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Early-onset autoimmunity associated with SOCS1 haploinsufficiency

Author

Listed:
  • Jérôme Hadjadj

    (Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
    Université de Paris, IHU-Imagine)

  • Carla Noemi Castro

    (Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Maud Tusseau

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon)

  • Marie-Claude Stolzenberg

    (Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
    Université de Paris, IHU-Imagine)

  • Fabienne Mazerolles

    (Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
    Université de Paris, IHU-Imagine)

  • Nathalie Aladjidi

    (Centre de Référence National des Cytopénies Auto-immunes de l’Enfant (CEREVANCE), CIC 1401, Inserm CICP
    University Hospital, place Amélie Raba Léon, CIC 1401, Inserm, CICP)

  • Martin Armstrong

    (Translational Medicine, UCB Pharma)

  • Houman Ashrafian

    (University of Oxford)

  • Ioana Cutcutache

    (Translational Medicine, UCB Pharma)

  • Georg Ebetsberger-Dachs

    (Kepler University Hospital and School of Medicine, Johannes Kepler University)

  • Katherine S. Elliott

    (University of Oxford)

  • Isabelle Durieu

    (Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon
    EA 7425 HESPER. Université de Lyon)

  • Nicole Fabien

    (Immunology laboratory; Centre Hospitalier Lyon Sud, Hospices Civils de Lyon)

  • Mathieu Fusaro

    (AP-HP, Necker Hospital for Sick Children)

  • Maximilian Heeg

    (Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Yohan Schmitt

    (Genomic Core Facility, INSERM UMR1163, Imagine Institute)

  • Marc Bras

    (Université de Paris, IHU-Imagine)

  • Julian C. Knight

    (University of Oxford)

  • Jean-Christophe Lega

    (Centre Hospitalier Lyon Sud, Hospices Civils de Lyon
    National Referee Centre for Pediatric-Onset Rheumatism and Autoimmune Diseases (RAISE)
    UMR 5558, Equipe Evaluation et Modélisation des Effets Thérapeutiques, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Claude Bernard University Lyon 1)

  • Gaetan Lesca

    (Service de Génétique, Hospices Civils de Lyon - GHE, and Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1)

  • Anne-Laure Mathieu

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon)

  • Marion Moreews

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon)

  • Baptiste Moreira

    (Immunology Laboratory, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris)

  • Audrey Nosbaum

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon
    Allergy and Clinical Immunology department, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon)

  • Matthew Page

    (Translational Medicine, UCB Pharma)

  • Cécile Picard

    (Institut de Pathologie Multisite, Groupement Hospitalier Est, Hospices Civils de Lyon, UCBL Lyon 1 University)

  • T. Ronan Leahy

    (Children’s Health Ireland at Crumlin)

  • Isabelle Rouvet

    (Centre de biotechnologie cellulaire et Biothèque, Groupe Hospitalier Est, Hospices Civils de Lyon)

  • Ethel Ryan

    (University Hospital Galway, Co)

  • Damien Sanlaville

    (Service de Génétique, Hospices Civils de Lyon - GHE, and Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1)

  • Klaus Schwarz

    (University Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen)

  • Andrew Skelton

    (Translational Medicine, UCB Pharma)

  • Jean-Francois Viallard

    (Université de Bordeaux)

  • Sebastien Viel

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon
    Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon)

  • Marine Villard

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon)

  • Isabelle Callebaut

    (Sorbonne Université, Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie)

  • Capucine Picard

    (AP-HP, Necker Hospital for Sick Children
    Université de Paris, Imagine institute, laboratory of Iymphocyte activation and susceptibility to EBV, INSERM UMR 1163)

  • Thierry Walzer

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon)

  • Stephan Ehl

    (Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
    University of Freiburg)

  • Alain Fischer

    (Université de Paris, IHU-Imagine
    Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris
    Collège de France)

  • Bénédicte Neven

    (Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
    Université de Paris, IHU-Imagine
    Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris)

  • Alexandre Belot

    (CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon
    National Referee Centre for Pediatric-Onset Rheumatism and Autoimmune Diseases (RAISE)
    Mother and Children University Hospital)

  • Frédéric Rieux-Laucat

    (Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
    Université de Paris, IHU-Imagine)

Abstract

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

Suggested Citation

  • Jérôme Hadjadj & Carla Noemi Castro & Maud Tusseau & Marie-Claude Stolzenberg & Fabienne Mazerolles & Nathalie Aladjidi & Martin Armstrong & Houman Ashrafian & Ioana Cutcutache & Georg Ebetsberger-Dac, 2020. "Early-onset autoimmunity associated with SOCS1 haploinsufficiency," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18925-4
    DOI: 10.1038/s41467-020-18925-4
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