Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
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 Rubin, Melike Emiroğlu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda‐Guillén, David I. Berrios, Linda Vong, Constance H. 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 A. Arias, Hagit Baris Feldman, Paul Bastard, Анастасія Бондаренко, A. Borghesi, Ahmed Aziz Bousfiha, Petter Brodin, Yenan T. Bryceson, Giorgio Casari, John Christodoulou, Roger Colobrán, Antonio Condino-Neto, Jacques Fellay, Carlos Flores, José Luis Franco, Filomeen Haerynck, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Yuval Itan, Elżbieta Kaja, Kai Kisand, Cheng‐Lung Ku, Yun Ling, YL Lau, Davood Mansouri, Isabelle Meyts, Joshua D. Milner, Trine H. 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
Abstract
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 pneumonia 3 . 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, p52 LOF /IκBδ GOF ). 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, p52 LOF /IκBδ LOF ) or gain-of-function of p52 (hereafter, p52 GOF /IκBδ LOF ). 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 alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.