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PMID: 26052098 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Aicardi-Goutières syndrome and the type I interferonopathies.

Nature reviews. Immunology ·Vol. 15 ·No. 7 ·2015-07-00 ·Pages 429-40

Crow YJ, Manel N

Abstract

Dissection of the genetic basis of Aicardi-Goutières syndrome has highlighted a fundamental link between nucleic acid metabolism, innate immune sensors and type I interferon induction. This had led to the concept of the human interferonopathies as a broader set of Mendelian disorders in which a constitutive upregulation of type I interferon activity directly relates to disease pathology. Here, we discuss the molecular and cellular basis of the interferonopathies, their categorization, future treatment strategies and the insights they provide into normal physiology.

MeSH Terms
Animals Autoimmune Diseases of the Nervous System/immunology Humans Interferon Type I/immunology Nervous System Malformations/immunology
Chemicals
Interferon Type I
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Crow Yanick J
1] Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris 75015, France. [2] Paris Descartes, Sorbonne Paris Cité University, Institute Imagine, Paris 75015, France. [3] Centre for Genomic Medicine, Institute of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9WL, UK.
Manel Nicolas
1] Institut Curie, 26 rue d'Ulm, Paris 75248, France. [2] Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 932, Paris 75005, France.
Supplementary Concepts
Aicardi-Goutieres syndrome (Disease)
References (105)
105 references, click to expand
  1. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome.
    Am J Hum Genet. 2010 Dec 10;87(6):866-72 PMID: 21129723
  2. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
    Am J Med Genet A. 2015 Feb;167A(2):296-312 PMID: 25604658
  3. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates.
    Nature. 2014 Oct 16;514(7522):372-5 PMID: 25119032
  4. Systemic lupus erythematosus due to C1q deficiency with progressive encephalopathy, intracranial calcification and acquired moyamoya cerebral vasculopathy.
    Lupus. 2013 May;22(6):639-43 PMID: 23651859
  5. Trex1 prevents cell-intrinsic initiation of autoimmunity.
    Cell. 2008 Aug 22;134(4):587-98 PMID: 18724932
  6. Genetic syndromes mimic congenital infections.
    J Pediatr. 2005 May;146(5):701-5 PMID: 15870678
  7. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutières syndrome.
    Hum Mol Genet. 2014 Nov 15;23(22):5950-60 PMID: 24986920
  8. Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies.
    Ann Rheum Dis. 2015 Oct;74(10):1931-9 PMID: 24906636
  9. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.
    Am J Hum Genet. 2007 Oct;81(4):713-25 PMID: 17846997
  10. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.
    Cell Rep. 2014 Nov 20;9(4):1482-94 PMID: 25456137
  11. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.
    Nature. 2015 Jan 1;517(7532):89-93 PMID: 25307056
  12. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
    Dev Med Child Neurol. 2010 Aug;52(8):725-32 PMID: 20653736
  13. Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?
    DNA Repair (Amst). 2008 Jun 1;7(6):834-48 PMID: 18339586
  14. 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 Nov 1;161(9):5016-26 PMID: 9794439
  15. Automated genome-wide visual profiling of cellular proteins involved in HIV infection.
    J Biomol Screen. 2011 Oct;16(9):945-58 PMID: 21841144
  16. Development of glaucoma in the course of interferon alpha therapy for chronic hepatitis B.
    Yonsei Med J. 2001 Feb;42(1):134-6 PMID: 11293492
  17. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis.
    Ann Neurol. 1984 Jan;15(1):49-54 PMID: 6712192
  18. Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C.
    Am J Med Genet A. 2013 Feb;161A(2):338-42 PMID: 23322642
  19. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity.
    J Exp Med. 2012 Jul 30;209(8):1419-26 PMID: 22802351
  20. USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response.
    PLoS One. 2011;6(7):e22200 PMID: 21779393
  21. High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus.
    Genes Immun. 2007 Sep;8(6):492-502 PMID: 17581626
  22. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy.
    J Neurol Sci. 1988 Apr;84(2-3):201-8 PMID: 2837539
  23. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1.
    J Med Genet. 2014 Feb;51(2):76-82 PMID: 24262145
  24. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.
    Nature. 2011 Nov 06;480(7377):379-82 PMID: 22056990
  25. C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes.
    J Immunol. 2010 Oct 15;185(8):4738-49 PMID: 20844193
  26. Type I interferon controls propagation of long interspersed element-1.
    J Biol Chem. 2015 Apr 17;290(16):10191-9 PMID: 25716322
  27. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells.
    Immunity. 2013 Dec 12;39(6):1132-42 PMID: 24269171
  28. Intrinsic self-DNA triggers inflammatory disease dependent on STING.
    J Immunol. 2014 Nov 1;193(9):4634-42 PMID: 25261479
  29. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency.
    Science. 2012 Sep 28;337(6102):1684-8 PMID: 22859821
  30. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein.
    Nature. 2011 Jun 29;474(7353):658-61 PMID: 21720370
  31. SAMHD1 prevents autoimmunity by maintaining genome stability.
    Ann Rheum Dis. 2015 Mar;74(3):e17 PMID: 24445253
  32. Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutières syndrome.
    Am J Med Genet A. 2004 Sep 1;129A(3):303-7 PMID: 15326633
  33. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.
    Am J Hum Genet. 2015 Feb 5;96(2):266-74 PMID: 25620203
  34. 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 Oct;60(10):3081-90 PMID: 19790049
  35. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration.
    Nature. 2011 Mar 17;471(7338):325-30 PMID: 21297615
  36. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis.
    Nat Struct Mol Biol. 2010 Sep;17(9):1043-50 PMID: 20694008
  37. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.
    Cell. 2013 Feb 14;152(4):714-26 PMID: 23415222
  38. Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism.
    J Med Genet. 2003 Mar;40(3):183-7 PMID: 12624136
  39. A proposed classification of the immunological diseases.
    PLoS Med. 2006 Aug;3(8):e297 PMID: 16942393
  40. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.
    Am J Hum Genet. 2006 Oct;79(4):731-7 PMID: 16960810
  41. Type I interferonopathies: a novel set of inborn errors of immunity.
    Ann N Y Acad Sci. 2011 Nov;1238:91-8 PMID: 22129056
  42. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.
    Immunity. 2015 Feb 17;42(2):332-43 PMID: 25692705
  43. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.
    Cell. 2012 May 25;149(5):1008-22 PMID: 22579044
  44. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.
    Nat Genet. 2006 Aug;38(8):917-20 PMID: 16845398
  45. Interferon-induced disease in mice and rats.
    Ann N Y Acad Sci. 1980;350:12-20 PMID: 6165266
  46. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.
    Nat Immunol. 2010 Nov;11(11):1005-13 PMID: 20871604
  47. Therapies in Aicardi-Goutières syndrome.
    Clin Exp Immunol. 2014 Jan;175(1):1-8 PMID: 23607857
  48. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction.
    Nat Med. 2014 Aug;20(8):936-41 PMID: 25038827
  49. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature.
    Nat Genet. 2012 Nov;44(11):1243-8 PMID: 23001123
  50. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.
    Immunity. 2012 Jan 27;36(1):120-31 PMID: 22284419
  51. The enemy within: endogenous retroelements and autoimmune disease.
    Nat Immunol. 2014 May;15(5):415-22 PMID: 24747712
  52. Aicardi-Goutières syndrome is caused by IFIH1 mutations.
    Am J Hum Genet. 2014 Jul 3;95(1):121-5 PMID: 24995871
  53. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.
    Hum Mol Genet. 2009 Oct 15;18(R2):R130-6 PMID: 19808788
  54. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus.
    Am J Med Genet A. 2011 Jan;155A(1):235-7 PMID: 21204240
  55. Elevation of proinflammatory cytokines in patients with Aicardi-Goutières syndrome.
    Neurology. 2013 Mar 12;80(11):997-1002 PMID: 23408864
  56. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling.
    Nat Immunol. 2009 Jan;10(1):109-15 PMID: 19060901
  57. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.
    J Clin Invest. 2015 Jan;125(1):413-24 PMID: 25500883
  58. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors.
    Nat Immunol. 2014 Sep;15(9):839-45 PMID: 25064072
  59. Human Genomics. Sleeping dogs of the genome.
    Science. 2014 Dec 5;346(6214):1187-8 PMID: 25477445
  60. RNA:DNA hybrids are a novel molecular pattern sensed by TLR9.
    EMBO J. 2014 Mar 18;33(6):542-58 PMID: 24514026
  61. Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response.
    Cell Rep. 2013 Aug 29;4(4):689-96 PMID: 23972988
  62. Familial systemic lupus erythematosus and congenital infection-like syndrome.
    Neuropediatrics. 2000 Jun;31(3):155-8 PMID: 10963105
  63. An autoimmune disease prevented by anti-retroviral drugs.
    Retrovirology. 2011 Nov 08;8:91 PMID: 22067273
  64. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses.
    Science. 2014 Dec 19;346(6216):1486-92 PMID: 25525240
  65. RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases.
    J Mol Med (Berl). 2009 Jan;87(1):25-30 PMID: 19034401
  66. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity.
    Nat Genet. 2011 Feb;43(2):132-7 PMID: 21217752
  67. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells.
    Nature. 2010 Sep 9;467(7312):214-7 PMID: 20829794
  68. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations.
    J Clin Invest. 2014 Dec;124(12):5516-20 PMID: 25401470
  69. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.
    Nat Genet. 2006 Aug;38(8):910-6 PMID: 16845400
  70. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.
    Immunity. 2014 Feb 20;40(2):199-212 PMID: 24530055
  71. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
    Nat Genet. 2014 May;46(5):503-9 PMID: 24686847
  72. The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis).
    J Med Genet. 1995 Nov;32(11):881-4 PMID: 8592332
  73. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.
    Nat Genet. 2009 Jul;41(7):829-32 PMID: 19525956
  74. Type I interferonopathies: mendelian type I interferon up-regulation.
    Curr Opin Immunol. 2015 Feb;32:7-12 PMID: 25463593
  75. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
    Arthritis Rheum. 2012 Mar;64(3):895-907 PMID: 21953331
  76. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.
    Am J Hum Genet. 2015 Feb 5;96(2):275-82 PMID: 25620204
  77. Activated STING in a vascular and pulmonary syndrome.
    N Engl J Med. 2014 Aug 7;371(6):507-18 PMID: 25029335
  78. Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour.
    J Intern Med. 1990 Mar;227(3):207-10 PMID: 1690258
  79. HIV-1-related encephalopathy in infants compared with children and adults. French Pediatric HIV Infection Study and the SEROCO Group.
    Neurology. 2000 Mar 14;54(5):1089-95 PMID: 10720279
  80. Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing.
    Cell. 2014 Jan 16;156(1-2):134-45 PMID: 24412650
  81. Immunoproteasomes are essential for survival and expansion of T cells in virus-infected mice.
    Eur J Immunol. 2010 Dec;40(12):3439-49 PMID: 21108466
  82. Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing.
    Arthritis Rheumatol. 2014 Dec;66(12):3382-6 PMID: 25138095
  83. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus.
    Nat Genet. 2007 Sep;39(9):1065-7 PMID: 17660818
  84. Interferon-stimulated genes: roles in viral pathogenesis.
    Curr Opin Virol. 2014 Jun;6:40-6 PMID: 24713352
  85. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.
    Cell. 2007 Nov 30;131(5):873-86 PMID: 18045533
  86. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.
    Cell. 2014 Dec 18;159(7):1549-62 PMID: 25525874
  87. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage.
    Blood. 2014 Feb 13;123(7):1021-31 PMID: 24335234
  88. Mitochondrial DNA stress primes the antiviral innate immune response.
    Nature. 2015 Apr 23;520(7548):553-7 PMID: 25642965
  89. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing.
    Immunity. 2013 Sep 19;39(3):482-95 PMID: 23993650
  90. Cytosolic RNA:DNA hybrids activate the cGAS-STING axis.
    EMBO J. 2014 Dec 17;33(24):2937-46 PMID: 25425575
  91. Brief Report: IFIH1 Mutation Causes Systemic Lupus Erythematosus With Selective IgA Deficiency.
    Arthritis Rheumatol. 2015 Jun;67(6):1592-7 PMID: 25777993
  92. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1.
    Cell Rep. 2013 Sep 26;4(6):1108-15 PMID: 24035396
  93. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.
    Lancet Neurol. 2013 Dec;12(12):1159-69 PMID: 24183309
  94. Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient.
    Eur J Dermatol. 2002 Jan-Feb;12 (1):99-102 PMID: 11809610
  95. Immune interferon in the circulation of patients with autoimmune disease.
    N Engl J Med. 1979 Jul 5;301(1):5-8 PMID: 449915
  96. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.
    Nature. 2011 May 25;474(7353):654-7 PMID: 21613998
  97. Reduction of hRNase H2 activity in Aicardi-Goutières syndrome cells leads to replication stress and genome instability.
    Hum Mol Genet. 2015 Feb 1;24(3):649-58 PMID: 25274781
  98. Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation.
    J Allergy Clin Immunol. 2014 Jan;133(1):265-7 PMID: 24035158
  99. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.
    Arthritis Rheum. 2010 May;62(5):1469-77 PMID: 20131292
  100. The prevalence of computed tomographic abnormalities of the cerebrum in 100 consecutive children symptomatic with the human immune deficiency virus.
    Ann Neurol. 1993 Aug;34(2):198-205 PMID: 8338344
  101. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.
    Elife. 2012 Dec 18;1:e00047 PMID: 23251783
  102. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    Nat Genet. 2011 Feb;43(2):127-31 PMID: 21217755
  103. CT and MR evaluation of intracranial involvement in pediatric HIV infection: a clinical-imaging correlation.
    AJNR Am J Neuroradiol. 1992 May-Jun;13(3):949-57 PMID: 1590197
  104. SAMHD1-dependent retroviral control and escape in mice.
    EMBO J. 2013 Sep 11;32(18):2454-62 PMID: 23872947
  105. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.
    Cell. 2012 May 11;149(4):847-59 PMID: 22541070
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri3850
Published
2015-07-00
Epub
2015-00-05
Pages
429-40
Language
English
Region
England
NLM ID
101124169
Subset
IM
External Links
PubMed source DOI: 10.1038/nri3850 View journal details
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