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

Rosain, J.; Voyer, T. L.; Liu, X.; Gervais, A.; Polivka, L.; Cederholm, A.; Berteloot, L.; Parent, A. V.; Pescatore, A.; Spinosa, E.; Minic, S.; Kiszewski, A. E.; Tsumura, M.; Thibault, C.; Azcoiti, M. E.; Martinovic, J.; Philippot, Q.; Khan, T.; Marchal, A.; Muylder, B. C. -D.; Bizien, L.; Deswarte, C.; Hadjem, L.; Fauvarque, M. -O.; Dorgham, K.; Eriksson, D.; Falcone, E. L.; Puel, M.; Unal, S.; Geraldo, A.; Floc'H, C. L.; Li, H.; Rheault, S.; Muti, C.; Bobrie-Moyrand, C.; Welfringer-Morin, A.; Fuleihan, R. L.; Levy, R.; Roelens, M.; Gao, L.; Materna, M.; Pellegrini, S.; Piemonti, L.; Catherinot, E.; Goffard, J. -C.; Fekkar, A.; Sacko-Sow, A.; Soudee, C.; Boucherit, S.; Neehus, A. -L.; Has, C.; Hubner, S.; Blanchard-Rohner, G.; Amador-Borrero, B.; Utsumi, T.; Taniguchi, M.; Tani, H.; Izawa, K.; Yasumi, T.; Kanai, S.; Migaud, M.; Aubart, M.; Lambert, N.; Gorochov, G.; Picard, C.; Soudais, C.; L'Honneur, A. -S.; Rozenberg, F.; Milner, J. D.; Zhang, S. -Y.; Vabres, P.; Trpinac, D.; Marr, N.; Boddaert, N.; Desguerre, I.; Pasparakis, M.; Miller, C. N.; Poziomczyk, C. S.; Abel, L.; Okada, S.; Jouanguy, E.; Cheynier, R.; Zhang, Q.; Cobat, A.; Beziat, V.; Boisson, B.; Steffann, J.; Fusco, F.; Ursini, M. V.; Hadj-Rabia, S.; Bodemer, C.; Bustamante, J.; Luche, H.; Puel, A.; Courtois, G.; Bastard, P.; Landegren, N.; Anderson, M. S.; Casanova, J. -L.

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.

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases / Rosain, J.; Voyer, T. L.; Liu, X.; Gervais, A.; Polivka, L.; Cederholm, A.; Berteloot, L.; Parent, A. V.; Pescatore, A.; Spinosa, E.; Minic, S.; Kiszewski, A. E.; Tsumura, M.; Thibault, C.; Azcoiti, M. E.; Martinovic, J.; Philippot, Q.; Khan, T.; Marchal, A.; Muylder, B. C. -D.; Bizien, L.; Deswarte, C.; Hadjem, L.; Fauvarque, M. -O.; Dorgham, K.; Eriksson, D.; Falcone, E. L.; Puel, M.; Unal, S.; Geraldo, A.; Floc'H, C. L.; Li, H.; Rheault, S.; Muti, C.; Bobrie-Moyrand, C.; Welfringer-Morin, A.; Fuleihan, R. L.; Levy, R.; Roelens, M.; Gao, L.; Materna, M.; Pellegrini, S.; Piemonti, L.; Catherinot, E.; Goffard, J. -C.; Fekkar, A.; Sacko-Sow, A.; Soudee, C.; Boucherit, S.; Neehus, A. -L.; Has, C.; Hubner, S.; Blanchard-Rohner, G.; Amador-Borrero, B.; Utsumi, T.; Taniguchi, M.; Tani, H.; Izawa, K.; Yasumi, T.; Kanai, S.; Migaud, M.; Aubart, M.; Lambert, N.; Gorochov, G.; Picard, C.; Soudais, C.; L'Honneur, A. -S.; Rozenberg, F.; Milner, J. D.; Zhang, S. -Y.; Vabres, P.; Trpinac, D.; Marr, N.; Boddaert, N.; Desguerre, I.; Pasparakis, M.; Miller, C. N.; Poziomczyk, C. S.; Abel, L.; Okada, S.; Jouanguy, E.; Cheynier, R.; Zhang, Q.; Cobat, A.; Beziat, V.; Boisson, B.; Steffann, J.; Fusco, F.; Ursini, M. V.; Hadj-Rabia, S.; Bodemer, C.; Bustamante, J.; Luche, H.; Puel, A.; Courtois, G.; Bastard, P.; Landegren, N.; Anderson, M. S.; Casanova, J. -L.. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - 221:11(2024). [10.1084/jem.20231152]