Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths
Authors: Bastard Paul , Gervais Adrian , Le Voyer Tom , Rosain Jérémie , Philippot Quentin , Manry Jérémy , Michailidis Eleftherios , Hoffmann Hans-Heinrich , Eto Shohei , Garcia-Prat Marina , Bizien Lucy , Parra-Martínez Alba , Yang Rui , Haljasmägi Liis , Migaud Mélanie , Särekannu Karita , Maslovskaja Julia , de Prost Nicolas , Tandjaoui-Lambiotte Yacine , Luyt Charles-Edouard , Amador-Borrero Blanca , Gaudet Alexandre , Poissy Julien , Morel Pascal , Richard Pascale , Cognasse Fabrice , Troya Jesus , Trouillet-Assant Sophie , Belot Alexandre , Saker Kahina , Garçon Pierre , Rivière Jacques G. , Lagier Jean-Christophe , Gentile Stéphanie , Rosen Lindsey B. , Shaw Elana , Morio Tomohiro , Tanaka Junko , Dalmau David , Tharaux Pierre-Louis , Sene Damien , Stepanian Alain , Megarbane Bruno , Triantafyllia Vasiliki , Fekkar Arnaud , Heath James R. , Franco José Luis , Anaya Juan-Manuel , Solé-Violán Jordi , Imberti Luisa , Biondi Andrea , Bonfanti Paolo , Castagnoli Riccardo , Delmonte Ottavia M. , Zhang Yu , Snow Andrew L. , Holland Steven M. , Biggs Catherine M. , Moncada-Vélez Marcela , Arias Andrés Augusto , Lorenzo Lazaro , Boucherit Soraya , Coulibaly Boubacar , Anglicheau Dany , Planas Anna M. , Haerynck Filomeen , Duvlis Sotirija , Nussbaum Robert L. , Ozcelik Tayfun , Keles Sevgi , Bousfiha Ahmed A. , El Bakkouri Jalila , Ramirez-Santana Carolina , Paul Stéphane , Pan-Hammarström Qiang , Hammarström Lennart , Dupont Annabelle , Kurolap Alina , Metz Christine N. , Aiuti Alessandro , Casari Giorgio , Lampasona Vito , Ciceri Fabio , Barreiros Lucila A. , Dominguez-Garrido Elena , Vidigal Mateus , Zatz Mayana , van de Beek Diederik , Sahanic Sabina , Tancevski Ivan , Stepanovskyy Yurii , Boyarchuk Oksana , Nukui Yoko , Tsumura Miyuki , Vidaur Loreto , Tangye Stuart G. , Burrel Sonia , Duffy Darragh , Quintana-Murci Lluis , Klocperk Adam , Kann Nelli Y. , Shcherbina Anna , Lau Yu-Lung , Leung Daniel , Coulongeat Matthieu , Marlet Julien , Koning Rutger , Reyes Luis Felipe , Chauvineau-Grenier Angélique , Venet Fabienne , Monneret Guillaume , Nussenzweig Michel C. , Arrestier Romain , Boudhabhay Idris , Baris-Feldman Hagit , Hagin David , Wauters Joost , Meyts Isabelle , Dyer Adam H. , Kennelly Sean P. , Bourke Nollaig M. , Halwani Rabih , Sharif-Askari Narjes Saheb , Dorgham Karim , Sallette Jérome , Mehlal Sedkaoui Souad , AlKhater Suzan , Rigo-Bonnin Raúl , Morandeira Francisco , Roussel Lucie , Vinh Donald C. , Ostrowski Sisse Rye , Condino-Neto Antonio , Prando Carolina , Bondarenko Anastasiia , Spaan András N. , Gilardin Laurent , Fellay Jacques , Lyonnet Stanislas , Bilguvar Kaya , Lifton Richard P. , Mane Shrikant ,   HGID Lab,   COVID Clinicians,   COVID-STORM Clinicians,   NIAID Immune Response to COVID Group,   NH-COVAIR Study Group,   Danish CHGE,   Danish Blood Donor Study,   St. James’s Hospital SARS CoV2 Interest group,   French COVID Cohort Study Group,   Imagine COVID-Group,   The Milieu Intérieur Consortium,   CoV-Contact Cohort,   Amsterdam UMC Covid-19 Biobank Investigators,   COVID Human Genetic Effort,   CONSTANCES cohort,   3C-Dijon Study,   Cerba HealthCare,   Etablissement du Sang study group, Anderson Mark S. , Boisson Bertrand , Béziat Vivien , Zhang Shen-Ying , Andreakos Evangelos , Hermine Olivier , Pujol Aurora , Peterson Pärt , Mogensen Trine H. , Rowen Lee , Mond James , Debette Stéphanie , de Lamballerie Xavier , Duval Xavier , Mentré France , Zins Marie , Soler-Palacin Pere , Colobran Roger , Gorochov Guy , Solanich Xavier , Susen Sophie , Martinez-Picado Javier , Raoult Didier , Vasse Marc , Gregersen Peter K. , Piemonti Lorenzo , Rodríguez-Gallego Carlos , Notarangelo Luigi D. , Su Helen C. , Kisand Kai , Okada Satoshi , Puel Anne , Jouanguy Emmanuelle , Rice Charles M. , Tiberghien Pierre , Zhang Qian , Cobat Aurélie , Abel Laurent , Casanova Jean-Laurent 
Published: August 2021

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.