A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity
Fahd Al Qureshah, Jérémie Le Pen, Nicole A. de Weerd, Marcela Moncada‐Vélez, Marie Materna, Daniel Chieh-Ding Lin, Baptiste Milisavljevic, Fernanda Sales Luiz Vianna, Lucy Bizien, Lazaro Lorenzo, Marc Lecuit, Jean‐David Pommier, Sevgi Keleş, Tayfun Özçelık, Sigifredo Pedraza‐Sánchez, Nicolas de Prost, Loubna El Zein, Hassan Hammoud, Lisa F. P. Ng, Rabih Halwani, Narjes Saheb Sharif‐Askari, YL Lau, Anthony Raymond Tam, Neha Singh, Sagar Bhattad, Yackov Berkun, Wasun Chantratita, Raúl Aguilar-López, Mohammad Shahrooei, Laurent Abel, Alessandro Aiuti, Saleh Al‐Muhsen, Ana Bertha Alcántara-Garduño, Evangelos Andreakos, Andrés A. Arias, Hagit Baris Feldman, Paul Bastard, Alexandre Bolze, A. Borghesi, Ahmed Aziz Bousfiha, Petter Brodin, John Christodoulou, Aurélie Cobat, Roger Colobrán, Antonio Condino-Neto, Sotiriјa Duvlis, Xavier Duval, Munis Dündar, Soha Fakhreddine, Jacques Fellay, Carlos Flores, José Luis Barrera Franco, Guy Gorochov, Peter K. Gregersen, David Hagin, Rabih Halwani, María Teresa Herrera, Ivan Fan-Ngai Hung, Emmanuelle Jouanguy, YL Lau, Daniel Leung, Tom Le-voyer, Davood Mansouri, Jesús Mercado-García, Isabelle Meyts, Trine H. Mogensen, Lisa F. P. Ng, Antonio Novelli, Giuseppe Novelli, Satoshi Okada, Fırat Özçelik, Tayfun Özçelık, Rebeca Pérez de Diego, Jordi Pérez‐Tur, Graziano Pesole, Anne Puel, Laurent Rénia, Igor Resnick, Carlos Rodríguez‐Gallego, Manal Sbeity, Sahar Sedighzadeh, Mohammad Shahrooei, Pere Soler‐Palacín, András N. Spaan, Stuart G. Tangye, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian Thorball, Ibrahim Torktaz, Sophie Trouillet‐Assant, Stuart E. Turvey, K. M. Furkan Uddin, Fernanda Sales Luiz Vianna, Donald C. Vinh, Oscar Zabaleta-Martínez, Qian Zhang, Shen‐Ying Zhang, Jean‐Laurent Casanova, Chanreaksmey Eng, Kimrong Bun
Abstract
Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.