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

Jérémie Rosain; Tom Le Voyer; Xian Liu; Adrian Gervais; Laura Polivka; Axel Cederholm; Laureline Berteloot; Audrey V Parent; Alessandra Pescatore; Ezia Spinosa; Snezana Minic; Ana Elisa Kiszewski; Miyuki Tsumura; Chloé Thibault; Maria Esnaola Azcoiti; Jelena Martinovic; Quentin Philippot; Taushif Khan; Astrid Marchal; Bénédicte Charmeteau-De Muylder; Lucy Bizien; Caroline Deswarte; Lillia Hadjem; Marie-Odile Fauvarque; Karim Dorgham; Daniel Eriksson; Emilia Liana Falcone; Mathilde Puel; Sinem Ünal; Amyrath Geraldo; Corentin Le Floc'h; Hailun Li; Sylvie Rheault; Christine Muti; Claire Bobrie-Moyrand; Anne Welfringer-Morin; Ramsay L Fuleihan; Romain Lévy; Marie Roelens; Liwei Gao; Marie Materna; Silvia Pellegrini; Lorenzo Piemonti; Emilie Catherinot; Jean-Christophe Goffard; Arnaud Fekkar; Aissata Sacko-Sow; Camille Soudée; Soraya Boucherit; Anna-Lena Neehus; Cristina Has; Stefanie Hübner; Géraldine Blanchard-Rohner; Blanca Amador-Borrero; Takanori Utsumi; Maki Taniguchi; Hiroo Tani; Kazushi Izawa; Takahiro Yasumi; Sotaro Kanai; Mélanie Migaud; Mélodie Aubart; Nathalie Lambert; Guy Gorochov; Capucine Picard; Claire Soudais; Anne-Sophie L'Honneur; Flore Rozenberg; Joshua D Milner; Shen-Ying Zhang; Pierre Vabres; Dusan Trpinac; Nico Marr; Nathalie Boddaert; Isabelle Desguerre; Manolis Pasparakis; Corey N Miller; Cláudia S Poziomczyk; Laurent Abel; Satoshi Okada; Emmanuelle Jouanguy; Rémi Cheynier; Qian Zhang; Aurélie Cobat; Vivien Béziat; Bertrand Boisson; Julie Steffann; Francesca Fusco; Matilde Valeria Ursini; Smail Hadj-Rabia; Christine Bodemer; Jacinta Bustamante; Hervé Luche; Anne Puel; Gilles Courtois; Paul Bastard; Nils Landegren; Mark S Anderson; Jean-Laurent Casanova

doi:10.1084/jem.20231152

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

J Exp Med. 2024 Nov 4;221(11):e20231152. doi: 10.1084/jem.20231152. Epub 2024 Oct 1.

Authors

Jérémie Rosain^{1

2

3

4}, Tom Le Voyer^#^{1

2

3

5}, Xian Liu^#⁶, Adrian Gervais^#^{1

2}, Laura Polivka^#^{7

8}, Axel Cederholm^#⁹, Laureline Berteloot^#¹⁰, Audrey V Parent^#⁶, Alessandra Pescatore^#¹¹, Ezia Spinosa^#¹¹, Snezana Minic^#^{12

13}, Ana Elisa Kiszewski^#^{14

15}, Miyuki Tsumura^#¹⁶, Chloé Thibault^#^{1

2}, Maria Esnaola Azcoiti^#^{1

2}, Jelena Martinovic^#¹⁷, Quentin Philippot^#^{1

2}, Taushif Khan^#¹⁸, Astrid Marchal^#^{1

2}, Bénédicte Charmeteau-De Muylder^#¹⁹, Lucy Bizien^#^{1

2}, Caroline Deswarte^#^{1

2}, Lillia Hadjem²⁰, Marie-Odile Fauvarque²¹, Karim Dorgham²², Daniel Eriksson²³, Emilia Liana Falcone^{24

25}, Mathilde Puel⁴, Sinem Ünal^{1

2}, Amyrath Geraldo^{1

2}, Corentin Le Floc'h^{1

2}, Hailun Li^{1

2}, Sylvie Rheault^{25

26}, Christine Muti²⁷, Claire Bobrie-Moyrand²⁸, Anne Welfringer-Morin⁷, Ramsay L Fuleihan²⁹, Romain Lévy^{1

2

3

30}, Marie Roelens^{2

4}, Liwei Gao^{1

2}, Marie Materna^{1

2}, Silvia Pellegrini³¹, Lorenzo Piemonti³¹, Emilie Catherinot³², Jean-Christophe Goffard³³, Arnaud Fekkar^{1

2

34}, Aissata Sacko-Sow³⁵, Camille Soudée^{1

2}, Soraya Boucherit^{1

2}, Anna-Lena Neehus^{1

2}, Cristina Has^{36

37}, Stefanie Hübner³⁶, Géraldine Blanchard-Rohner³⁸, Blanca Amador-Borrero³⁹, Takanori Utsumi¹⁶, Maki Taniguchi¹⁶, Hiroo Tani^{40

41}, Kazushi Izawa⁴², Takahiro Yasumi⁴², Sotaro Kanai⁴³, Mélanie Migaud^{1

2}, Mélodie Aubart^{1

2

44}, Nathalie Lambert⁴, Guy Gorochov^{22

45}, Capucine Picard^{2

4

46}, Claire Soudais⁴⁶, Anne-Sophie L'Honneur⁴⁷, Flore Rozenberg⁴⁷, Joshua D Milner²⁹, Shen-Ying Zhang^{1

2

3}, Pierre Vabres⁴⁸, Dusan Trpinac⁴⁹, Nico Marr^{18

50}, Nathalie Boddaert¹⁰, Isabelle Desguerre⁴⁴, Manolis Pasparakis⁵¹, Corey N Miller⁶, Cláudia S Poziomczyk⁵², Laurent Abel^{1

2

3}, Satoshi Okada¹⁶, Emmanuelle Jouanguy^{1

2

3}, Rémi Cheynier¹⁹, Qian Zhang^{1

2

3}, Aurélie Cobat^{1

2

3}, Vivien Béziat^{1

2

3}, Bertrand Boisson^{1

2

3}, Julie Steffann⁵³, Francesca Fusco¹¹, Matilde Valeria Ursini¹¹, Smail Hadj-Rabia⁷, Christine Bodemer⁷, Jacinta Bustamante^{1

2

3

4}, Hervé Luche²⁰, Anne Puel^#^{1

2

3}, Gilles Courtois^#²¹, Paul Bastard^#^{1

2

3

30}, Nils Landegren^#^{9

54}, Mark S Anderson^#⁶, Jean-Laurent Casanova^#^{1

2

3

55

56}

Affiliations

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

^# Contributed equally.

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.

MeSH terms

Adolescent
Adult
Autoantibodies* / immunology
Child
Child, Preschool
Female
Humans
I-kappa B Kinase* / genetics
I-kappa B Kinase* / immunology
Incontinentia Pigmenti* / genetics
Incontinentia Pigmenti* / immunology
Incontinentia Pigmenti* / pathology
Infant
Interferon Type I* / immunology
Interferon Type I* / metabolism
Thymus Gland* / immunology
Thymus Gland* / pathology
Virus Diseases / immunology
Young Adult

Substances

Interferon Type I
Autoantibodies
I-kappa B Kinase
IKBKG protein, human

Abstract

MeSH terms

Substances

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