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Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

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A Commentary to this article was published on 25 July 2020

Abstract

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8+ T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

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Acknowledgments

We thank Yanick Crow, Barry Coller, Charlie Rice, James Krueger, and Timothy Wang for helpful discussions and critical reading. We thank Y. Nemirovskaya, T. Kochetkov, M. Romanick, L. Amar, C. Patissier, C. Desvallées, M. Woollett, A. Gall, and J. Gonzalez for technical and secretarial assistance and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. X-F.K was supported by the Jerome Lejeune Foundation and Alexander’s Angels Inc. X-F.K is currently a gastroenterology fellow in CUIMC supported by NIH grant T32 DK083256. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number UL1TR001866 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grants 5R01AI127564 and 5R37AI095983), grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01), ANR-IFNGPHOX (ANR-13-ISV3-0001-01) and ANR-GENMSMD (ANR-16-CE17-0005-01), LTh-MSMD-CMCD (ANR-18-CE93-0008-01), HGDIFD (ANR-14-CE15-0006-01), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, and The Rockefeller University and the Helmut Horten Foundation.

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Author notes

  1. Stuart G Tangye, Stéphanie Boisson-Dupuis and Anne Puel contributed equally to this work.

Authors and Affiliations

  1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Xiao-Fei Kong, Laurent Abel, Jean-Laurent Casanova & Stéphanie Boisson-Dupuis

  2. Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Xiao-Fei Kong

  3. Immunity & Inflammatory Diseases, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Lisa Worley, Cindy S. Ma & Stuart G Tangye

  4. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia

    Lisa Worley, Cindy S. Ma & Stuart G Tangye

  5. Sidra Medicine, Sidra Medical and Research Center, Doha, Qatar

    Darawan Rinchai, Puthen Veettil Jithesh, Mohammed Elanbari, Tanwir Habib & Damien Chaussabel

  6. Immunobiology of Dendritic Cells Unit, Institut Pasteur, Paris, France

    Vincent Bondet & Darragh Duffy

  7. Inserm U1223, Institut Pasteur, Paris, France

    Vincent Bondet & Darragh Duffy

  8. Institute Jérôme Lejeune, Paris, France

    Marie Goulet, Emilie Nonnotte, Anne Sophie Rebillat, Martine Conte, Clotilde Mircher & Aimé Ravel

  9. Department of Otorhinolaryngology, University Hospital of Basel, Basel, Switzerland

    Nicolas Gürtler

  10. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France

    Luyan Liu, Mélanie Migaud, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova & Anne Puel

  11. Howard Hughes Medical Institute, New York, USA

    Jean-Laurent Casanova

  12. Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, 75015, Paris, France

    Jacinta Bustamante & Jean-Laurent Casanova

  13. Laboratory of Genetics and Embryology of Congenital Malformation, INSERM U1163, Imagine Institute, Université de Paris, Paris, France

    Stanislas Lyonnet

  14. Fédération de Génétique et Institut Imagine, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France

    Arnold Munnich

  15. Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova

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  1. Xiao-Fei Kong
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Correspondence to Xiao-Fei Kong.

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Dr. Casanova reports personal fees from Celgene, personal fees from ADMA, personal fees from Nimbus, personal fees from Vitae Pharmaceuticals, Inc., personal fees from KymeraTX, personal fees from Sanofi, personal fees from Asahi Kasei, personal fees from Pfizer, personal fees from Elixiron Immunotherapeutics, outside the submitted work. The other authors declare that they have no conflicts of interest.

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Kong, XF., Worley, L., Rinchai, D. et al. Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome. J Clin Immunol 40, 807–819 (2020). https://doi.org/10.1007/s10875-020-00803-9

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