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Type I interferonopathies—an expanding disease spectrum of immunodysregulation

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Abstract

Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN signaling is activated by pattern recognition receptors upon sensing of viral nucleic acids and induces antiviral programs through modulation of innate and adaptive immune responses. Type I interferonopathies comprise a heterogenous group of genetically determined diseases that are characterized by inappropriate activation of type I IFN. While their phenotypic spectrum is broad, ranging from severe neurological impairment to mild cutaneous disease, systemic autoinflammation, and autoimmunity are commonly shared signs of type I interferonopathies. Although the mechanisms underlying various disease phenotypes associated with inappropriate type I IFN activation have yet to be fully elucidated, our current understanding of the molecular pathogenesis of type I interferonopathies has provided a set of candidate molecules that can be interrogated in search of targeted therapies.

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Abbreviations

ADAR:

Adenosine deaminase, RNA-specific

AGS:

Aicardi-Goutières syndrome

CANDLE:

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome

cGAMP:

Cyclic GMP-AMP

cGAS:

Cyclic GMP-AMP synthase

IFIH1:

Interferon induced with helicase C domain 1

IFN:

Interferon

IRF:

Interferon-regulatory factor

ISG:

Interferon-stimulated gene

MAVS:

Mitochondrial antiviral signaling protein

MDA5:

Melanoma differentiation-associated gene 5

MYD88:

Myeloid differentiation primary-response protein 88

NF-κB:

Nuclear factor-κB

RIG-I:

Retinoic acid-inducible gene 1

RNASEH2:

Ribonuclease H2

RVCL:

Retinal vasculopathy with cerebral leukodystrophy

SAMHD1:

SAM domain and HD domain-containing protein 1

SAVI:

STING-associated vasculopathy, infantile-onset

SLE:

Systemic lupus erythematosus

STING:

Stimulator of interferon genes

TBK1:

TANK-binding kinase 1

TLR:

Toll-like receptor

TREX1:

3′ Repair exonuclease 1

TRIF:

TIR domain-containing adaptor protein inducing IFN-β

References

  1. Stetson DB, Medzhitov R (2006) Type I interferons in host defense. Immunity 25:373–381

    Article  CAS  PubMed  Google Scholar 

  2. Taniguchi T, Takaoka A (2001) A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol 2:378–386

    Article  CAS  PubMed  Google Scholar 

  3. Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6:823–835

    Article  CAS  PubMed  Google Scholar 

  4. O’Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13:453–460

    Article  PubMed  Google Scholar 

  5. Atianand MK, Fitzgerald KA (2013) Molecular basis of DNA recognition in the immune system. J Immunol 190:1911–1918

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Kawai T, Takahashi K, Sato S et al (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988

    Article  CAS  PubMed  Google Scholar 

  7. Hornung V, Ellegast J, Kim S et al (2006) 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997

    Article  PubMed  Google Scholar 

  8. Goubau D, Schlee M, Deddouche S et al (2014) Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature 514:372–375

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ablasser A, Bauernfeind F, Hartmann G et al (2009) RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 10:1065–1072

    Article  CAS  PubMed  Google Scholar 

  10. Chiu YH, Macmillan JB, Chen ZJ (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Sun L, Wu J, Du F et al (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791

    Article  CAS  PubMed  Google Scholar 

  12. Wu J, Sun L, Chen X et al (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–830

    Article  CAS  PubMed  Google Scholar 

  13. Xiao TS, Fitzgerald KA (2013) The cGAS-STING pathway for DNA sensing. Mol Cell 51:135–139

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386

    Article  CAS  PubMed  Google Scholar 

  15. Lovgren T, Eloranta ML, Bave U et al (2004) Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 50:1861–1872

    Article  PubMed  Google Scholar 

  16. Napirei M, Karsunky H, Zevnik B et al (2000) Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 25:177–181

    Article  CAS  PubMed  Google Scholar 

  17. Kawane K, Ohtani M, Miwa K et al (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998–1002

    Article  CAS  PubMed  Google Scholar 

  18. Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91–98

    Article  CAS  PubMed  Google Scholar 

  19. Aicardi J, Goutieres F (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49–54

    Article  CAS  PubMed  Google Scholar 

  20. Lebon P, Badoual J, Ponsot G et al (1988) Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 84:201–208

    Article  CAS  PubMed  Google Scholar 

  21. Tolmie JL, Shillito P, Hughes-Benzie R et al (1995) The Aicardi-Goutieres syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 32:881–884

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ramantani G, Kohlhase J, Hertzberg C et al (2010) Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum 62:1469–1477

    Article  CAS  PubMed  Google Scholar 

  23. Rice GI, Forte GM, Szynkiewicz M et al (2013) 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 12:1159–1169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Vogt J, Agrawal S, Ibrahim Z et al (2013) Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2C. Am J Med Genet A 161A:338–342

    Article  PubMed  Google Scholar 

  25. Tüngler V, Schmidt F, Hieronimus S et al (2014) Phenotypic variability in a family with Aicardi-Goutières syndrome due to the common A177T RNASEH2B mutation. Case Rep Clin Med 3:153–156

    Article  Google Scholar 

  26. Crow YJ, Hayward BE, Parmar R et al (2006) Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet 38:917–920

    Article  CAS  PubMed  Google Scholar 

  27. Chowdhury D, Beresford PJ, Zhu P et al (2006) The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell 23:133–142

    Article  CAS  PubMed  Google Scholar 

  28. Yang YG, Lindahl T, Barnes DE (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–886

    Article  CAS  PubMed  Google Scholar 

  29. Stetson DB, Ko JS, Heidmann T et al (2008) Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–598

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Gall A, Treuting P, Elkon KB et al (2012) Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Ablasser A, Hemmerling I, Schmid-Burgk JL et al (2014) TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 192:5993–5997

    Article  CAS  PubMed  Google Scholar 

  32. Rice G, Newman WG, Dean J et al (2007) Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet 80:811–815

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Tungler V, Silver RM, Walkenhorst H et al (2012) Inherited or de novo mutation affecting aspartate 18 of TREX1 results in either familial chilblain lupus or Aicardi-Goutieres syndrome. Br J Dermatol 167:212–214

    Article  CAS  PubMed  Google Scholar 

  34. Crow YJ, Leitch A, Hayward BE et al (2006) Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet 38:910–916

    Article  CAS  PubMed  Google Scholar 

  35. Reijns MA, Rabe B, Rigby RE et al (2012) Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–1022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Hiller B, Achleitner M, Glage S et al (2012) Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med 209:1419–1426

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Sparks JL, Chon H, Cerritelli SM et al (2012) RNase H2-initiated ribonucleotide excision repair. Mol Cell 47:980–986

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Kim N, Huang SN, Williams JS et al (2011) Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332:1561–1564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kind B, Muster B, Staroske W et al (2014) Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum Mol Genet 23:5950–5960

    Article  PubMed  Google Scholar 

  40. Gunther C, Kind B, Reijns MA et al (2015) Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest 125:413–424

    Article  PubMed Central  PubMed  Google Scholar 

  41. Goldstone DC, Ennis-Adeniran V, Hedden JJ et al (2011) HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480:379–382

    Article  CAS  PubMed  Google Scholar 

  42. Hrecka K, Hao C, Gierszewska M et al (2011) Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474:658–661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Laguette N, Sobhian B, Casartelli N et al (2011) SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474:654–657

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Lahouassa H, Daddacha W, Hofmann H et al (2012) SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13:223–228

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Goncalves A, Karayel E, Rice GI et al (2012) SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi-goutieres syndrome-associated mutations. Hum Mutat 33:1116–1122

    Article  CAS  PubMed  Google Scholar 

  46. Tungler V, Staroske W, Kind B et al (2013) Single-stranded nucleic acids promote SAMHD1 complex formation. J Mol Med (Berl) 91:759–770

    Article  Google Scholar 

  47. Beloglazova N, Flick R, Tchigvintsev A et al (2013) Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J Biol Chem 288:8101–8110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ryoo J, Choi J, Oh C et al (2014) The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med 20:936–941

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Cribier A, Descours B, Valadao AL et al (2013) Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep 3:1036–1043

    Article  CAS  PubMed  Google Scholar 

  50. Kretschmer S, Wolf C, Konig N et al (2014) SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis

  51. Rice GI, Kasher PR, Forte GM et al (2012) Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet 44:1243–1248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Wang Q, Khillan J, Gadue P et al (2000) Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290:1765–1768

    Article  CAS  PubMed  Google Scholar 

  53. Mannion NM, Greenwood SM, Young R et al (2014) The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep 9:1482–1494

    Article  CAS  PubMed  Google Scholar 

  54. Rice GI, Del Toro DY, Jenkinson EM et al (2014) Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet 46:503–509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Richards A, van den Maagdenberg AM, Jen JC et al (2007) C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39:1068–1070

    Article  CAS  PubMed  Google Scholar 

  56. Schuh E, Ertl-Wagner B, Lohse P et al (2015) Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL. Neurol Neuroimmunol Neuroinflamm 2:e55

    Article  PubMed Central  PubMed  Google Scholar 

  57. Lee-Kirsch MA, Gong M, Schulz H et al (2006) Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 79:731–737

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Gunther C, Hillebrand M, Brunk J et al (2013) Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad Dermatol 69:e179–e181

    Article  PubMed  Google Scholar 

  59. Lee-Kirsch MA, Chowdhury D, Harvey S et al (2007) A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med 85:531–537

    Article  CAS  PubMed  Google Scholar 

  60. Dale RC, Gornall H, Singh-Grewal D et al (2010) Familial Aicardi-Goutieres syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A 152A:938–942

    Article  PubMed  Google Scholar 

  61. Liu Y, Jesus AA, Marrero B et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518

    Article  PubMed Central  PubMed  Google Scholar 

  62. Jeremiah N, Neven B, Gentili M et al (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124:5516–5520

    Article  PubMed Central  PubMed  Google Scholar 

  63. Harley IT, Kaufman KM, Langefeld CD et al (2009) Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 10:285–290

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Baechler EC, Batliwalla FM, Karypis G et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Lee-Kirsch MA, Gong M, Chowdhury D et al (2007) Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39:1065–1067

    Article  CAS  PubMed  Google Scholar 

  66. Namjou B, Kothari PH, Kelly JA et al (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270–279

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Yasutomo K, Horiuchi T, Kagami S et al (2001) Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 28:313–314

    Article  CAS  PubMed  Google Scholar 

  68. Al-Mayouf SM, Sunker A, Abdwani R et al (2011) Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet 43:1186–1188

    Article  CAS  PubMed  Google Scholar 

  69. Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–456

    Article  CAS  PubMed  Google Scholar 

  70. Renella R, Schaefer E, LeMerrer M et al (2006) Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: clinical and radiographic delineation of a pleiotropic disorder. Am J Med Genet A 140:541–550

    Article  PubMed  Google Scholar 

  71. Briggs TA, Rice GI, Daly S et al (2011) Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 43:127–131

    Article  CAS  PubMed  Google Scholar 

  72. Lausch E, Janecke A, Bros M et al (2011) Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 43:132–137

    Article  CAS  PubMed  Google Scholar 

  73. Gay BB Jr, Kuhn JP (1976) A syndrome of widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness (the Singleton-Merten syndrome). Radiology 118:389–395

    Article  PubMed  Google Scholar 

  74. Rutsch F, MacDougall M, Lu C et al (2015) A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet 96:275–282

    Article  CAS  PubMed  Google Scholar 

  75. Jang MA, Kim EK, Now H et al (2015) Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet 96:266–274

    Article  CAS  PubMed  Google Scholar 

  76. Bogunovic D, Byun M, Durfee LA et al (2012) Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science 337:1684–1688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Zhang X, Bogunovic D, Payelle-Brogard B et al (2015) Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517:89–93

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Liu Y, Ramot Y, Torrelo A et al (2012) 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 64:895–907

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Basler M, Kirk CJ, Groettrup M (2013) The immunoproetasome iin antigen processing and other immunolgical functions. Curr Opin Immunol 25:74–80

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinsschaft (Clinical Research Group 249 to M.L.-K. and A.R.) and the Friede Springer Stiftung to M.L.-K.

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Authors and Affiliations

  1. Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Min Ae Lee-Kirsch, Christine Wolf & Stefanie Kretschmer

  2. Institute for Immunology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Axel Roers

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  1. Min Ae Lee-Kirsch
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  2. Christine Wolf
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Correspondence to Min Ae Lee-Kirsch.

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This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases - Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen

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Lee-Kirsch, M.A., Wolf, C., Kretschmer, S. et al. Type I interferonopathies—an expanding disease spectrum of immunodysregulation. Semin Immunopathol 37, 349–357 (2015). https://doi.org/10.1007/s00281-015-0500-x

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