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dc.contributor.authorBastard, Paul-
dc.contributor.authorRosen, Lindsey B.-
dc.contributor.authorZhang, Qian-
dc.contributor.authorMichailidis, Eleftherios-
dc.contributor.authorHoffmann, Hans-Heinrich-
dc.contributor.authorZhang, Yu-
dc.contributor.authorDorgham, Karim-
dc.contributor.authorPhilippo, Quentin-
dc.contributor.authorRosain, Jérémie-
dc.contributor.authorBéziat, Vivien-
dc.contributor.authorNotarangelo, Luigi D.-
dc.contributor.authorAbel, Laurent-
dc.contributor.authorSu, Helen C.-
dc.contributor.authorCasanova, Jean-Laurent-
dc.contributor.authorБондаренко, А.В.-
dc.contributor.authorСтепановський, Ю.С.-
dc.date.accessioned2020-12-31T09:57:56Z-
dc.date.available2020-12-31T09:57:56Z-
dc.date.issued2020-
dc.identifier.citationPaul Bastard, B. Rosen et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19//Science 23 Oct 2020: Vol. 370, Issue 6515, eabd4585 DOI: 10.1126/science.abd4585uk_UK
dc.identifier.urihttp://lib.inmeds.com.ua:8080/jspui/handle/lib/2880-
dc.description.abstractINTRODUCTION Interindividual clinical variability is vast in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from silent infection to rapid death. Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified—being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms of morbidity and mortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial. RATIONALE B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist, in which neutralizing autoantibodies (auto-Abs) against interferon-γ (IFN-γ) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes that encode the corresponding cytokines or receptors. Human inborn errors of type I IFNs underlie severe viral respiratory diseases. Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying noninfectious conditions, have not been unequivocally shown to underlie severe viral infections. While searching for inborn errors of type I IFN immunity in patients with life-threatening COVID-19 pneumonia, we also tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19. We searched for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID-19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARS-CoV-2, and 1227 healthy controls from whom samples were collected before the COVID-19 pandemic. RESULTS At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G (IgG) auto-Abs against IFN-ω (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three individual type I IFNs. These auto-Abs neutralize high concentrations of the corresponding type I IFNs, including their ability to block SARS-CoV-2 infection in vitro. Moreover, all of the patients tested had low or undetectable serum IFN-α levels during acute disease. These auto-Abs were present before infection in the patients tested and were absent from 663 individuals with asymptomatic or mild SARS-CoV-2 infection (P < 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals (P < 10−16) before the pandemic. The patients with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. Notably, 95 of the 101 patients with auto-Abs were men (94%). CONCLUSION A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. These findings provide a first explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β).uk_UK
dc.description.sponsorshipHoward 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, the 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 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 (ANRS-COV05), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Institut Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. Samples from San Raffaele Hospital were obtained through the Covid-BioB project and by healthcare personnel of San Raffaele Hospital, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) clinical laboratory and clinical research unit, funded by the Program Project COVID-19 OSR-UniSR and Fondazione Telethon. 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)uk_UK
dc.language.isoenuk_UK
dc.publisherAmerican Association for the Advancement of Scienceuk_UK
dc.relation.ispartofseriesScience;Vol. 370, Issue 6515-
dc.subjectCOVID-19, SARS-CoV2uk_UK
dc.subjectpneumoniauk_UK
dc.subjectinterferonuk_UK
dc.subjectimmunityuk_UK
dc.subjectautoantibodiesuk_UK
dc.titleAutoantibodies against type I IFNs in patients with life-threatening COVID-19uk_UK
dc.typeArticleuk_UK
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