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Cited by 489interferon and immune responsesImmune Response and InflammationImmunodeficiency and Autoimmune Disorders

The type I interferonopathies: 10 years on

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Crow, Yanick J., Stetson, Daniel B.·2022·Nature Reviews Immunology
DOI 10.1038/s41577-021-00633-9PMC PMC8527296
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Abstract

As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential for survival. Developed over evolutionary time, viral nucleic acid detection is a central pillar in the defensive armamentarium used to combat foreign microbial invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host. In 2011, it was suggested that an upregulation of type I interferon signalling might serve as a defining feature of a novel set of Mendelian inborn errors of immunity, where antiviral sensors are triggered by host nucleic acids due to a failure of self versus non-self discrimination. These rare disorders have played a surprisingly significant role in informing our understanding of innate immunity and the relevance of type I interferon signalling for human health and disease. Here we consider what we have learned in this time, and how the field may develop in the future.

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  • Inappropriate upregulation of type I IFN signaling and ISG expression in the CNS has been linked to several interferonopathies including Aicardi-Goutieres syndrome and USP18-deficiency in humans.

    “Inappropriate upregulation of type I IFN signaling and ISG expression in the CNS have been linked to several interferonopathies including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency in humans.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [83]

    The 'Phenotypes, expression and penetrance' section (page unavailable) identifies the CNS as the primary site of interferon production in AGS. 'Interferon receptor signalling' links USP18 deficiency to unrestrained type I interferon signalling and neurological involvement, and 'Definitions' explains that this signalling induces ISGs. The copy does not establish increased ISG expression specifically in the CNS for both human conditions. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Peripheral dysregulation of IFN production is linked with the pathogenesis of CNS neurodegenerative conditions.

    “peripheral dysregulation of IFN production is linked with the pathogenesis of CNS neurodegenerative conditions.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [83]

    The mitochondria section links type I interferon induction to Parkinson disease and motor neuron disease, supporting a connection with neurodegenerative conditions. It does not establish that peripheral IFN production drives their pathogenesis. The Phenotypes, expression and penetrance section instead identifies the CNS as the primary site of IFN production in neurologically focused AGS, while peripheral production predominates in SAVI, where neurological disease is rare (page numbers unavailable). (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Despite acute host protection, chronically elevated IFN-I signaling in the brain is detrimental to neurogenesis, synaptic connections, and structural integrity.

    “Despite acute host protection, chronically elevated IFN-I signaling in the brain is detrimental to neurogenesis, synaptic connections, and structural integrity [94].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [94]

    The Introduction (page unavailable) describes the neurotoxic potential of type I interferon and reports neuropathology in mice chronically producing IFNα from astrocytes. This supports chronic brain harm, but the paper passages do not establish the claimed effects on neurogenesis or synaptic connections; searches for those terms found no such discussion. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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  1. [1]Crow YJ Type I interferonopathies: a novel set of inborn errors of immunity Ann. N. Y. Acad. Sci. 2011 1238 91 98 10.1111/j.1749-6632.2011.06220.x 22129056 · DOI
  2. [2]Crow YJ Lebon P Casanova JL Gresser I A brief historical perspective on the pathological consequences of excessive Type I interferon exposure in vivo J. Clin. Immunol. 2018 38 694 698 10.1007/s10875-018-0543-6 30187308 · DOI
  3. [3]Gresser I Can interferon induce disease? Interferon 1982 4 95 127 6195115
  4. [4]Casanova JL Ion Gresser J. Interferon Cytokine Res. 2019 39 317 320 10.1089/jir.2018.29015.mem · DOI
  5. [5]Lebon P Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy J. Neurol. Sci. 1988 84 201 208 10.1016/0022-510X(88)90125-6 2837539 · DOI
  6. [6]Aicardi J Goutieres F A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis Ann. Neurol. 1984 15 49 54 10.1002/ana.410150109 6712192 · DOI
  7. [7]Smedley H Katrak M Sikora K Wheeler T Neurological effects of recombinant human interferon Br. Med. J. 1983 286 262 264 10.1136/bmj.286.6361.262 6402063 PMC1546481 · DOI
  8. [8]Vesikari T Nuutila A Cantell K Neurologic sequelae following interferon therapy of juvenile laryngeal papilloma Acta Paediatr. Scand. 1988 77 619 622 10.1111/j.1651-2227.1988.tb10718.x 2455956 · DOI
  9. [9]Ronnblom LE Alm GV Oberg KE Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour J. Intern. Med. 1990 227 207 210 10.1111/j.1365-2796.1990.tb00144.x 1690258 · DOI
  10. [10]Tolaymat A Leventhal B Sakarcan A Kashima H Monteiro C Systemic lupus erythematosus in a child receiving long-term interferon therapy J. Pediatr. 1992 120 429 432 10.1016/S0022-3476(05)80913-8 1538292 · DOI
  11. [11]Akwa Y Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration J. Immunol. 1998 161 5016 5026 9794439
  12. [12]Campbell IL Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha Brain Res. 1999 835 46 61 10.1016/S0006-8993(99)01328-1 10448195 · DOI
  13. [13]Crow YJ Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism J. Med. Genet. 2003 40 183 187 10.1136/jmg.40.3.183 12624136 PMC1735395 · DOI
  14. [14]Crow YJ Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus Nat. Genet. 2006 38 917 920 10.1038/ng1845 16845398 · DOI
  15. [15]Crow YJ Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection Nat. Genet. 2006 38 910 916 10.1038/ng1842 16845400 · DOI
  16. [16]Rice GI Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response Nat. Genet. 2009 41 829 832 10.1038/ng.373 19525956 PMC4154505 · DOI
  17. [17]Stetson DB Ko JS Heidmann T Medzhitov R Trex1 prevents cell-intrinsic initiation of autoimmunity Cell 2008 134 587 598 10.1016/j.cell.2008.06.032 18724932 PMC2626626 · DOI · Paper page
  18. [18]Briggs TA Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature Nat. Genet. 2011 43 127 131 10.1038/ng.748 21217755 PMC3030921 · DOI
  19. [19]Lausch E Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity Nat. Genet. 2011 43 132 137 10.1038/ng.749 21217752 · DOI
  20. [20]Lood C C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis Arthritis Rheum. 2009 60 3081 3090 10.1002/art.24852 19790049 · DOI
  21. [21]Santer DM C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes J. Immunol. 2010 185 4738 4749 10.4049/jimmunol.1001731 20844193 PMC3065655 · DOI
  22. [22]Manthiram K Zhou Q Aksentijevich I Kastner DL The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation Nat. Immunol. 2017 18 832 842 10.1038/ni.3777 28722725 · DOI
  23. [23]Notarangelo LD Bacchetta R Casanova JL Su HC Human inborn errors of immunity: An expanding universe Sci. Immunol. 2020 5 eabb1662 10.1126/sciimmunol.abb1662 32651211 PMC7647049 · DOI
  24. [24]Casanova JL Abel L Lethal infectious diseases as inborn errors of immunity: toward a synthesis of the germ and genetic theories Annu. Rev. Pathol. 2021 16 23 50 10.1146/annurev-pathol-031920-101429 32289233 PMC7923385 · DOI
  25. [25]Ablasser A Hur S Regulation of cGAS- and RLR-mediated immunity to nucleic acids Nat. Immunol. 2020 21 17 29 10.1038/s41590-019-0556-1 31819255 · DOI
  26. [27]Uggenti C Lepelley A Crow YJ Self-Awareness: Nucleic Acid-Driven Inflammation and the Type I Interferonopathies Annu. Rev. Immunol. 2019 37 247 267 10.1146/annurev-immunol-042718-041257 30633609 · DOI
  27. [28]Rice GI Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study Lancet Neurol. 2013 12 1159 1169 10.1016/S1474-4422(13)70258-8 24183309 PMC4349523 · DOI
  28. [29]Rodero MP Detection of interferon alpha protein reveals differential levels and cellular sources in disease J. Exp. Med. 2017 214 1547 1555 10.1084/jem.20161451 28420733 PMC5413335 · DOI
  29. [30]Lodi L Differential expression of interferon-alpha protein provides clues to tissue specificity across type I interferonopathies J. Clin. Immunol. 2021 41 603 609 10.1007/s10875-020-00952-x 33411153 · DOI
  30. [31]Rice GI Genetic and phenotypic spectrum associated with IFIH1 gain-of-function Hum. Mutat. 2020 41 837 849 10.1002/humu.23975 31898846 PMC7457149 · DOI
  31. [32]Rice GI Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling Nat. Genet. 2014 46 503 509 10.1038/ng.2933 24686847 PMC4004585 · DOI
  32. [33]Agarwal AK PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome Am. J. Hum. Genet. 2010 87 866 872 10.1016/j.ajhg.2010.10.031 21129723 PMC2997366 · DOI
  33. [34]Liu Y Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity Arthritis Rheum. 2012 64 895 907 10.1002/art.33368 21953331 PMC3278554 · DOI
  34. [35]Watkin LB COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis Nat. Genet. 2015 47 654 660 10.1038/ng.3279 25894502 PMC4513663 · DOI
  35. [36]Volpi S Type I interferon pathway activation in COPA syndrome Clin. Immunol. 2018 187 33 36 10.1016/j.clim.2017.10.001 29030294 · DOI
  36. [37]Harel T Recurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes Am. J. Hum. Genet. 2016 99 831 845 10.1016/j.ajhg.2016.08.007 27640307 PMC5065660 · DOI
  37. [38]Lepelley A Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A J. Exp. Med. 2021 218 e20201560 10.1084/jem.20201560 34387651 PMC8374862 · DOI
  38. [39]Kim H Development of a validated interferon score using nanostring technology J. Interferon Cytokine Res. 2018 38 171 185 10.1089/jir.2017.0127 29638206 PMC5963606 · DOI
  39. [40]Mommert M Type-I Interferon assessment in 45 minutes using the FilmArray® PCR platform in SARS-CoV-2 and other viral infections Eur. J. Immunol. 2021 51 989 994 10.1002/eji.202048978 33314090 PMC8248375 · DOI
  40. [41]Armangue T Neonatal detection of Aicardi Goutières syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots Mol. Genet. Metab. 2017 122 134 139 10.1016/j.ymgme.2017.07.006 28739201 PMC5722655 · DOI
  41. [42]Tise CG Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy Am. J. Med. Genet. A 2021 185 1848 1853 10.1002/ajmg.a.62160 33683010 · DOI
  42. [43]Ferreira AR Marques M Ribeiro D Peroxisomes and innate immunity: antiviral response and beyond Int. J. Mol. Sci. 2019 20 3795 10.3390/ijms20153795 PMC6695817 31382586 · DOI
  43. [44]Dixit E Peroxisomes are signaling platforms for antiviral innate immunity Cell 2010 141 668 681 10.1016/j.cell.2010.04.018 20451243 PMC3670185 · DOI
  44. [45]Gratia M Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS J. Exp. Med. 2019 216 1199 1213 10.1084/jem.20181329 30936263 PMC6504208 · DOI
  45. [46]Gul E Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency J. Allergy Clin. Immunol. 2018 142 246 257 10.1016/j.jaci.2017.10.030 29155101 · DOI
  46. [47]Hartlova A DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immun Immunity 2015 42 332 343 10.1016/j.immuni.2015.01.012 25692705 · DOI · Paper page
  47. [49]Sun L Wu J Du F Chen X Chen ZJ Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway Science 2013 339 786 791 10.1126/science.1232458 23258413 PMC3863629 · DOI · Paper page
  48. [50]Wu J Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA Science 2013 339 826 830 10.1126/science.1229963 23258412 PMC3855410 · DOI
  49. [51]Stetson DB Medzhitov R Recognition of cytosolic DNA activates an IRF3-dependent innate immune response Immunity 2006 24 93 103 10.1016/j.immuni.2005.12.003 16413926 · DOI
  50. [53]Uggenti C cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing Nat. Genet. 2020 52 1364 1372 10.1038/s41588-020-00737-3 33230297 · DOI · Paper page
  51. [55]Zierhut C The cytoplasmic DNA sensor cGAS promotes mitotic cell death Cell 2019 178 302 315.e23 10.1016/j.cell.2019.05.035 31299200 PMC6693521 · DOI
  52. [57]Pathare GR Structural mechanism of cGAS inhibition by the nucleosome Nature 2020 587 668 672 10.1038/s41586-020-2750-6 32911482 · DOI · Paper page
  53. [58]Boyer JA Structural basis of nucleosome-dependent cGAS inhibition Science 2020 370 450 454 10.1126/science.abd0609 32913000 PMC8189757 · DOI · Paper page
  54. [59]Michalski S Structural basis for sequestration and autoinhibition of cGAS by chromatin Nature 2020 587 678 682 10.1038/s41586-020-2748-0 32911480 · DOI · Paper page
  55. [60]Kujirai T Structural basis for the inhibition of cGAS by nucleosomes Science 2020 370 455 458 10.1126/science.abd0237 32912999 PMC7584773 · DOI · Paper page
  56. [61]Dhir A Mitochondrial double-stranded RNA triggers antiviral signalling in humans Nature 2018 560 238 242 10.1038/s41586-018-0363-0 30046113 PMC6570621 · DOI · Paper page
  57. [62]Yang K Huang R Fujihira H Suzuki T Yan N N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1 J. Exp. Med. 2018 215 2600 2616 10.1084/jem.20180783 30135079 PMC6170171 · DOI
  58. [63]Riley JS Tait SW Mitochondrial DNA in inflammation and immunity EMBO Rep. 2020 21 e49799 10.15252/embr.201949799 32202065 PMC7132203 · DOI
  59. [65]Yu CH TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS Cell 2020 183 636 649 10.1016/j.cell.2020.09.020 33031745 PMC7599077 · DOI · Paper page
  60. [67]Fremond ML Crow YJ STING-mediated lung inflammation and beyond J. Clin. Immunol. 2021 41 501 514 10.1007/s10875-021-00974-z 33532887 · DOI
  61. [68]Liu Y Activated STING in a vascular and pulmonary syndrome N. Engl. J. Med. 2014 371 507 518 10.1056/NEJMoa1312625 25029335 PMC4174543 · DOI
  62. [69]Dobbs N STING activation by translocation from the ER is associated with infection and autoinflammatory disease Cell Host Microbe 2015 18 157 168 10.1016/j.chom.2015.07.001 26235147 PMC4537353 · DOI
  63. [70]Gonugunta VK Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response Cell Rep. 2017 21 3234 3242 10.1016/j.celrep.2017.11.061 29241549 PMC5905341 · DOI
  64. [71]Gui X Autophagy induction via STING trafficking is a primordial function of the cGAS pathway Nature 2019 567 262 266 10.1038/s41586-019-1006-9 30842662 PMC9417302 · DOI · Paper page
  65. [72]Lepelley A Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling J. Exp. Med. 2020 217 e20200600 10.1084/jem.20200600 32725128 PMC7596811 · DOI
  66. [73]Deng Z A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome J. Exp. Med. 2020 217 e20201045 10.1084/jem.20201045 32725126 PMC7596814 · DOI
  67. [74]Mukai K Homeostatic regulation of STING by retrograde membrane traffic to the ER Nat. Commun. 2021 12 61 10.1038/s41467-020-20234-9 33397928 PMC7782846 · DOI
  68. [75]Rivara S Ablasser A COPA silences STING J. Exp. Med. 2020 217 e20201517 10.1084/jem.20201517 32991673 PMC7527967 · DOI
  69. [76]Zhang X Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation Nature 2015 517 89 93 10.1038/nature13801 25307056 PMC4303590 · DOI · Paper page
  70. [77]Meuwissen ME Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome J. Exp. Med. 2016 213 1163 1174 10.1084/jem.20151529 27325888 PMC4925017 · DOI
  71. [78]Duncan CJA Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 Sci. Immunol. 2019 4 eaav7501 10.1126/sciimmunol.aav7501 31836668 PMC7115903 · DOI
  72. [79]Gruber C Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy J. Exp. Med. 2020 217 e20192319 10.1084/jem.20192319 32092142 PMC7201920 · DOI
  73. [80]Arimoto KI STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling Nat. Struct. Mol. Biol. 2017 24 279 289 10.1038/nsmb.3378 28165510 PMC5365074 · DOI
  74. [81]Alsohime F JAK inhibitor therapy in a child with inherited USP18 deficiency N. Engl. J. Med. 2020 382 256 265 10.1056/NEJMoa1905633 31940699 PMC7155173 · DOI
  75. [82]Kaleviste E Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined Eur. J. Immunol. 2019 49 790 800 10.1002/eji.201847955 30801692 · DOI
  76. [83]Okada S Human STAT1 gain-of-function heterozygous mutations: chronic mucocutaneous candidiasis and type I interferonopathy J. Clin. Immunol. 2020 40 1065 1081 10.1007/s10875-020-00847-x 32852681 PMC8561788 · DOI
  77. [84]Stellacci E The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies Clin. Genet. 2019 96 585 589 10.1111/cge.13632 31448411 · DOI
  78. [85]Smyth AE Aortic calcification in a patient with a gain-of-function STAT1 mutation J. Clin. Immunol. 2018 38 468 470 10.1007/s10875-018-0513-z 29804236 · DOI
  79. [86]Del Bel KL JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome J. Allergy Clin. Immunol. 2017 139 2016 2020 10.1016/j.jaci.2016.12.957 28111307 · DOI
  80. [87]Gruber CN Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function Immunity 2020 53 672 684 10.1016/j.immuni.2020.07.006 32750333 PMC7398039 · DOI
  81. [88]Sanchez GA de Jesus AA Goldbach-Mansky R Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation Rheum. Dis. Clin. North. Am. 2013 39 701 734 10.1016/j.rdc.2013.08.001 24182851 PMC3888876 · DOI
  82. [89]Ebstein F Poli Harlowe MC Studencka-Turski M Krüger E Contribution of the unfolded protein response (UPR) to the pathogenesis of proteasome-associated autoinflammatory syndromes (PRAAS) Front. Immunol. 2019 10 2756 10.3389/fimmu.2019.02756 31827472 PMC6890838 · DOI
  83. [90]Brehm A Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production J. Clin. Invest. 2015 125 4196 4211 10.1172/JCI81260 26524591 PMC4639987 · DOI
  84. [91]Frémond ML Overview of STING-associated vasculopathy with inset in infancy (SAVI) among 21 patients J. Allergy Clin. Immunol. Pract. 2021 9 803 818 10.1016/j.jaip.2020.11.007 33217613 · DOI
  85. [92]Briggs TA Paul A Rice GI Herrick AL RNASEH2B related adult-onset interferonopathy J. Clin. Immunol. 2019 39 620 622 10.1007/s10875-019-00673-w 31367981 · DOI
  86. [93]Abe J A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study Rheumatology 2013 53 448 458 10.1093/rheumatology/ket372 24300241 · DOI
  87. [94]V T Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation Neurology. Genet. 2019 6 e384 PMC6936312 32042913
  88. [95]Livingston JH A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1 J. Med. Genet. 2014 51 76 82 10.1136/jmedgenet-2013-102038 24262145 · DOI
  89. [96]Crowl JT Gray EE Pestal K Volkman HE Stetson DB Intracellular nucleic acid detection in autoimmunity Annu. Rev. Immunol. 2017 35 313 336 10.1146/annurev-immunol-051116-052331 28142323 PMC6435037 · DOI
  90. [97]Picard C Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency Medicine 2010 89 403 425 10.1097/MD.0b013e3181fd8ec3 21057262 PMC3103888 · DOI
  91. [98]Gruber C Bogunovic D Incomplete penetrance in primary immunodeficiency: a skeleton in the closet Hum. Genet. 2020 139 745 757 10.1007/s00439-020-02131-9 32067110 PMC7275875 · DOI · Paper page
  92. [99]Gall A Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease Immunity 2012 36 120 131 10.1016/j.immuni.2011.11.018 22284419 PMC3269499 · DOI · Paper page
  93. [100]Gao D Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases Proc. Natl Acad. Sci. USA 2015 112 5699 5705 PMC4620884 26371324
  94. [101]Gray EE Treuting PM Woodward JJ Stetson DB Cutting edge: cGAS is required for lethal autoimmune disease in the trex1-deficient mouse model of Aicardi-Goutieres syndrome J. Immunol. 2015 195 1939 1943 10.4049/jimmunol.1500969 26223655 PMC4546858 · DOI
  95. [102]Mackenzie KJ Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response EMBO J. 2016 35 831 844 10.15252/embj.201593339 26903602 PMC4855687 · DOI · Paper page
  96. [103]Pokatayev V RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice J. Exp. Med. 2016 213 329 336 10.1084/jem.20151464 26880576 PMC4813680 · DOI · Paper page
  97. [104]Maelfait J Bridgeman A Benlahrech A Cursi C Rehwinkel J Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1 Cell Rep. 2016 16 1492 1501 10.1016/j.celrep.2016.07.002 27477283 PMC4978700 · DOI
  98. [105]Mannion NM The RNA-editing enzyme ADAR1 controls innate immune responses to RNA Cell. Rep. 2014 9 1482 1494 10.1016/j.celrep.2014.10.041 25456137 PMC4542304 · DOI
  99. [106]Liddicoat BJ RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself Science 2015 349 1115 1120 10.1126/science.aac7049 26275108 PMC5444807 · DOI
  100. [107]Pestal K Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development Immunity 2015 43 933 944 10.1016/j.immuni.2015.11.001 26588779 PMC4654992 · DOI
  101. [108]Luksch H STING-associated lung disease in mice relies on T cells but not type I interferon J. Allergy Clin. Immunol. 2019 144 254 266 10.1016/j.jaci.2019.01.044 30772497 PMC6612314 · DOI
  102. [109]Belot A Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts Lancet Rheumatol. 2021 2 99 109 10.1016/S2665-9913(19)30142-0 38263665 · DOI
  103. [110]Crow YJ Lupus: how much “complexity” is really (just) genetic heterogeneity? Arthritis Rheum. 2011 63 3661 3664 10.1002/art.30603 22127688 · DOI
  104. [111]Morita M Gene-targeted mice lacking the Trex1 (DNase III) 3′–>5′ DNA exonuclease develop inflammatory myocarditis Mol. Cell. Biol. 2004 24 6719 6727 10.1128/MCB.24.15.6719-6727.2004 15254239 PMC444847 · DOI
  105. [112]Maurano M PKR and the integrated stress response drive immunopathology caused by ADAR1 mutation Immunity 2021 54 1948 1960.e5 10.1016/j.immuni.2021.07.001 34343497 PMC8446335 · DOI
  106. [113]Chung H Human ADAR1 prevents endogenous RNA from triggering translational shutdown Cell 2018 172 811 824 e14 10.1016/j.cell.2017.12.038 29395325 PMC5831367 · DOI · Paper page
  107. [115]Michaud AP Bauman NM Burke DK Manaligod JM Smith RJ Spastic diplegia and other motor disturbances in infants receiving interferon-alpha Laryngoscope 2004 114 1231 1236 10.1097/00005537-200407000-00017 15235352 · DOI
  108. [116]Warner JD STING-associated vasculopathy develops independently of IRF3 in mice J. Exp. Med. 2017 214 3279 3292 10.1084/jem.20171351 28951494 PMC5679177 · DOI
  109. [117]Bouis D Severe combined immunodeficiency in Sting V154M/WT mice J. Allergy Clin. Immunol. 2018 143 712 725 10.1016/j.jaci.2018.04.034 29800647 · DOI
  110. [118]Gaidt MM The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3 Cell 2017 171 1110 1124 10.1016/j.cell.2017.09.039 29033128 PMC5901709 · DOI · Paper page
  111. [119]Yamashiro LH Interferon-independent STING signaling promotes resistance to HSV-1 in vivo Nat. Commun. 2020 11 3382 10.1038/s41467-020-17156-x 32636381 PMC7341812 · DOI
  112. [120]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 10.1016/j.immuni.2020.06.009 32640258 PMC7365768 · DOI · Paper page
  113. [121]Yum S Li M Fang Y Chen ZJ TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections Proc. Natl Acad. Sci. USA 2021 118 e2100225118 10.1073/pnas.2100225118 33785602 PMC8040795 · DOI
  114. [122]Kawane K Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver Science 2001 292 1546 1549 10.1126/science.292.5521.1546 11375492 · DOI
  115. [123]Yoshida H Okabe Y Kawane K Fukuyama H Nagata S Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA Nat. Immunol. 2005 6 49 56 10.1038/ni1146 15568025 · DOI
  116. [124]Kawane K Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages Nature 2006 443 998 1002 10.1038/nature05245 17066036 · DOI
  117. [125]Beck-Engeser GB Eilat D Wabl M An autoimmune disease prevented by anti-retroviral drugs Retrovirology 2011 8 91 10.1186/1742-4690-8-91 22067273 PMC3264515 · DOI · Paper page
  118. [126]Rice GI Reverse-transcriptase inhibitors in the Aicardi–Goutières syndrome N. Engl. J. Med. 2018 379 2275 2277 10.1056/NEJMc1810983 30566312 · DOI · Paper page
  119. [127]Rodero MP Fremond ML Rice GI Neven B Crow YJ JAK inhibition in STING-associated interferonopathy Ann. Rheum. Dis. 2016 75 e75 10.1136/annrheumdis-2016-210504 27733349 · DOI
  120. [128]Kothur K An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation Neurology 2018 90 289 291 10.1212/WNL.0000000000004921 29321238 · DOI
  121. [129]Briand C Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency Ann. Rheum. Dis. 2019 78 431 433 10.1136/annrheumdis-2018-214037 30282666 · DOI
  122. [130]Vanderver A Janus kinase inhibition in the aicardi-goutières syndrome N. Engl. J. Med. 2020 383 986 989 10.1056/NEJMc2001362 32877590 PMC7495410 · DOI
  123. [131]Forbes LR Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations J. Allergy Clin. Immunol. 2018 142 1665 1669 10.1016/j.jaci.2018.07.020 30092289 PMC6322659 · DOI
  124. [132]Sanchez GAM JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies J. Clin. Invest. 2018 128 3041 3052 10.1172/JCI98814 29649002 PMC6026004 · DOI
  125. [133]Crow YJ Neven B Frémond ML JAK inhibition in the type I interferonopathies J. Allergy Clin. Immunol. 2021 10.1016/j.jaci.2021.07.028 34375617 · DOI
  126. [134]Neven B JAK inhibition in the Aicardi-Goutières syndrome N. Engl. J. Med. 2020 383 2190 2191 10.1056/NEJMc2031081 33252884 · DOI
  127. [136]Gunther C Defective removal of ribonucleotides from DNA promotes systemic autoimmunity J. Clin. Invest. 2015 125 413 424 10.1172/JCI78001 25500883 PMC4382239 · DOI
  128. [137]Crow YJ Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR and IFIH1 Am. J. Med. Genet. 2015 167A 296 312 10.1002/ajmg.a.36887 25604658 PMC4382202 · DOI
  129. [138]Rice GI Genetic, phenotypic and interferon biomarker status in ADAR1-related neurological disease Neuropediatrics 2017 48 166 184 10.1055/s-0037-1601449 28561207 PMC5985975 · DOI
  130. [139]Briggs TA Spondyloenchondrodysplasia due to mutations in ACP5: a comprehensive survey J. Clin. Immunol. 2016 36 220 234 10.1007/s10875-016-0252-y 26951490 PMC4792361 · DOI
  131. [140]Vece TJ Copa syndrome: a novel autosomal dominant immune dysregulatory disease J. Clin. Immunol. 2016 36 377 387 10.1007/s10875-016-0271-8 27048656 PMC4842120 · DOI

Cited by

Sorted by citations

Authors
Crow, Y. J., & Stetson, D. B.
Affiliations
  • Université Paris Cité (FR)
  • University of Washington (US)
Corresponding author
Crow, Yanick J.
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2021-10-20
Volume
22
Issue
8
Pages
471-483
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-021-00633-9
PMC
PMC8527296
OpenAlex
W3207712170
Cited by
489
References
9
Citations by year
2026: 106 · 2025: 112 · 2024: 116 · 2023: 86 · 2022: 66 · 2021: 2
FWCI
6.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Howard Hughes Medical Institute
  • National Institute for Health and Care Research
  • European Commission (HORIZON2020)
  • Agence Nationale de la Recherche (ANR-10-IAHU- 01, ANR-10-IAHU-0001, 10-IAHU-01, ANR-10)
  • National Institute of Allergy and Infectious Diseases (R01AI084914, R01AI150716)
  • H2020 European Research Council (786142)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Keywords
type I interferonopathy, type I interferon signaling, primary immunodeficiency, innate immunity, viral nucleic acid detection, rare genetic disorders, COVID-19 pandemic
MeSH terms
COVID-19, Humans, Immunity, Innate, Interferon Type I, Nucleic Acids, Pandemics

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