2. Academic Validation
  3. Early-onset autoimmunity associated with SOCS1 haploinsufficiency

Early-onset autoimmunity associated with SOCS1 haploinsufficiency

  • Nat Commun. 2020 Oct 21;11(1):5341. doi: 10.1038/s41467-020-18925-4.
Jérôme Hadjadj 1 2,  Carla Noemi Castro 3,  Maud Tusseau 4,  Marie-Claude Stolzenberg 1 2,  Fabienne Mazerolles 1 2,  Nathalie Aladjidi 5 6,  Martin Armstrong 7,  Houman Ashrafian 8,  Ioana Cutcutache 9,  Georg Ebetsberger-Dachs 10,  Katherine S Elliott 11,  Isabelle Durieu 12 13,  Nicole Fabien 14,  Mathieu Fusaro 15,  Maximilian Heeg 3,  Yohan Schmitt 16,  Marc Bras 2,  Julian C Knight 11,  Jean-Christophe Lega 17 18 19,  Gaetan Lesca 20,  Anne-Laure Mathieu 4,  Marion Moreews 4,  Baptiste Moreira 21,  Audrey Nosbaum 4 22,  Matthew Page 7,  Cécile Picard 23,  T Ronan Leahy 24,  Isabelle Rouvet 25,  Ethel Ryan 26,  Damien Sanlaville 20,  Klaus Schwarz 27,  Andrew Skelton 9,  Jean-Francois Viallard 28,  Sebastien Viel 4 29,  Marine Villard 4,  Isabelle Callebaut 30,  Capucine Picard 15 31,  Thierry Walzer 4,  Stephan Ehl 3 32,  Alain Fischer 2 33 34,  Bénédicte Neven 1 2 33,  Alexandre Belot 35 36 37,  Frédéric Rieux-Laucat 38 39
Affiliations

Affiliations

  • 1 Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 24 boulevard du Montparnasse, 75015, Paris, France.
  • 2 Université de Paris, IHU-Imagine, 24 boulevard du Montparnasse, Paris, 75015, France.
  • 3 Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 4 Centre International de Recherche en Infectiologie, CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon, Lyon, France.
  • 5 Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), CIC 1401, Inserm CICP, Bordeaux, France.
  • 6 Pediatric Oncology Hematology Unit, University Hospital, place Amélie Raba Léon, CIC 1401, Inserm, CICP, Bordeaux, France.
  • 7 Translational Medicine, UCB Pharma, Braine-l'Alleud, Belgium.
  • 8 Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • 9 Translational Medicine, UCB Pharma, Slough, United Kingdom.
  • 10 Department of Pediatrics, Kepler University Hospital and School of Medicine, Johannes Kepler University, Linz, Austria.
  • 11 Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 12 Internal Medicine and Vascular Pathology Department, Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
  • 13 EA 7425 HESPER. Université de Lyon, Lyon, France.
  • 14 Immunology laboratory; Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
  • 15 Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
  • 16 Genomic Core Facility, INSERM UMR1163, Imagine Institute, Paris, France.
  • 17 Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
  • 18 National Referee Centre for Pediatric-Onset Rheumatism and Autoimmune Diseases (RAISE), Lyon, France.
  • 19 UMR 5558, Equipe Evaluation et Modélisation des Effets Thérapeutiques, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Claude Bernard University Lyon 1, Lyon, France.
  • 20 Service de Génétique, Hospices Civils de Lyon - GHE, and Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
  • 21 Immunology Laboratory, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 22 Allergy and Clinical Immunology department, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
  • 23 Institut de Pathologie Multisite, Groupement Hospitalier Est, Hospices Civils de Lyon, UCBL Lyon 1 University, Lyon, France.
  • 24 Department of Paediatric Immunology and Infectious Diseases, Children's Health Ireland at Crumlin, Dublin, Ireland.
  • 25 Centre de biotechnologie cellulaire et Biothèque, Groupe Hospitalier Est, Hospices Civils de Lyon, 69677, Bron, France.
  • 26 Department of Paediatrics, University Hospital Galway, Co, Galway, Ireland.
  • 27 Institute for Transfusion Medicin, University Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, 89081, Ulm, Germany.
  • 28 Département de Médecine Interne et Maladies Infectieuses, Centre Hospitalier Universitaire Haut Lévêque, Université de Bordeaux, Pessac, France.
  • 29 Service d'Immunologie Biologique, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
  • 30 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, Paris, France.
  • 31 Université de Paris, Imagine institute, laboratory of Iymphocyte activation and susceptibility to EBV, INSERM UMR 1163, 24 boulevard du Montparnasse, Paris, 75015, France.
  • 32 CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
  • 33 Paediatric Immuno-Haematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, 75015, Paris, France.
  • 34 Collège de France, Paris, France.
  • 35 Centre International de Recherche en Infectiologie, CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon, Lyon, France. [email protected].
  • 36 National Referee Centre for Pediatric-Onset Rheumatism and Autoimmune Diseases (RAISE), Lyon, France. [email protected].
  • 37 Hospices Civils de Lyon, Paediatric Nephrology, Rheumatology, Dermatology Unit, Mother and Children University Hospital, Bron, France. [email protected].
  • 38 Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 24 boulevard du Montparnasse, 75015, Paris, France. [email protected].
  • 39 Université de Paris, IHU-Imagine, 24 boulevard du Montparnasse, Paris, 75015, France. [email protected].
PMID: 33087723 DOI: 10.1038/s41467-020-18925-4
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.

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