Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency

作者：Tom Le Voyer, Audrey V. Parent, Xian Liu, Axel Cederholm, Adrian Gervais, Jérémie Rosain, Tina Nguyen, Malena Pérez Lorenzo, Elze Rackaityte, Darawan Rinchai, Peng Zhang, Lucy Bizien, Gonca Hancıoğlu, Pascale Ghillani‐Dalbin, Jean‐Luc Charuel, Quentin Philippot, M Guèye, Majistor Raj Luxman Maglorius Renkilaraj, Masato Ogishi, Camille Soudée, Mélanie Migaud, Flore Rozenberg, Mana Momenilandi, Quentin Riller, Luisa Imberti, Ottavia M. Delmonte, Gabriele Müller, Baerbel Keller, Julio César Orrego, William Alexander Franco Gallego, Tamar S. Rubin, Melike Emiroğlu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda‐Guillén, David I. Berrios, Linda Vong, Constance Helen Katelaris, Peter Mustillo, Johannes Raedler, Jonathan Bohlen, Jale Bengi Çelik, Camila Astudillo, Sarah Winter, Stéphanie Boisson‐Dupuis, Éric Oksenhendler, Satoshi Okada, Oana Caluseriu, Mathilde Valeria Ursini, Éric Ballot, Geoffroy Lafarge, Tomáš Freiberger, Carlos A. Arango-Franco, Romain Lévy, COVID Human Genetic Effort, Alessandro Aiuti, Saleh Al‐Muhsen, Fahd Al‐Mulla, Evangelos Andreakos, Andrés Augusto Arias, Hagit Baris Feldman, Paul Bastard, Anastasiia V. Bondarenko, Alessandro Borghesi, Ahmed Aziz Bousfiha, Petter Brodin, Yenan Troi Bryceson, Giorgio Casari, John Christodoulou, Roger Colobrán, Antonio Condino-Neto, Jacques Fellay, Carlos A. Flores, José Luis Franco, Filomeen Haerynck, Rabih Halwani, Lennart L G Hammarström, James R. Heath, Elena W.Y. Hsieh, Yuval Itan, Elżbieta Kaja, Kai E. Kisand, Cheng‐Lung Ku, Yun Ling, YL Lau, Davood Mansouri, Isabelle Meyts, Joshua D. Milner, Trine Hyrup Mogensen, Antonio Novelli, Giuseppe Novelli, Keisuke Okamoto, Tayfun Özçelık, Rebeca Pérez de Diego, Jordi Pérez‐Tur, David S. Perlin, Carolina Prando, Aurora Pujol, Lluís Quintana‐Murci, Laurent Rénia, Igor B. Resnick, Carlos Rodríguez‐Gallego, Vanessa Sancho‐Shimizu, Anna Šedivá, Mikko R. J. Seppänen, Mohammed Shahrooei, Anna Yu. Shcherbina, Pere Soler‐Palacín, Graziano Pesole, András N. Spaan, Helen C. Su, Ivan Tancevski, Ahmad N. Abou Tayoun, Ali Amara, Guy Gorochov, Şehime Gülsün Temel, Christian Wandell Thorball, Pierre Tiberghien, Sophie Trouillet‐Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed Uddin, Diederik van de Beek, Mateus Vidigal, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Shen‐Ying Zhang, Lisa F. P. Ng, COVID Human Genetic Effort, Catriona McLean, Aurélien Guffroy, Joseph L. DeRisi, David Yu, Corey N. Miller, Yi Feng, Audrey Guichard, Vivien Béziat, Jacinta C. Bustamante, Qiang Pan‐Hammarström, Yu Zhang, Lindsey B. Rosen, Steven M. Holland, Marita Bosticardo, Heather Kenney, Riccardo Castagnoli, Charlotte A. Slade, Kaan Boztuǧ, Nizar Mahlaoui, Sylvain Latour, Roshini Sarah Abraham, Vassilios Lougaris, Fabian H. Hauck, Anna Šedivá, Faranaz Atschekzei, Georgios Sogkas, M. Cecilia Poli, Mary Anne Slatter, Boaz Palterer, Michael Daniel Keller, Alberto Pinzón‐Charry, Anna Sullivan, Luke Droney, Dan Suan, Melanie Wong, Alisa Kane, Hannah F. Hu, Cindy S. Ma, Hana Grombiříková, Peter Čižnár, Ilan Dalal, Nathalie Aladjidi, Miguel Hie, Estibaliz Lazaro, José Luis Franco, Sevgi Keleş, Marion Malphettes, Marlène Pasquet, Maria Elena Maccari, Andrea Meinhardt, Aydan İkincioğulları, Mohammad Shahrooei, Fatih Çelmeli, Patrick Frosk, Christopher Carl Goodnow, Paul Edgar Gray, Alexandre Bélot, Hye Sun Kuehn, Sergio D. Rosenzweig, Makoto Miyara, Francesco Licciardi, Amélie Servettaz, Vincent Barlogis, G. Le Guenno, Vera-Maria Herrmann, Taco Willem Kuijpers, Grégoire Ducoux, F. Sarrot-Reynauld, Catharina Schuetz, Charlotte Cunningham‐Rundles, Frédéric Rieux‐Laucat, Stuart G. Tangye, Cristina Sobacchi, Rainer Döffinger, Klaus Warnatz, Bodo Grimbacher, Claire Fieschi, Laureline Berteloot, Vanessa L. Bryant, Sophie Trouillet‐Assant, Helen C. Su, Bénédicte Neven, Laurent Abel, Qian Zhang, Bertrand Boisson, Aurélie Cobat, Emmanuelle Jouanguy, Olle Kämpe, Paul Bastard, Chaim M. Roifman, Nils Landegren, Luigi Daniele Notarangelo, Mark Stuart Anderson, Jean‐Laurent Casanova, Anne Puel · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06717-x · 被引用次数：110 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Immune Response and Inflammation

Abstract Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alte...