Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
Authors: Le Voyer Tom , Parent Audrey V. , Liu Xian , Cederholm Axel , Gervais Adrian , Rosain Jérémie , Nguyen Tina , Perez Lorenzo Malena , Rackaityte Elze , Rinchai Darawan , Zhang Peng , Bizien Lucy , Hancioglu Gonca , Ghillani-Dalbin Pascale , Charuel Jean-Luc , Philippot Quentin , Gueye Mame Sokhna , Maglorius Renkilaraj Majistor Raj Luxman , Ogishi Masato , Soudée Camille , Migaud Mélanie , Rozenberg Flore , Momenilandi Mana , Riller Quentin , Imberti Luisa , Delmonte Ottavia M. , Müller Gabriele , Keller Baerbel , Orrego Julio , Franco Gallego William Alexander , Rubin Tamar , Emiroglu Melike , Parvaneh Nima , Eriksson Daniel , Aranda-Guillen Maribel , Berrios David I. , Vong Linda , Katelaris Constance H. , Mustillo Peter , Raedler Johannes , Bohlen Jonathan , Bengi Celik Jale , Astudillo Camila , Winter Sarah ,   NF-κB Consortium, Boisson-Dupuis Stéphanie , Oksenhendler Eric , Okada Satoshi , Caluseriu Oana , Ursini Mathilde Valeria , Ballot Eric , Lafarge Geoffroy , Freiberger Tomas , Arango-Franco Carlos A. , Levy Romain ,   COVID Human Genetic Effort, Aiuti Alessandro , Al-Muhsen Saleh , Al-Mulla Fahd , Andreakos Evangelos , Arias Andrés A. , Feldman Hagit Baris , Bastard Paul , Bondarenko Anastasia , Borghesi Alessandro , Bousfiha Ahmed A. , Brodin Petter , Bryceson Yenan , Casari Giorgio , Christodoulou John , Colobran Roger , Condino-Neto Antonio , Fellay Jacques , Flores Carlos , Franco José Luis , Haerynck Filomeen , Halwani Rabih , Hammarström Lennart , Heath James R. , Hsieh Elena W. Y. , Itan Yuval , Kaja Elżbieta , Kisand Kai , Ku Cheng-Lung , Ling Yun , Lau Yu-Lung , Mansouri Davood , Meyts Isabelle , Milner Joshua D. , Mogensen Trine H. , Novelli Antonio , Novelli Giuseppe , Okamoto Keisuke , Ozcelik Tayfun , de Diego Rebeca Perez , Perez-Tur Jordi , Perlin David S. , Prando Carolina , Pujol Aurora , Quintana-Murci Lluis , Renia Laurent , Resnick Igor , Rodríguez-Gallego Carlos , Sancho-Shimizu Vanessa , Sediva Anna , Seppänen Mikko R. J. , Shahrooei Mohammed , Shcherbina Anna , Palacín Pere Soler , Pesole Graziano , Spaan András N. , Su Helen C. , Tancevski Ivan , Tayoun Ahmad Abou , Amara Ali , Gorochov Guy , Temel Şehime Gülsün , Thorball Christian , Tiberghien Pierre , Trouillet-Assant Sophie , Turvey Stuart , Uddin K. M. Furkan , Uddin Mohammed J. , van de Beek Diederik , Vidigal Mateus , Vinh Donald C. , von Bernuth Horst , Wauters Joost , Zatz Mayana , Zhang Shen-Ying , Ng Lisa F. P. ,   COVID Human Genetic Effort, McLean Catriona , Guffroy Aurélien , DeRisi Joseph L. , Yu David , Miller Corey , Feng Yi , Guichard Audrey , Béziat Vivien , Bustamante Jacinta , Pan-Hammarström Qiang , Zhang Yu , Rosen Lindsey B. , Holland Steve M. , Bosticardo Marita , Kenney Heather , Castagnoli Riccardo , Slade Charlotte A. , Boztuğ Kaan , Mahlaoui Nizar , Latour Sylvain , Abraham Roshini S. , Lougaris Vassilios , Hauck Fabian , Sediva Anna , Atschekzei Faranaz , Sogkas Georgios , Poli M. Cecilia , Slatter Mary A. , Palterer Boaz , Keller Michael D. , Pinzon-Charry Alberto , Sullivan Anna , Droney Luke , Suan Daniel , Wong Melanie , Kane Alisa , Hu Hannah , Ma Cindy , Grombiříková Hana , Ciznar Peter , Dalal Ilan , Aladjidi Nathalie , Hie Miguel , Lazaro Estibaliz , Franco Jose , Keles Sevgi , Malphettes Marion , Pasquet Marlene , Maccari Maria Elena , Meinhardt Andrea , Ikinciogullari Aydan , Shahrooei Mohammad , Celmeli Fatih , Frosk Patrick , Goodnow Christopher C. , Gray Paul E. , Belot Alexandre , Kuehn Hye Sun , Rosenzweig Sergio D. , Miyara Makoto , Licciardi Francesco , Servettaz Amélie , Barlogis Vincent , Le Guenno Guillaume , Herrmann Vera-Maria , Kuijpers Taco , Ducoux Grégoire , Sarrot-Reynauld Françoise , Schuetz Catharina , Cunningham-Rundles Charlotte , Rieux-Laucat Frédéric , Tangye Stuart G. , Sobacchi Cristina , Doffinger Rainer , Warnatz Klaus , Grimbacher Bodo , Fieschi Claire , Berteloot Laureline , Bryant Vanessa L. , Trouillet Assant Sophie , Su Helen , Neven Benedicte , Abel Laurent , Zhang Qian , Boisson Bertrand , Cobat Aurélie , Jouanguy Emmanuelle , Kampe Olle , Bastard Paul , Roifman Chaim M. , Landegren Nils , Notarangelo Luigi D. , Anderson Mark S. , Casanova Jean-Laurent , Puel Anne 
Published: November 2023

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.