Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
Masato Ogishi, Andrés A. Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramirez‐Alejo, Nioosha Nekooie‐Marnany, Andrea Guennoun, Ingrid Müller‐Fleckenstein, Bernhard Fleckenstein, Sara Şebnem Kılıç, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser‐Labusch, Yasemin Kendir Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen‐Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, André Willasch, Gerd Horneff, Genevieve Llanora, Lynette Pei‐Chi Shek, Louis Yi Ann Chai, Sen Hee Tay, Hamid Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarström, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kıykım, Esra Yücel, Sevgi Keleş, Jacinta Bustamante, Laurent Abel, Jean‐Laurent Casanova, Stéphanie Boisson‐Dupuis
Abstract
Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.