    Article  CAS  PubMed  Google Scholar 

  104. Prenzel F, Harfst J, Schwerk N, Ahrens F, Rietschel E, Schmitt-Grohé S, et al. Lymphocytic interstitial pneumonia and follicular bronchiolitis in children: a registry-based case series. Pediatr Pulmonol. 2020;55:909–17.

    Article  PubMed  Google Scholar 

  105. Bader-Meunier B, Bustaffa M, Iskounen T, Carter E, Marsh JA, Baujat G, et al. Rheumatology. 2020; https://doi.org/10.1093/rheumatology/keaa763.

  106. Frémond M-L, Rodero MP, Jeremiah N, Belot A, Jeziorski E, Duffy D, et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752–5.

    Article  PubMed  Google Scholar 

  107. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128:3041–52.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Volpi S, Insalaco A, Caorsi R, Santori E, Messia V, Sacco O, et al. Efficacy and adverse events during janus kinase inhibitor treatment of SAVI syndrome. J Clin Immunol. 2019;39:476–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Manoussakis MN, Mavragani CP, Nezos A, Zampeli E, Germenis A, Moutsopoulos HM. Type I interferonopathy in a young adult. Rheumatology. 2017;56:2241–3.

    Article  CAS  PubMed  Google Scholar 

  110. Balci S, Ekinci RMK, de Jesus AA, Goldbach-Mansky R, Yilmaz M. Baricitinib experience on STING-associated vasculopathy with onset in infancy: a representative case from Turkey. Clin Immunol. 2019;108273.

  111. Ewart DT, Peterson EJ, Steer CJ. Gene editing for inflammatory disorders. Ann Rheum Dis. 2019;78:6–15.

    Article  CAS  PubMed  Google Scholar 

  112. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559:269–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Alice Lepelley, Nadia Nathan, Bénédicte Neven, Brigitte Bader-Meunier, Karen McKenzie, and Isabelle Melki for stimulating discussions relating to COPA and STING.

Funding

YJC acknowledges a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” program bearing (no. ANR- 10-IAHU-01) and the National Institute for Health Research UK Rare Genetic Disease Research Consortium. This project was supported by MSDAVENIR (Devo-Decode Project).

Author information

Authors and Affiliations

  1. Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, F-75015, Paris, France

    Marie-Louise Frémond & Yanick J. Crow

  2. Paediatric Haematology-Immunology and Rheumatology Unit, AP-HP, Necker Hospital, F-75015, Paris, France

    Marie-Louise Frémond

  3. Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh, UK

    Yanick J. Crow

Authors
  1. Marie-Louise Frémond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanick J. Crow
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M-LF and YJC designed the work. M-LF drafted the article. M-LF and YJC revised and edited the manuscript.

Corresponding author

Correspondence to Marie-Louise Frémond.

Ethics declarations

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 43 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frémond, ML., Crow, Y.J. STING-Mediated Lung Inflammation and Beyond. J Clin Immunol 41, 501–514 (2021). https://doi.org/10.1007/s10875-021-00974-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-021-00974-z

Keywords

Search

Navigation