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Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

Affiliations
  • 1Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France.
  • 2Imagine Institute, University of Paris Cité , Paris, France.
  • 3St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 4Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris, France.
  • 5Clinical Immunology Department, AP-HP, Saint-Louis Hospital, Paris, France.
  • 6Diabetes Center, University of California San Francisco , San Francisco, CA, USA.
  • 7Department of Dermatology, Reference Center for Genodermatosis and Rare Skin Diseases (MAGEC), University of Paris Cité, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 8Reference Center for Mastocytosis (CEREMAST), Necker Hospital for Sick Children, AP-HP , Paris, France.
  • 9Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  • 10Pediatric Radiology Department, Necker Hospital for Sick Children, Imagine Inserm Institute, U1163, AP-HP, Paris, France.
  • 11Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” IGB-CNR , Naples, Italy.
  • 12Clinics of Dermatovenerology, Clinical Center of Serbia , Belgrade, Serbia.
  • 13School of Medicine, University of Belgrade , Belgrade, Serbia.
  • 14Section of Dermatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.
  • 15Section of Pediatric Dermatology, Hospital da Criança Santo Antônio, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.
  • 16Hiroshima University Graduate School of Biomedical and Health Sciences , Hiroshima, Japan.
  • 17Unit of Fetal Pathology, Hospital Antoine Béclère, Paris Saclay University , Paris, France.
  • 18Department of Immunology, Sidra Medicine, Doha, Qatar.
  • 19University of Paris Cité, CNRS, Inserm, Institut Cochin , Paris, France.
  • 20Immunophenomics Center (CIPHE), Aix Marseille University, Inserm, CNRS , Marseille, France.
  • 21University Grenoble Alpes, CEA, Inserm , BGE UA13, Grenoble, France.
  • 22Sorbonne University, Inserm, Centre for Immunology and Microbial Infections, CIMI-Paris , Paris, France.
  • 23Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
  • 24Center for Immunity, Inflammation and Infectious Diseases, Montréal Clinical Research Institute (IRCM) , Montréal, Canada.
  • 25Department of Medicine, Montréal University, Montréal, Canada.
  • 26Center of Research of the Geriatric University Institute of Montréal, University of Montréal , Montréal, Canada.
  • 27Department of Genetics, André Mignot Hospital, Versailles, France.
  • 28Department of Obstetrics and Gynecology, André Mignot Hospital, Versailles, France.
  • 29Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
  • 30Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 31Diabetes Research Institute, IRCCS Ospedale San Raffaele , Milan, Italy.
  • 32Department of Respiratory Diseases, Foch Hospital, Suresnes, France.
  • 33Internal Medicine, Brussels University Hospital, Free University of Brussels, Anderlecht, Belgium.
  • 34Department of Parasitology Mycology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
  • 35Department of Pediatrics, Jean Verdier Hospital, AP-HP, Bondy, France.
  • 36Department of Dermatology, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
  • 37European Reference Network (ERN) for Rare and Undiagnosed Skin Disorders.
  • 38Unit of Immunology, Vaccinology, and Rheumatology, Division of General Pediatrics, Department of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • 39Internal Medicine Department, Lariboisière Hospital, AP-HP, University of Paris Cité, Paris, France.
  • 40Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan.
  • 41Department of Pediatrics, Hiroshima Prefectural Hospital, Hiroshima, Japan.
  • 42Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 43Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
  • 44Departments of Pediatric Neurology, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
  • 45Department of Immunology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
  • 46Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm U1163, Paris, France.
  • 47Department of Virology, University of Paris Cité and Cochin Hospital, AP-HP, Paris, France.
  • 48MAGEC Reference Center for Rare Skin Diseases, Dijon Bourgogne University Hospital, Dijon, France.
  • 49Institute of Histology and Embryology, School of Medicine, University of Belgrade , Belgrade, Serbia.
  • 50College of Health and Life Sciences, Hamad Bin Khalifa University , Doha, Qatar.
  • 51Institute for Genetics, University of Cologne , Cologne, Germany.
  • 52Private Dermatology Practice , Porto Alegre, Brazil.
  • 53Department of Genomic Medicine, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
  • 54Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
  • 55Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 56Howard Hughes Medical Institute, New York, NY, USA.

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October 1, 2024

Abstract

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

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