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.authorBastard, Paul
dc.contributor.authorGervais, Adrian
dc.contributor.authorLe Voyer, Tom
dc.contributor.authorRosain, Jeremie
dc.contributor.authorPhilippot, Quentin
dc.contributor.authorManry, Jeremy
dc.contributor.authorMichailidis, Eleftherios
dc.date.accessioned2024-02-23T14:26:09Z
dc.date.available2024-02-23T14:26:09Z
dc.date.issued2021
dc.departmentNEÜen_US
dc.description.abstractCirculating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega 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-alpha and/or IFN-omega (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-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega 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-beta 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.en_US
dc.description.sponsorshipHoward Hughes Medical Institute; Rockefeller University; St. Giles Foundation; National Institutes of Health (NIH) [R01AI088364]; National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Awards (CTSA) program [UL1 TR001866]; Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; Yale Center for Mendelian Genomics; GSP Coordinating Center - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]; Yale High Performance Computing Center [S10OD018521]; Fisher Center for Alzheimer's Research Foundation; Meyer Foundation; JPB Foundation; French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; French Foundation for Medical Research (FRM) [EQU201903007798]; FRM; ANR GENCOVID project [ANR-20-COVI-0003]; ANRS Nord-Sud [ANRS-COV05]; ANR GENVIR [ANR-20-CE93-003]; ANR AABIFNCOV [ANR-20-CO11-0001]; European Union [824110]; Square Foundation; Grandir-Fonds de solidarite pour l'Enfance; Fondation du Souffle; SCOR Corporate Foundation for Science; Institut National de la Sante et de la Recherche Medicale (INSERM); REACTing-INSERM; University of Paris; MD-PhD program of the Imagine Institute (Fondation Bettencourt Schueller); NIH [P01AI138398-S1, 2U19AI111825, R01AI091707-10S1]; George Mason University Fast Grant; G. Harold and Leila Y. Mathers Charitable Foundation; INSERM; REACTing consortium; French Ministry of Health [PHRC 20-0424]; French Ministry of Health; European Commission [RECOVER WP 6]; NIAID; NIDCR, NIH [ZIA AI001270, 1ZIAAI001265]; Agence Nationale de la Recherche [ANR-10-LABX-69-01]; Estonian Research Council [PRG117, PRG377]; Al Jalila Foundation Seed Grant, Dubai, UAE [AJF202019]; University of Sharjah, UAE [CoV19-0307]; National Health and Medical Research Council of Australia; UNSW Sydney COVID Rapid Response Initiative Grant; Regione Lombardia, Italy; Instituto de Salud Carlos III [COV20/0968, PI17/00660]; Biomedical Advanced Research and Development Authority [HHSO10201600031C]; Japan Agency for Medical Research and Development, AMED [JP20fk0108531]; ANR Flash COVID-19 program; SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs; Fondation pour la Recherche Medicale; Caisse Nationale d'Assurance Maladie des Travailleurs Salaries; Direction generale de la Sante; Mutuelle Generale de l'Education Nationale (MGEN); Institut de la Longevite; Conseils Regionaux of Aquitaine and Bourgogne; Fondation de France; Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques; University of Bordeaux Initiative of Excellence; National Cancer Institute, NIH [75N91019D00024, 75N91021F00001]; FWO Fundamental Clinical Mandate [1833317N]; European Regional Development Fund (ERDF); Instituto de Salud Carlos III (Spanish Ministry for Science and Innovation; AEI/FEDER, UE) [RTC-2017-6471-1, COV20_01333, COV20_01334]; Fundacion DISA [OA18/017, OA20/024]; Cabildo Insular de Tenerife [CGIEU0000219140]; Cabildo Insular de Tenerife (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19); MSFHR Health Professional-Investigator Award; European Union's Horizon 2020 research and innovation program (ATAC) [101003650]; Society for the Relief of Disabled Children; Croucher Foundation; Cooperation Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX) [806-2018]; Colciencias [713-2016, 111574455633]; Czech Health Research Council [NU20-05-00282, NV18-05-00162]; Ministry of Health, Czech Republic; Program Project COVID-19 OSR-UniSR; Ministero della Salute [COVID-2020-12371617]; CSL Behring Chair of Primary Immunodeficiencies; KU Leuven C1 grant [C16/18/007]; VIB-GC PID grant; FWO [G0C8517N, G0B5120N, G0E8420N]; Jeffrey Modell Foundation; European Union's Horizon 2020 research and innovation programme [948959]; Hellenic Foundation for Research and Innovation (INTERFLU) [1574]; Sao Paulo Research Foundation (FAPESP) [2020/09702-1]; JBS SA [69004]; Meath Foundation; FRM [EA20170638020]; European Research Council (ERC) [948959] Funding Source: European Research Council (ERC); Agence Nationale de la Recherche (ANR) [ANR-20-COVI-0003] Funding Source: Agence Nationale de la Recherche (ANR)en_US
dc.description.sponsorshipS 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 Awards (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 solidarite pour l'Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM; and the University of Paris. P.B. was supported by the FRM (EA20170638020). P.B., J.R., and T.L.V. 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 L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (reference ANR-10-LABX-69-01). K.K.'s group was supported by the Estonian Research Council grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (AJF202019), Dubai, UAE, and a COVID-19 research grant (CoV19-0307) from the University of Sharjah, UAE. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a UNSW Sydney COVID Rapid Response Initiative Grant. L.I. reported funding from Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidita). L.I. and G. L. Marseglia reported funding from Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidita). This research was partially supported by the Instituto de Salud Carlos III (COV20/0968). J.R.H. reported funding from Biomedical Advanced Research and Development Authority HHSO10201600031C. S.O.; reports funding Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development, AMED (grant number JP20fk0108531). G.G. 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 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d'Assurance Maladie des Travailleurs Salaries, Direction generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN), Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques. S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. 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 for Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE), Fundacion DISA (OA18/017 and OA20/024), and Cabildo Insular de Tenerife (CGIEU0000219140 and Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19). C.M.B. is supported by a MSFHR Health Professional-Investigator Award. P.Q.H. and L.H. were funded by the European Union's Horizon 2020 research and innovation program (ATAC, 101003650). Work at Y.-L.L.'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. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Cooperation 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 FoundationFlanders 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 frants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. 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.Vi received funding from the Sao Paulo Research Foundation (FAPESP) (grant number 2020/09702-1) and JBS SA (grant number 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.en_US
dc.identifier.doi10.1126/sciimmunol.abl4340
dc.identifier.issn2470-9468
dc.identifier.issue62en_US
dc.identifier.pmid34413139en_US
dc.identifier.scopus2-s2.0-85113517428en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1126/sciimmunol.abl4340
dc.identifier.urihttps://hdl.handle.net/20.500.12452/14070
dc.identifier.volume6en_US
dc.identifier.wosWOS:000695969700002en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Assoc Advancement Scienceen_US
dc.relation.ispartofScience Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleAutoantibodies neutralizing type I IFNs are present in ?4% of uninfected individuals over 70 years old and account for ?20% of COVID-19 deathsen_US
dc.typeArticleen_US

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