Early-onset autoimmunity associated with SOCS1 haploinsufficiency

Jérôme Hadjadj, Carla Noemi Castro, Maud Tusseau, Marie-Claude Stolzenberg, Fabienne Mazerolles, Nathalie Aladjidi, Martin Armstrong, Houman Ashrafian, Ioana Cutcutache, Georg Ebetsberger-Dachs, Katherine S. Elliott, Isabelle Durieu, Nicole Fabien, Mathieu Fusaro, Maximilian Heeg, Yohan Schmitt, Marc Bras, Julian C. Knight, Jean-Christophe Lega, Gaetan Lesca, Anne-Laure Mathieu, Marion Moreews, Baptiste Moreira, Audrey Nosbaum, Matthew Page, Cécile Picard, T. Ronan Leahy, Isabelle Rouvet, Ethel Ryan, Damien Sanlaville, Klaus Schwarz, Andrew Skelton, Jean-Francois Viallard, Sebastien Viel, Marine Villard, Isabelle Callebaut, Capucine Picard, Thierry Walzer, Stephan Ehl, Alain Fischer, Bénédicte Neven, Alexandre Belot () and Frédéric Rieux-Laucat ()
Additional contact information
Jérôme Hadjadj: Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
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
Fabienne Mazerolles: Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
Nathalie Aladjidi: Centre de Référence National des Cytopénies Auto-immunes de l’Enfant (CEREVANCE), 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
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
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
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
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
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
Alain Fischer: Université de Paris, IHU-Imagine
Bénédicte Neven: Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
Alexandre Belot: CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon
Frédéric Rieux-Laucat: Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18925-4

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