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Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.

Stéphanie Boisson-Dupuis 1, 2 Noe Ramirez-Alejo 1 Zhi Li 3 Etienne Patin 4, 5 Geetha Rao 6 Gaspard Kerner 2 Che Kang Lim Dimitry Krementsov Nicholas Hernandez 1 Cindy Ma 6 Qian Zhang 7, 1 Janet Markle 1 Ruben Martinez-Barricarte 1 Kathryn Payne 6 Robert Fisch 1 Caroline Deswarte 2 Joshua Halpern 1 Matthieu Bouaziz 2 Jeanette Mulwa 1 Durga Sivanesan Tomi Lazarov 8 Rodrigo Naves Patricia Garcia Yuval Itan 1 Bertrand Boisson 1, 2 Alix Checchi 2 Fabienne Jabot-Hanin 2 Aurélie Cobat 2 Andrea Guennoun 9 Carolyn Jackson 1 Sevgi Pekcan Zafer Caliskaner Jaime Inostroza Beatriz Tavares Costa-Carvalho Antonio de Albuquerque Humberto Garcia-Ortiz Lorena Orozco Tayfun Ozcelik Ahmed Abid 10 Ismail Rhorfi Hicham Souhi Hicham Naji Amrani Adil Zegmout Frederic Geissmann 8 Stephen Michnick Ingrid Fleckenstein Bernhard Fleckenstein 11 Anne Puel 1, 2 Michael Ciancanelli 1 Nico Marr 12 Hassan Abolhassani 13 María Elvira Balcells 14 Antonio Condino-Neto 15 Alexis Strickler 16 Katia Abarca Cory Teuscher Hans Ochs 17 Ismail Reisli 18 Esra Sayar Jamila El-Baghdadi Jacinta Bustamante 1, 2, 19 Lennart Hammarström Stuart Tangye 20 Sandra Pellegrini 3 Lluis Quintana-Murci 5, 4 Laurent Abel 21, 2 Jean-Laurent Casanova 21, 2, 22
1 St. Giles Laboratory of Human Genetics of Infectious Diseases
2 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
3 Signalisation des Cytokines
4 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
5 Génétique Evolutive Humaine - Human Evolutionary Genetics
6 Garvan Institute of Medical Research [Darlinghurst, Australia]
7 MoBS - Laboratory for the Modeling of Biological and Socio-technical Systems [Boston]
8 Memorial Sloane Kettering Cancer Center [New York]
9 Laboratory of Genetic Medicine & Immunology
10 BDTLN - Bases de données et traitement des langues naturelles
LIFAT - Laboratoire d'Informatique Fondamentale et Appliquée de Tours
11 Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
12 Sidra Medicine [Doha, Qatar]
13 TUMS - Tehran University of Medical Sciences
14 Infectious Diseases Department, School of Medicine
15 Institute of Biomedical Sciences - Department of Immunology [Sao Paulo]
16 Hosp Puerto Montt
17 University of Washington [Seattle]
18 Selcuk University
19 CHU Necker - Enfants Malades [AP-HP]
20 Garvan Institute for Medical Research
21 Inserm U980 - Génétique Humaine des Maladies Infectieuses
22 Service d'immuno-hématologie pédiatrique [CHU Necker]
Abstract : Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02070591
Contributor : Zhi Li <>
Submitted on : Monday, March 18, 2019 - 10:26:12 AM
Last modification on : Thursday, May 27, 2021 - 5:08:03 PM

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Stéphanie Boisson-Dupuis, Noe Ramirez-Alejo, Zhi Li, Etienne Patin, Geetha Rao, et al.. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.. Science Immunology, American Association for the Advancement of Science, 2018, 3 (30), pp.eaau8714. ⟨10.1126/sciimmunol.aau8714⟩. ⟨pasteur-02070591⟩

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