Advertisement

Genetic Interferonopathies

  • Despina EleftheriouEmail author
  • Antonio Torrelo
  • Paul A. Brogan
Chapter

Abstract

The interferonopathies comprise an expanding group of monogenic diseases characterised by disturbance of the homeostatic control of interferon (IFN)-mediated immune responses. Although differing in the degree of phenotypic expression and severity, the clinical presentation of these diseases shows a considerable degree of overlap, reflecting their common pathogenesis. Increased understanding of the molecular basis of these Mendelian disorders has led to the identification of targeted therapies for these diseases, which could also be of potential relevance for non-genetic IFN-mediated diseases such as systemic lupus erythematosus (SLE) and juvenile dermatomyositis. In this chapter we summarise the current knowledge of the molecular basis, clinical features, and treatment of monogenic interferonopathies.

Keywords

Interferonopathies Aicardi Goutières syndrome Proteasome CANDLE SAVI 

Abbreviations

AGS

Aicardi-Goutières syndrome

ALDD

Autoinflammation lipodystrophy and dermatitis

ANA

Antinuclear antibody

APECED

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

APLAID

Autoinflammation and PLCG2-associated Antibody Deficiency and Immune Dysregulation

CANDLE

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature

CK

Creatine kinase

COPA

Coatomer protein complex subunit alpha

CRP

C-Reactive protein

CRV

Cerebroretinal vasculopathy

CSF

Cerebrospinal fluid

DADA2

Deficiency of adenosine deaminase 2

ESR

Erythrocyte sedimentation rate

HVR

Hereditary vascular retinopathy

HERNS

Hereditary endotheliopathy with retinopathy, nephropathy and stroke

IFN

Interferon

ISG

Interferon stimulated genes

JAK

Janus kinase

NSAID

Nonsteroidal anti-inflammatory drug

PLCG2

Phospholipase C gamma 2

PRAAS

Proteasome associated autoinflammatory syndrome

PSM

Proteasome subunit

RVCL

Retinal vasculopathy with cerebral leukodystrophy

SAVI

STING associated vasculitis with onset in infancy

SGMRT

Singleton-Merten syndrome

SLE

Systemic lupus erythematosus

SPENCDI

Spondyloenchondrodysplasia with immunodysregulation

STAT

Signal transducer and activator of transcription

STING

Stimulator of interferon genes

THES

Trichohepatoenteric syndrome

TLR

Toll-like receptor

TORCH

Toxoplasmosis, others, rubella, syphilis, herpes

USP

Ubiquitin-specific protease

References

  1. 1.
    García-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in detente. Science. 2006;312(5775):879–82.PubMedGoogle Scholar
  2. 2.
    Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238(1):91–8.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Lee-Kirsch MA, Wolf C, Kretschmer S, Roers A. Type I interferonopathies—an expanding disease spectrum of immunodysregulation. Semin Immunopathol. 2015;37(4):349–57.PubMedGoogle Scholar
  4. 4.
    Volpi S, Picco P, Caorsi R, Candotti F, Gattorno M. Type I interferonopathies in pediatric rheumatology. Pediatr Rheumatol. 2016;14(1):35.Google Scholar
  5. 5.
    Crow YJ. Type I interferonopathies: Mendelian type I interferon up-regulation. Curr Opin Immunol. 2015;32:7–12.PubMedGoogle Scholar
  6. 6.
    Liu Y, Ramot Y, Torrelo A, et al. Mutations in PSMB8 cause CANDLE syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64(3):895.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Torrelo A, Patel S, Colmenero I, et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol. 2010;62(3):489–95.Google Scholar
  8. 8.
    Garg A, Hernandez MD, Sousa AB, et al. An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endocrinol Metab. 2010;95(9):E58–63.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Kanazawa N. Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy. Allergol Int. 2012;61(2):197–206.PubMedGoogle Scholar
  10. 10.
    McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L. Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management. Int J Dermatol. 2015;54(2):121–9.PubMedGoogle Scholar
  11. 11.
    Touitou I, Galeotti C, Rossi-Semerano L, Hentgen V, Piram M, Koné-Paut I. The expanding spectrum of rare monogenic autoinflammatory diseases. Orphanet J Rare Dis. 2013;8(1):162.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Agarwal AK, Xing C, DeMartino GN, et al. 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;87(6):866–72.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Arima K, Kinoshita A, Mishima H, et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci. 2011;108(36):14914–9.PubMedGoogle Scholar
  14. 14.
    Kitamura A, Maekawa Y, Uehara H, et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011;121(10):4150.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125(11):4196.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Rodero MP, Decalf J, Bondet V, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med. 2017;214(5):1547–55.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Rice GI, Melki I, Frémond M-L, et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol. 2017;37(2):123–32.PubMedGoogle Scholar
  18. 18.
    Krüger E, Kloetzel P-M. Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme. Curr Opin Immunol. 2012;24(1):77–83.PubMedGoogle Scholar
  19. 19.
    Jegalian AG, Facchetti F, Jaffe ES. Plasmacytoid dendritic cells: physiologic roles and pathologic states. Adv Anat Pathol. 2009;16(6):392–404.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Torrelo A, Colmenero I, Requena L, et al. The Histological and Immunohistochemical Features of the Skin Lesions in CANDLE Syndrome. Am J Dermatopathol. 2015;37(7):517.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Torrelo A, Noguera-Morel L, Hernández-Martín A, et al. Recurrent lipoatrophic panniculitis of children. J Eur Acad Dermatol Venereol. 2017;31(3):536–43.PubMedGoogle Scholar
  22. 22.
    Zhou Q, Yu X, Demirkaya E, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci. 2016;113(36):10127–32.PubMedGoogle Scholar
  23. 23.
  24. 24.
    Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Omoyinmi E, Melo Gomes S, Nanthapisal S, et al. Stimulator of Interferon Genes–Associated Vasculitis of Infancy. Arthritis Rheum. 2015;67(3):808.Google Scholar
  26. 26.
    Clarke SL, 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(5):639–42.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Jeremiah N, Neven B, Gentili M, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124(12):5516.PubMedPubMedCentralGoogle Scholar
  28. 28.
    http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n=24. In fever website TMEM 173 variants. 2017.
  29. 29.
    Chia J, Eroglu FK, Özen S, et al. Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. J Am Acad Dermatol. 2016;74(1):186–9.PubMedGoogle Scholar
  30. 30.
    Munoz J, Rodière M, Jeremiah N, et al. Stimulator of interferon genes–associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 2015;151(8):872–7.Google Scholar
  31. 31.
    Kim H, Sanchez GAM, Goldbach-Mansky R. Insights from Mendelian interferonopathies: comparison of CANDLE, SAVI with AGS, monogenic lupus. J Mol Med. 2016;94(10):1111–27.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Watkin LB, Jessen B, Wiszniewski W, et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015;47(6):654–60.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Frémond M-L, Rodero MP, Jeremiah N, 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(6):1752–5.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Volpi S, Caorsi R, Picco P, et al., editors. Efficacy of the JAK inhibitor ruxolitinib in two patiens with SAVI syndrome. Journal of Clinical Immunology; 2017. New York: Springer/Plenum Publishers.Google Scholar
  35. 35.
    Crow YJ, Livingston JH. Aicardi-Goutieres syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol. 2008;50(6):410–6.PubMedGoogle Scholar
  36. 36.
    Crow YJ, Rehwinkel J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet. 2009;18(R2):R130–R6.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167(2):296–312.Google Scholar
  38. 38.
    Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet. 2006;38(8):917–20.PubMedGoogle Scholar
  39. 39.
    Crow YJ, Leitch A, Hayward BE, et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet. 2006;38(8):910–7.PubMedGoogle Scholar
  40. 40.
    Dale RC, Gornall H, Singh-Grewal D, Alcausin M, Rice GI, Crow YJ. Familial Aicardi–Goutieres syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A. 2010;152(4):938–42.Google Scholar
  41. 41.
    Goncalves A, Karayel E, Rice GI, et al. SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi–goutières syndrome-associated mutations. Hum Mutat. 2012;33(7):1116–22.PubMedGoogle Scholar
  42. 42.
    Livingston JH, Lin J-P, Dale RC, et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet. 2013;51(2):76–82.PubMedGoogle Scholar
  43. 43.
    Rice GI, Kasher PR, Forte GM, et al. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet. 2012;44(11):1243–8.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Rice GI, Kitabayashi N, Barth M, et al. Genetic, phenotypic, and interferon biomarker status in ADAR1-related neurological disease. Neuropediatrics. 2017;48(3):166–84.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Rice GI, del Toro Duany Y, Jenkinson EM, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503–9.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Straussberg R, Marom D, Sanado-Inbar E, et al. A possible genotype-phenotype correlation in Ashkenazi-Jewish individuals with Aicardi-Goutières syndrome associated with SAMHD1 mutation. J Child Neurol. 2015;30(4):490–5.PubMedGoogle Scholar
  47. 47.
    Xin B, Jones S, Puffenberger EG, et al. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci. 2011;108(13):5372–7.PubMedGoogle Scholar
  48. 48.
    Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol. 2014;192(12):5993–7.PubMedGoogle Scholar
  49. 49.
    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–Goutières syndrome. J Immunol. 2015;195(5):1939–43.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med. 2012;209(8):1419–26.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Reijns MA, Rabe B, Rigby RE, et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell. 2012;149(5):1008–22.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Pokatayev V, Hasin N, Chon H, et al. RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice. J Exp Med. 2016;213(3):329–36.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Ramesh V, Bernardi B, Stafa A, et al. Intracerebral large artery disease in Aicardi–Goutières syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol. 2010;52(8):725–32.PubMedGoogle Scholar
  54. 54.
    Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011;155(1):235–7.Google Scholar
  55. 55.
    Rice GI, Bond J, Asipu A, et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41(7):829–32.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Behrendt R, Schumann T, Gerbaulet A, et al. Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response. Cell Rep. 2013;4(4):689–96.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2009;10(1):109–15.PubMedGoogle Scholar
  58. 58.
    Funabiki M, Kato H, Miyachi Y, et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity. 2014;40(2):199–212.PubMedGoogle Scholar
  59. 59.
    Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235–43.PubMedGoogle Scholar
  60. 60.
    Haaxma CA, Crow YJ, Van Steensel MA, et al. A de novo p. Asp18Asn mutation in TREX1 in a patient with Aicardi–Goutières syndrome. Am J Med Genet A. 2010;152(10):2612–7.Google Scholar
  61. 61.
    Rice G, Newman WG, Dean J, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80(4):811–5.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Rice GI, Forte GM, Szynkiewicz M, et al. 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(12):1159–69.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Henrickson M, Wang H. Tocilizumab reverses cerebral vasculopathy in a patient with homozygous SAMHD1 mutation. Clin Rheumatol. 2017;36(6):1445–51.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;81(4):713–25.PubMedPubMedCentralGoogle Scholar
  65. 65.
    DiFrancesco JC, Novara F, Zuffardi O, et al. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol Sci. 2015;36(2):323–30.PubMedGoogle Scholar
  66. 66.
    Richards A, Van Den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39(9):1068–70.PubMedGoogle Scholar
  67. 67.
    Briggs TA, Rice GI, Adib N, et al. Spondyloenchondrodysplasia due to mutations in ACP5: A comprehensive survey. J Clin Immunol. 2016;36(3):220–34.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Renella R, Schaefer E, LeMerrer M, et al. Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: clinical and radiographic delineation of a pleiotropic disorder. Am J Med Genet A. 2006;140(6):541–50.PubMedGoogle Scholar
  69. 69.
    Briggs TA, Rice GI, Daly S, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet. 2011;43(2):127–31.Google Scholar
  70. 70.
    Rutsch F, MacDougall M, Lu C, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):275–82.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Jang M-A, Kim EK, Nguyen NT, et al. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):266–74.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Meuwissen ME, Schot R, Buta S, et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 2016;213(7):1163–74.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Zhang X, Bogunovic D, Payelle-Brogard B, et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature. 2015;517(7532):89.PubMedGoogle Scholar
  74. 74.
    Fabre A, Charroux B, Martinez-Vinson C, et al. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am J Hum Genet. 2012;90(4):689–92.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6):711–23.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Baechler EC, Bilgic H, Reed AM. Type I interferon pathway in adult and juvenile dermatomyositis. Arthritis Res Ther. 2011;13(6):249.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Despina Eleftheriou
    • 1
    Email author
  • Antonio Torrelo
    • 2
  • Paul A. Brogan
    • 3
  1. 1.ARUK Centre for Paediatric and Adolescent Rheumatology, Department of Paediatric RheumatologyUCL Great Ormond Street Institute of Child Health and Great Ormond St Hospital NHS Foundation TrustLondonUK
  2. 2.Department of DermatologyHospital Infantil Universitario Niño JesúsMadridSpain
  3. 3.Department of Paediatric RheumatologyUCL Great Ormond Street Institute of Child Health, and Great Ormond St Hospital NHS Foundation TrustLondonUK

Personalised recommendations