Skip to main content
SpringerLink
Log in

Toward a better understanding of type I interferonopathies: a brief summary, update and beyond

  • Review Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Backgrounds

Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the clinical phenotypes are diverse. This review briefly summarized the recent progresses of type I interferonopathy focusing on the clinical and molecular features, pathogeneses, diagnoses and potential therapies.

Data sources

Original research articles and literature reviews published in PubMed-indexed journals.

Results

Type I interferonopathies include Aicardi-Goutières syndrome, spondyloenchondro-dysplasia with immune dysregulation, stimulator of interferon genes-associated vasculopathy with onset in infancy, X-linked reticulate pigmentary disorder, ubiquitin-specific peptidase 18 deficiency, chronic atypical neutrophilic dermatitis with lipodystrophy, and Singleton-Merten syndrome originally. Other disorders including interferon-stimulated gene 15 deficiency and DNAse II deficiency are believed to be interferonopathies as well. Intracranial calcification, skin vasculopathy, interstitial lung disease, failure to thrive, skeletal development problems and autoimmune features are common. Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis. First generation Janus kinase inhibitors including baricitinib, tofacitinib and ruxolitinib are useful for disease control. Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome.

Conclusions

Tremendous progress has been made for the discovery of type I interferonopathies and responsible genes. Janus kinase inhibitors and other agents have potential therapeutic roles. Future basic, translational and clinical studies towards disease monitoring and powerful therapies are warranted.

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

Similar content being viewed by others

References

  1. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44.

    CAS  PubMed  Google Scholar 

  2. Canna SW, Goldbach-Mansky R. New monogenic autoinflammatory diseases—a clinical overview. Semin Immunopathol. 2015;37:387–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kopitar-Jerala N. The role of interferons in inflammation and inflammasome activation. Front Immunol. 2017;8:873.

    PubMed  PubMed Central  Google Scholar 

  4. Moghaddas F, Masters SL. The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders. Clin Sci (Lond). 2018;132:1901–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, et al. Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature. 2015;517:89–93.

    CAS  PubMed  Google Scholar 

  6. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38:96–128.

    PubMed  Google Scholar 

  7. Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, 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;167a:296–312.

  8. Davidson S, Steiner A, Harapas CR, Masters SL. An update on autoinflammatory diseases: interferonopathies. Curr Rheumatol Rep. 2018;20:38.

    PubMed  Google Scholar 

  9. Briggs TA, Rice GI, Adib N, Ades L, Barete S, Baskar K, et al. Spondyloenchondrodysplasia due to mutations in ACP5: a comprehensive survey. J Clin Immunol. 2016;36:220–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhong LQ, Wang L, Song HM, Wang W, Wei M, He YY. Spondyloenchondrodysplasia with immune dysregulation: a case report and literature review. Zhonghua Er Ke Za Zhi. 2018;56:611–6 (in Chinese).

    CAS  PubMed  Google Scholar 

  11. Volpi S, Picco P, Caorsi R, Candotti F, Gattorno M. Type I interferonopathies in pediatric rheumatology. Pediatric Rheumatol. 2016;14:35.

    Google Scholar 

  12. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Melki I, Rose Y, Uggenti C, Van Eyck L, Fremond ML, 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(543–52):e545.

    Google Scholar 

  14. Stoffels M, Kastner DL. Old dogs, new tricks: monogenic autoinflammatory disease unleashed. Annu Rev Genom Hum Genet. 2016;17:245–72.

    CAS  Google Scholar 

  15. Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, et al. DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol. 2016;17:495–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 2016;213:1163–74.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    PubMed  PubMed Central  Google Scholar 

  20. Poli MC, Ebstein F, Nicholas SK, de Guzman MM, Forbes LR, Chinn IK, et al. Heterozygous truncating variants in POMP escape nonsense-mediated decay and cause a unique immune dysregulatory syndrome. Am J Hum Genet. 2018;102:1126–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ben-Chetrit E, Gattorno M, Gul A, Kastner DL, Lachmann HJ, Touitou I, et al. Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study. Ann Rheum Dis. 2018;77:1558–655.

    CAS  PubMed  Google Scholar 

  22. de Jesus AA, Brehm A, VanTries R, Pillet P, Parentelli AS, Montealegre Sanchez GA, et al. Novel proteasome assembly chaperone mutations in PSMG2/PAC2, cause the autoinflammatory interferonopathy CANDLE/PRAAS4. J Allergy Clin Immunol. 2019;143:1939–43.e8.

    PubMed  Google Scholar 

  23. Oda H, Kastner DL. Genomics, biology, and human illness: advances in the monogenic autoinflammatory diseases. Rheum Dis Clin North Am. 2017;43:327–45.

    PubMed  PubMed Central  Google Scholar 

  24. Singleton EB, Merten DF. An unusual syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition. Pediatr Radiol. 1973;1:2–7.

    CAS  PubMed  Google Scholar 

  25. Lu C, MacDougall M. RIG-I-like receptor signaling in Singleton–Merten syndrome. Front Genet. 2017;8:118.

    PubMed  PubMed Central  Google Scholar 

  26. Ferreira CR, Crow YJ, Gahl WA, Gardner PJ, Goldbach-Mansky R, Hur S, et al. DDX58 and classic Singleton–Merten syndrome. J Clin Immunol. 2019;39:75–80.

    PubMed  Google Scholar 

  27. 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.

    PubMed  PubMed Central  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. Kumrah R, Mathew B, Vignesh P, Singh S, Rawat A. Genetics of COPA syndrome. Appl Clin Genet. 2019;12:11–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Eckard SC, Rice GI, Fabre A, Badens C, Gray EE, Hartley JL, et al. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat Immunol. 2014;15:839–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rice GI, Forte GM, Szynkiewicz M, Chase DS, Aeby A, Abdel-Hamid MS, 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;12:1159–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pescarmona R, Belot A, Villard M, Besson L, Lopez J, Mosnier I, et al. Comparison of RT-qPCR and Nanostring in the measurement of blood interferon response for the diagnosis of type I interferonopathies. Cytokine. 2019;113:446–52.

    CAS  PubMed  Google Scholar 

  35. Martinez-Quiles N, Goldbach-Mansky R. Updates on autoinflammatory diseases. Curr Opin Immunol. 2018;55:97–105.

    CAS  PubMed  Google Scholar 

  36. Vignesh P, Rawat A, Singh S. An update on the use of immunomodulators in primary immunodeficiencies. Clin Rev Allergy Immunol. 2017;52:287–303.

    CAS  PubMed  Google Scholar 

  37. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis. 2018;77:175–87.

    CAS  PubMed  Google Scholar 

  38. Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:376–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cao J, Sun L, Aramsangtienchai P, Spiegelman NA, Zhang X, Huang W, et al. HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2. Proc Natl Acad Sci USA. 2019;116:5487–92.

    CAS  PubMed  Google Scholar 

  40. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016;111:784–803.

    CAS  PubMed  Google Scholar 

  41. Ghoreschi K, Gadina M. Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol. 2014;23:7–11.

    CAS  PubMed  Google Scholar 

  42. Yu ZX, Zhong LQ, Song HM, Wang CY, Wang W, Li J, et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: first case report in China. Zhonghua Er Ke Za Zhi. 2018;56:179–85 (in Chinese).

    CAS  PubMed  Google Scholar 

  43. Meesilpavikkai K, Dik WA, Schrijver B, van Helden-Meeuwsen CG, Bijlsma EK, Ruivenkamp CAL, et al. Efficacy of baricitinib in the treatment of chilblains associated with the type I interferonopathy Aicardi-Goutieres syndrome. Arthritis Rheumatol. 2019. https://doi.org/10.1002/art.40805.

    Google Scholar 

  44. Kothur K, Bandodkar S, Chu S, Wienholt L, Johnson A, Barclay P, et al. An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation. Neurology. 2018;90:289–91.

    CAS  PubMed  Google Scholar 

  45. Parra-Izquierdo I, Castanos-Mollor I, López J, Gómez C, San Román JA, Sánchez Crespo M, et al. Calcification Induced by type I interferon in human aortic valve interstitial cells is larger in males and blunted by a janus kinase inhibitor. Arterioscler Thromb Vasc Biol. 2018;38:2148–59.

    CAS  PubMed  Google Scholar 

  46. 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.

    PubMed  PubMed Central  Google Scholar 

  47. 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. https://doi.org/10.1016/j.jaci.2019.01.044.

    Article  PubMed  Google Scholar 

  48. Bodewes ILA, Huijser E, van Helden-Meeuwsen CG, Tas L, Huizinga R, Dalm VASH, et al. TBK1: a key regulator and potential treatment target for interferon positive Sjogren's syndrome, systemic lupus erythematosus and systemic sclerosis. J Autoimmun. 2018;91:97–102.

    CAS  PubMed  Google Scholar 

  49. 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.

    CAS  PubMed  Google Scholar 

  50. Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, et al. Reverse-transcriptase inhibitors in the Aicardi-Goutieres syndrome. N Engl J Med. 2018;379:2275–7.

    PubMed  Google Scholar 

Download references

Funding

This study was supported by funds from Public Welfare Scientific Research Project of China (201402012), CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses to HW (2016ZX310182-1), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-008) and The Capital Health Research and Development of Special (2016-2-40114).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Zhong-Xun Yu & Hong-Mei Song

Authors
  1. Zhong-Xun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-Mei Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZXY contributed to the methodology and writing of the original draft. HMS contributed to conceptualization, methodology, writing of the original draft, editing, funding acquisition, and supervision. Both authors approved the final version of the manuscript.

Corresponding author

Correspondence to Hong-Mei Song.

Ethics declarations

Ethical approval

Not needed.

Conflict of interest

The authors state no conflict of interest. No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, ZX., Song, HM. Toward a better understanding of type I interferonopathies: a brief summary, update and beyond. World J Pediatr 16, 44–51 (2020). https://doi.org/10.1007/s12519-019-00273-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-019-00273-z

Keywords

Search

Navigation