Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years old and account for ~ 20% of COVID-19 deaths

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• dc.contributor.author Bastard, Paul
• dc.contributor.author Gut, Marta
• dc.contributor.author Casanova, Jean-Laurent
• dc.date.accessioned 2022-09-28T07:15:43Z
• dc.date.available 2022-09-28T07:15:43Z
• dc.date.issued 2021
• dc.description.abstract Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 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 1,124 deceased patients (aged 20 days-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 subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -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 subjects 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.
• dc.description.sponsorship The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation programme under grant agreement No 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM) and the University of Paris. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020). PB, JR and TLV were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the NIAID and NIDCR, NIH (grants ZIA AI001270 to LDN and 1ZIAAI001265 to HCS). This program is supported by the Agence Nationale de la Recherche, reference ANR-10-LABX-69-01. K. Kisand’s group was supported by the Estonian Research Council grant PRG117 and PRG377. R. Halwani is supported by a grant from Al Jalila Foundation Seed Grant (AJF202019), Dubai, UAE, and a COVID-19 research grant (COV19-0307) from University of Sharjah, UAE. L. Imberti reported funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). L. Imberti and G.L. Marseglia reported funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (COV20/0968). J. R. Heath reported funding from Biomedical Advanced Research and Development Authority HHSO10201600031C. S. Okada reports funding Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and development, AMED (Grant Number: JP20fk0108531). G. Gorochov was supported by ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University ICOViD programs. The Three-City (3C) Study was conducted under a partnership agreement among the INSERM, the Victor Segalen–Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme “Cohortes et collections de données biologiques”. S. Debette was supported by the University of Bordeaux Initiative of Excellence. P. K. Gregersen reports funding from the National Cancer Institute, NIH, under Contract No. 75N91019D00024, Task Order No. 75N91021F00001. J.W. is supported by an FWO Fundamental Clinical Mandate (1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF). C.R.G. and colleagues of the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334, Spanish Ministry of Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE); from Grupo DISA (OA18/017 and OA20/024); and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). CMB is supported by a MSFHR Health Professional-Investigator Award. PQH and LH were funded by the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650). Work at Y.-L. Lau’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. Leung in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX (806-2018) and Colciencias contract 713-2016 (code 111574455633). A.K. was in part supported by grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation – Flanders, and is supported by the CSL Behring Chair of Primary Immunodeficiencies, by the KU Leuven C1 Grant C16/18/007, by a VIB GC PID Grant, by the FWO Grants G0C8517N, G0B5120N and G0E8420N and by the Jeffrey Modell Foundation. IM has received funding under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 948959)”. E.A. received funding from the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). M.V. received funding from the Sao Paulo Research Foundation (FAPESP) [grant number: 2020/09702-1] and JBS S.A [grant number 69004]. The NH-COVAIR was supported by a grant from the Meath Foundation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, et al. Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years old and account for ~ 20% of COVID-19 deaths. Sci Immunol. 2021 Aug 19; 6(62): eabl4340. DOI: 10.1126/sciimmunol.abl4340
• dc.identifier.doi http://dx.doi.org/10.1126/sciimmunol.abl4340
• dc.identifier.issn 2470-9468
• dc.identifier.uri http://hdl.handle.net/10230/54189
• dc.language.iso eng
• dc.publisher American Association for the Advancement of Science (AAAS)
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/824110
• dc.rights This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, permitting unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; authorization from the rights holder before using such material. For patients enrolled in the Italian cohort, patient specimens may be available from Monza, subject to approval by their local IRB, through an MTA.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other COVID-19 (Malaltia)
• dc.subject.other Immunoglobulines
• dc.subject.other Immunologia
• dc.subject.other Interferó
• dc.title Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years old and account for ~ 20% of COVID-19 deaths
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion