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Aicardi–Goutières syndrome and the type I interferonopathies

Key Points

  • Type I interferons (IFNs) are antiviral cytokines, the regulation of which is tightly controlled. A type I IFN response is typically initiated by the sensing of exogenous nucleic acid ligands.

  • The term 'type I interferonopathies' refers to Mendelian disorders in which an upregulation of type I IFN expression is considered to have a central role in disease pathogenesis.

  • Inborn errors of type I IFN upregulation might be caused by the accumulation of an endogenous agonistic ligand or by unchecked signalling.

  • So far, mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH1, TMEM173, ACP5, ISG15 or DDX58 (possibly also PSMB8), as well as early components of the complement cascade (particularly C1 and C4), might all be considered to be causes of type I interferonopathies.

  • The definition of phenotypes as type I interferonopathies will be important in the context of directed therapeutics, and the identification of the source of endogenous ligands implicated in the respective interferonopathies may guide future treatment decisions.

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.

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Figure 1: Molecular function of type I interferonopathy-related proteins and relevant innate immune signalling pathways in the context of AGS.

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Acknowledgements

Y.J.C. acknowledges the Manchester Biomedical Research Centre, the European Research Council (GA 309449: fellowship to Y.J.C) and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” programme bearing the reference ANR-10-IAHU-01. N.M. acknowledges the ATIP–Avenir programme, the Agence Nationale de Recherche sur le SIDA (ANRS), the Ville de Paris Emergence programme, European FP7 Marie Curie Actions (grant 268311), the Laboratory of Excellence (LABEX) Vaccine Research Institute (VRI; ANR-10-LABX-77), LABEX Dendritic Cell Biology (DCBIOL;ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), Acting on European Research in Immunology and Allergology (ACTERIA) Foundation, the Fondation Schlumberger pour l'Education et la Recherche (FSER) and a European Research Council grant (309848 HIVINNATE). Y.J.C. would like to extend special thanks to G. Rice for help with preparing the manuscript and, together with M. Rodero and I. Melki, for discussions relating to its content.

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Crow, Y., Manel, N. Aicardi–Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 15, 429–440 (2015). https://doi.org/10.1038/nri3850

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  • DOI: https://doi.org/10.1038/nri3850

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