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 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 Soudée, 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, 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, Benedicte 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 () and Anne Puel ()
Additional contact information
Tom Le Voyer: Necker Branch, INSERM UMR1163
Audrey V. Parent: University of California, San Francisco
Xian Liu: University of California, San Francisco
Axel Cederholm: Uppsala University
Adrian Gervais: Necker Branch, INSERM UMR1163
Jérémie Rosain: Necker Branch, INSERM UMR1163
Tina Nguyen: Garvan Institute of Medical Research
Malena Perez Lorenzo: Necker Branch, INSERM UMR1163
Elze Rackaityte: University of California San Francisco
Darawan Rinchai: Rockefeller Branch, The Rockefeller University
Peng Zhang: Rockefeller Branch, The Rockefeller University
Lucy Bizien: Necker Branch, INSERM UMR1163
Gonca Hancioglu: Ondokuz Mayıs University Faculty of Medicine
Pascale Ghillani-Dalbin: AP-HP, Pitié-Salpêtrière Hospital
Jean-Luc Charuel: AP-HP, Pitié-Salpêtrière Hospital
Quentin Philippot: Necker Branch, INSERM UMR1163
Mame Sokhna Gueye: Necker Branch, INSERM UMR1163
Majistor Raj Luxman Maglorius Renkilaraj: Necker Branch, INSERM UMR1163
Masato Ogishi: Rockefeller Branch, The Rockefeller University
Camille Soudée: Necker Branch, INSERM UMR1163
Mélanie Migaud: Necker Branch, INSERM UMR1163
Flore Rozenberg: Cochin-Saint-Vincent de Paul Hospital, University of Paris
Mana Momenilandi: Necker Branch, INSERM UMR1163
Quentin Riller: Paris Cité University, Imagine Institute, INSERM UMR1163
Luisa Imberti: University of Brescia
Ottavia M. Delmonte: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gabriele Müller: Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center—University Hospital Freiburg, and Faculty of Medicine, Albert-Ludwigs-University
Baerbel Keller: University of Freiburg
Julio Orrego: University of Antioquia
William Alexander Franco Gallego: University of Antioquia
Tamar Rubin: University of Manitoba
Melike Emiroglu: Selcuk University
Nima Parvaneh: Tehran University of Medical Sciences
Daniel Eriksson: Uppsala University Hospital
Maribel Aranda-Guillen: Karolinska Institute
David I. Berrios: University of California, San Francisco
Linda Vong: Hospital for Sick Children and University of Toronto
Constance H. Katelaris: University of Western Sydney and Campbelltown Hospital
Peter Mustillo: Nationwide Children’s Hospital, The Ohio State University College of Medicine
Johannes Raedler: Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München
Jonathan Bohlen: Necker Branch, INSERM UMR1163
Jale Bengi Celik: Selcuk University Faculty of Medicine
Camila Astudillo: Hospital de Niños Roberto del Río
Sarah Winter: Paris Cité University, Imagine Institute, Inserm UMR1163
Catriona McLean: The Alfred Hospital
Aurélien Guffroy: Strasbourg University Hospital
Joseph L. DeRisi: University of California San Francisco
David Yu: University of California, San Francisco
Corey Miller: University of California, San Francisco
Yi Feng: Rockefeller Branch, The Rockefeller University
Audrey Guichard: Joint Unit Hospices Civils de Lyon—BioMérieux
Vivien Béziat: Necker Branch, INSERM UMR1163
Jacinta Bustamante: Necker Branch, INSERM UMR1163
Qiang Pan-Hammarström: Karolinska Institutet
Yu Zhang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Lindsey B. Rosen: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Steve M. Holland: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Marita Bosticardo: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Heather Kenney: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Riccardo Castagnoli: University of Pavia
Charlotte A. Slade: Walter and Eliza Hall Institute
Kaan Boztuğ: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Nizar Mahlaoui: Necker-Enfants University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP)
Sylvain Latour: Paris Cité University, Imagine Institute, Inserm UMR1163
Roshini S. Abraham: Nationwide Children’s Hospital
Vassilios Lougaris: University of Brescia ASST-Spedali Civili di Brescia
Fabian Hauck: Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München
Anna Sediva: Second Faculty of Medicine Charles University and Motol University Hospital
Faranaz Atschekzei: Hannover Medical School
Georgios Sogkas: Hannover Medical School
M. Cecilia Poli: Hospital de Niños Roberto del Río
Mary A. Slatter: Great North Children’s Hospital, Newcastle-upon-Tyne Hospital NHS Foundation Trust
Boaz Palterer: University of Florence
Michael D. Keller: Children’s National Medical Center
Alberto Pinzon-Charry: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Anna Sullivan: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Luke Droney: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Daniel Suan: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Melanie Wong: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Alisa Kane: UNSW Medicine & Health
Hannah Hu: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Cindy Ma: Garvan Institute of Medical Research
Hana Grombiříková: Masaryk University
Peter Ciznar: Comenius University Bratislava
Ilan Dalal: E. Wolfson Medical Center, Tel Aviv University
Nathalie Aladjidi: University Hospital, Plurithématique CIC (CICP), Centre d’Investigation Clinique (CIC) 1401
Miguel Hie: Pitié-Salpêtrière Hospital
Estibaliz Lazaro: Bordeaux Hospital University
Jose Franco: University of Antioquia
Sevgi Keles: Necmettin Erbakan University
Marion Malphettes: Saint Louis Hospital
Marlene Pasquet: Toulouse University Hospital
Maria Elena Maccari: Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center—University Hospital Freiburg, and Faculty of Medicine, Albert-Ludwigs-University
Andrea Meinhardt: University Children’s Hospital Gießen
Aydan Ikinciogullari: Ankara University School of Medicine
Mohammad Shahrooei: Dr. Shahrooei Lab
Fatih Celmeli: University of Medical Science, Antalya Education and Research Hospital
Patrick Frosk: University of Manitoba
Christopher C. Goodnow: Garvan Institute of Medical Research
Paul E. Gray: Clinical Immunogenomics Research Consortium Australasia (CIRCA)
Alexandre Belot: CNRS UMR 5308, ENS, UCBL
Hye Sun Kuehn: National Institutes of Health
Sergio D. Rosenzweig: National Institutes of Health
Makoto Miyara: AP-HP, Pitié-Salpêtrière Hospital
Francesco Licciardi: Università degli Studi di Torino
Amélie Servettaz: University Hospital Center
Vincent Barlogis: CHU Marseille, Hôpital La Timone, Service d’Hémato-oncologie Pédiatrique, Assistance Publique-Hôpitaux de Marseille
Guillaume Le Guenno: Centre Hospitalier Universitaire Estaing
Vera-Maria Herrmann: University of Leipzig Medical Center
Taco Kuijpers: Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam
Grégoire Ducoux: Edouard Herriot Hospital
Françoise Sarrot-Reynauld: Hôpital Michallon, CHU de Grenoble Alpes
Catharina Schuetz: Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden
Charlotte Cunningham-Rundles: Mount Sinai School of Medicine
Frédéric Rieux-Laucat: Paris Cité University, Imagine Institute, INSERM UMR1163
Stuart G. Tangye: Garvan Institute of Medical Research
Cristina Sobacchi: IRCCS Humanitas Research Hospital
Rainer Doffinger: Addenbrooke’s Hospital
Klaus Warnatz: University of Freiburg
Bodo Grimbacher: Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center—University Hospital Freiburg, and Faculty of Medicine, Albert-Ludwigs-University
Claire Fieschi: Saint Louis Hospital
Laureline Berteloot: Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children
Vanessa L. Bryant: Walter and Eliza Hall Institute
Sophie Trouillet Assant: Joint Unit Hospices Civils de Lyon—BioMérieux
Helen Su: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Benedicte Neven: Necker-Enfants Malades Hospital, AP-HP
Laurent Abel: Necker Branch, INSERM UMR1163
Qian Zhang: Necker Branch, INSERM UMR1163
Bertrand Boisson: Necker Branch, INSERM UMR1163
Aurélie Cobat: Necker Branch, INSERM UMR1163
Emmanuelle Jouanguy: Necker Branch, INSERM UMR1163
Olle Kampe: Karolinska University Hospital
Paul Bastard: Necker Branch, INSERM UMR1163
Chaim M. Roifman: Hospital for Sick Children and University of Toronto
Nils Landegren: Uppsala University
Luigi D. Notarangelo: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mark S. Anderson: University of California, San Francisco
Jean-Laurent Casanova: Necker Branch, INSERM UMR1163
Anne Puel: Necker Branch, INSERM UMR1163

Nature, 2023, vol. 623, issue 7988, 803-813

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 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.

Date: 2023
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DOI: 10.1038/s41586-023-06717-x

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