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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
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
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Submitted on : Monday, March 18, 2019 - 10:26:12 AM
Last modification on : Thursday, August 27, 2020 - 3:10:05 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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