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

Xiao Fei Kong, Lisa Worley, Darawan Rinchai, Vincent Bondet, Puthen Veettil Jithesh, Marie Goulet, Emilie Nonnotte, Anne Sophie Rebillat, Martine Conte, Clotilde Mircher, Nicolas Gürtler, Luyan Liu, Mélanie Migaud, Mohammed Elanbari, Tanwir Habib, Cindy S. Ma, Jacinta Bustamante, Laurent Abel, Aimé Ravel, Stanislas LyonnetArnold Munnich, Darragh Duffy, Damien Chaussabel, Jean Laurent Casanova, Stuart G. Tangye, Stéphanie Boisson-Dupuis, Anne Puel

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18 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)807-819
Number of pages13
JournalJournal of Clinical Immunology
Issue number6
StatePublished - Aug 1 2020
Externally publishedYes


  • Down syndrome
  • interferon receptors
  • interferonopathy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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