Abstract

The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1T946) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1T946 exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.

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NCBI Reference Sequence

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Acknowledgements

We thank K. Sommer for laboratory management and assistance with manuscript editing; the University of Washington Histology and Imaging Core and Benaroya Clinical Core; M. Kinsman for technical assistance with RNA preparation; and E. Whalen and V. Gersuk for assistance with Fluidigm assays. Supported by the US National Institutes of Health (DP3-DK097672 to J.H.B.; DP3-DK111802 to D.J.R.; R01-AI084914 to D.B.S.; R01-AI104002, R01-AI060389 and R01-AI127463 to M.G.; U19-AI083019 to M.G.; U19-AI100625 to M.G.; R01-DK106718 to P.C.; T32-AR007108 to J.A.G; and T32-GM007270 to K.P.), the Juvenile Diabetes Research Foundation (3-APF-2016-177-A-N to Y.G.), the Children's Guild Association Endowed Chair in Pediatric Immunology and the Benaroya Family Gift Fund (D.J.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Affiliations

  1. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Jacquelyn A Gorman
    • , Eric J Allenspach
    • , Tanvi Arkatkar
    • , Courtnee Clough
    • , Xuezhi Dai
    • , Socheath Khim
    • , Richard G James
    • , Mohamed Oukka
    •  & David J Rawlings
  2. Benaroya Research Institute, Seattle, Washington, USA.

    • Christian Hundhausen
    • , Karen Cerosaletti
    •  & Jane H Buckner
  3. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.

    • John S Errett
    • , Amy E Stone
    •  & Michael Gale Jr
  4. Department of Immunology, University of Washington, Seattle, Washington, USA.

    • John S Errett
    • , Amy E Stone
    • , Kathleen Pestal
    • , Daniel B Stetson
    • , Mohamed Oukka
    • , Michael Gale Jr
    •  & David J Rawlings
  5. Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Eric J Allenspach
    • , Richard G James
    • , Mohamed Oukka
    •  & David J Rawlings
  6. Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.

    • Yan Ge
    •  & Patrick Concannon
  7. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.

    • Denny Liggitt

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Contributions

J.A.G., C.H., A.E.S. and Y.G. designed and performed experiments, analyzed data and wrote and/or edited the manuscript; J.S.E. designed and performed experiments and analyzed data; E.J.A, T.A., C.C., X.D., S.K., K.P., K.C. and M.O. developed required models, strains or reagents and/or performed experiments; D.L., D.B.S., R.G.J., P.C. and M.G. analyzed data and edited the manuscript; J.H.B. designed and interpreted human-subject studies; and D.J.R. conceived of and supervised the study, interpreted data and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David J Rawlings.

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https://doi.org/10.1038/ni.3766

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