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

• Published in: The Journal of experimental medicine Vol. 221; no. 11
• Main Authors: Rosain, Jérémie, Le Voyer, Tom, Liu, Xian, Gervais, Adrian, Polivka, Laura, Cederholm, Axel, Berteloot, Laureline, Parent, Audrey V, Pescatore, Alessandra, Spinosa, Ezia, Minic, Snezana, Kiszewski, Ana Elisa, Tsumura, Miyuki, Thibault, Chloé, Esnaola Azcoiti, Maria, Martinovic, Jelena, Philippot, Quentin, Khan, Taushif, Marchal, Astrid, Charmeteau-De Muylder, Bénédicte, Bizien, Lucy, Deswarte, Caroline, Hadjem, Lillia, Fauvarque, Marie-Odile, Dorgham, Karim, Eriksson, Daniel, Falcone, Emilia Liana, Puel, Mathilde, Ünal, Sinem, Geraldo, Amyrath, Le Floc'h, Corentin, Li, Hailun, Rheault, Sylvie, Muti, Christine, Bobrie-Moyrand, Claire, Welfringer-Morin, Anne, Fuleihan, Ramsay L, Lévy, Romain, Roelens, Marie, Gao, Liwei, Materna, Marie, Pellegrini, Silvia, Piemonti, Lorenzo, Catherinot, Emilie, Goffard, Jean-Christophe, Fekkar, Arnaud, Sacko-Sow, Aissata, Soudée, Camille, Boucherit, Soraya, Neehus, Anna-Lena, Has, Cristina, Hübner, Stefanie, Blanchard-Rohner, Géraldine, Amador-Borrero, Blanca, Utsumi, Takanori, Taniguchi, Maki, Tani, Hiroo, Izawa, Kazushi, Yasumi, Takahiro, Kanai, Sotaro, Migaud, Mélanie, Aubart, Mélodie, Lambert, Nathalie, Gorochov, Guy, Picard, Capucine, Soudais, Claire, L'Honneur, Anne-Sophie, Rozenberg, Flore, Milner, Joshua D, Zhang, Shen-Ying, Vabres, Pierre, Trpinac, Dusan, Marr, Nico, Boddaert, Nathalie, Desguerre, Isabelle, Pasparakis, Manolis, Miller, Corey N, Poziomczyk, Cláudia S, Abel, Laurent, Okada, Satoshi, Jouanguy, Emmanuelle, Cheynier, Rémi, Zhang, Qian, Cobat, Aurélie, Béziat, Vivien, Boisson, Bertrand, Steffann, Julie, Fusco, Francesca, Ursini, Matilde Valeria, Hadj-Rabia, Smail, Bodemer, Christine, Bustamante, Jacinta, Luche, Hervé, Puel, Anne, Courtois, Gilles, Bastard, Paul, Landegren, Nils, Anderson, Mark S, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.11.2024
• Subjects: Adolescent; Adult; Autoantibodies - immunology; Autoimmunity; Child; Child, Preschool; Female; Human Disease Genetics; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - immunology; Incontinentia Pigmenti - genetics; Incontinentia Pigmenti - immunology; Incontinentia Pigmenti - pathology; Infant; Infectious Disease and Host Defense; Interferon Type I - immunology; Interferon Type I - metabolism; Medicin och hälsovetenskap; Thymus Gland - immunology; Thymus Gland - pathology; Virus Diseases - immunology; Young Adult
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20231152

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.