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

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

Nature

10.1038/s41586-023-06717-x

https://doi.org/10.1038/s41586-023-06717-x

Tom Le Voyer, Audrey V. Parent, Xian Liu, Axel Cederholm, Adrian Gervais, Jérémie Rosain, Tina Nguyen, Malena Perez Lorenzo, Elze Rackaityte, Darawan Rinchai, Peng Zhang, Lucy Bizien, Gonca Hancioglu, Pascale Ghillani-Dalbin, Jean-Luc Charuel, Quentin Philippot, Mame Sokhna Gueye, Majistor Raj Luxman Maglorius Renkilaraj, Masato Ogishi, Camille Soudee, Mélanie Migaud, Flore Rozenberg, Mana Momenilandi, Quentin Riller, Luisa Imberti, Ottavia M. Delmonte, Gabriele Müller, Baerbel Keller, Julio Orrego, William Alexander Franco Gallego, Tamar Rubin, Melike Emiroglu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda-Guillen, David I. Berrios, Linda Vong, Constance H. Katelaris, Peter Mustillo, Johannes Raedler, Jonathan Bohlen, Jale Bengi Celik, Camila Astudillo, Sarah Winter, , Stéphanie Boisson-Dupuis, Eric Oksenhendler, Satoshi Okada, Oana Caluseriu, Mathilde Valeria Ursini, Eric Ballot, Geoffroy Lafarge, Tomas Freiberger, Carlos A. Arango-Franco, Romain Lévy, , Alessandro Aiuti, Saleh Al-Muhsen, Fahd Al-Mulla, Evangelos Andreakos, Andrés A. Arias, Hagit Baris Feldman, Paul Bastard, Anastasia Bondarenko, Alessandro Borghesi, Ahmed A. Bousfiha, Petter Brodin, Yenan Bryceson, Giorgio Casari, John Christodoulou, Roger Colobran, 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, Yu-Lung Lau, Davood Mansouri, Isabelle Meyts, Joshua D. Milner, Trine H. Mogensen, Antonio Novelli, Giuseppe Novelli, Keisuke Okamoto, Tayfun Ozcelik, Rebeca Perez de Diego, Jordi Perez-Tur, David S. Perlin, Carolina Prando, Aurora Pujol, Lluis Quintana-Murci, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Vanessa Sancho-Shimizu, Anna Sediva, Mikko R. J. Seppänen, Mohammed Shahrooei, Anna Shcherbina, Pere Soler Palacín, Graziano Pesole, András N. Spaan, Helen C. Su, Ivan Tancevski, Ahmad Abou Tayoun, Ali Amara, Guy Gorochov, Şehime Gülsün Temel, Christian Thorball, Pierre Tiberghien, Sophie Trouillet-Assant, Stuart Turvey, K. M. Furkan Uddin, Mohammed J. Uddin, Diederik van de Beek, Mateus Vidigal, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Shen-Ying Zhang, Lisa F. P. Ng, , Catriona McLean, Aurélien Guffroy, Joseph L. DeRisi, David Yu, Corey Miller, Yi Feng, Audrey Guichard, Vivien Béziat, Jacinta Bustamante, Qiang Pan-Hammarström, Yu Zhang, Lindsey B. Rosen, Steve M. Holland, Marita Bosticardo, Heather Kenney, Riccardo Castagnoli, Charlotte A. Slade, Kaan Boztuğ, Nizar Mahlaoui, Sylvain Latour, Roshini S. Abraham, Vassilios Lougaris, Fabian Hauck, Anna Sediva, Faranaz Atschekzei, Georgios Sogkas, M. Cecilia Poli, Mary A. Slatter, Boaz Palterer, Michael D. Keller, Alberto Pinzon-Charry, Anna Sullivan, Luke Droney, Daniel Suan, Melanie Wong, Alisa Kane, Hannah Hu, Cindy Ma, Hana Grombiříková, Peter Ciznar, Ilan Dalal, Nathalie Aladjidi, Miguel Hie, Estibaliz Lazaro, Jose Franco, Sevgi Keles, Marion Malphettes, Marlene Pasquet, Maria Elena Maccari, Andrea Meinhardt, Aydan Ikinciogullari, Mohammad Shahrooei, Fatih Celmeli, Patrick Frosk, Christopher C. Goodnow, Paul E. Gray, Alexandre Belot, Hye Sun Kuehn, Sergio D. Rosenzweig, Makoto Miyara, Francesco Licciardi, Amélie Servettaz, Vincent Barlogis, Guillaume Le Guenno, Vera-Maria Herrmann, Taco Kuijpers, Grégoire Ducoux, Françoise Sarrot-Reynauld, Catharina Schuetz, Charlotte Cunningham-Rundles, Frédéric Rieux-Laucat, Stuart G. Tangye, Cristina Sobacchi, Rainer Doffinger, Klaus Warnatz, Bodo Grimbacher, Claire Fieschi, Laureline Berteloot, Vanessa L. Bryant, Sophie Trouillet Assant, Helen Su, Bénédicte Neven, Laurent Abel, Qian Zhang, Bertrand Boisson, Aurélie Cobat, Emmanuelle Jouanguy, Olle Kampe, Paul Bastard, Chaim M. Roifman, Nils Landegren, Luigi D. Notarangelo, Mark S. Anderson, Jean-Laurent Casanova, Anne Puel

08 November 2023

Le Voyer, T., Parent, A. V., Liu, X., Cederholm, A., Gervais, A., Rosain, J., Nguyen, T., Perez Lorenzo, M., Rackaityte, E., Rinchai, D., Zhang, P., Bizien, L., Hancioglu, G., Ghillani-Dalbin, P., Charuel, J.-L., Philippot, Q., Gueye, M. S., Maglorius Renkilaraj, M. R. L., Ogishi, M., … Puel, A. (2023). Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency. Nature, 623(7988), 803–813. https://doi.org/10.1038/s41586-023-06717-x

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 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.

Attribution 4.0 International (CC BY 4.0)

There was no specific funding for the research done

https://oar.a-star.edu.sg/communities-collections/articles/22607

0028-0836
1476-4687

A*STAR Infectious Disease Labs

https://doi.org/10.1038/s41586-023-06717-x