Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Paul Bastard; Lindsey B Rosen; Qian Zhang; Eleftherios Michailidis; Hans-Heinrich Hoffmann; Yu Zhang; Karim Dorgham; Quentin Philippot; Jérémie Rosain; Vivien Béziat; Jérémy Manry; Elana Shaw; Liis Haljasmägi; Pärt Peterson; Lazaro Lorenzo; Lucy Bizien; Sophie Trouillet-Assant; Kerry Dobbs; Adriana Almeida de Jesus; Alexandre Belot; Anne Kallaste; Emilie Catherinot; Yacine Tandjaoui-Lambiotte; Jeremie Le Pen; Gaspard Kerner; Benedetta Bigio; Yoann Seeleuthner; Rui Yang; Alexandre Bolze; András N Spaan; Ottavia M Delmonte; Michael S Abers; Alessandro Aiuti; Giorgio Casari; Vito Lampasona; Lorenzo Piemonti; Fabio Ciceri; Kaya Bilguvar; Richard P Lifton; Marc Vasse; David M Smadja; Mélanie Migaud; Jérome Hadjadj; Benjamin Terrier; Darragh Duffy; Lluis Quintana-Murci; Diederik van de Beek; Lucie Roussel; Donald C Vinh; Stuart G Tangye; P. Bruijning-Verhagen

doi:10.1126/science.abd4585

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Paul Bastard^*
, Lindsey B Rosen
, Qian Zhang
, Eleftherios Michailidis
, Hans-Heinrich Hoffmann
, Yu Zhang
, Karim Dorgham
, Quentin Philippot
, Jérémie Rosain
, Vivien Béziat
, Jérémy Manry
, Elana Shaw
, Liis Haljasmägi
, Pärt Peterson
, Lazaro Lorenzo
, Lucy Bizien
, Sophie Trouillet-Assant
, Kerry Dobbs
, Adriana Almeida de Jesus
, Alexandre Belot

Anne Kallaste, Emilie Catherinot, Yacine Tandjaoui-Lambiotte, Jeremie Le Pen, Gaspard Kerner, Benedetta Bigio, Yoann Seeleuthner, Rui Yang, Alexandre Bolze, András N Spaan, Ottavia M Delmonte, Michael S Abers, Alessandro Aiuti, Giorgio Casari, Vito Lampasona, Lorenzo Piemonti, Fabio Ciceri, Kaya Bilguvar, Richard P Lifton, Marc Vasse, David M Smadja, Mélanie Migaud, Jérome Hadjadj, Benjamin Terrier, Darragh Duffy, Lluis Quintana-Murci, Diederik van de Beek, Lucie Roussel, Donald C Vinh, Stuart G Tangye, , P. Bruijning-Verhagen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. 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.

Original language	English
Article number	eabd4585
Journal	Science
Volume	370
Issue number	6515
DOIs	https://doi.org/10.1126/science.abd4585
Publication status	Published - 23 Oct 2020

Keywords

Adult
Aged
Aged, 80 and over
Antibodies, Neutralizing/blood
Asymptomatic Infections
Autoantibodies/blood
Betacoronavirus
COVID-19
Case-Control Studies
Coronavirus Infections/immunology
Critical Illness
Female
Humans
Immunoglobulin G/blood
Interferon Type I/immunology
Interferon alpha-2/immunology
Male
Middle Aged
Pandemics
Pneumonia, Viral/immunology
SARS-CoV-2

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10.1126/science.abd4585Licence: CC BY

science.abd4585Final published version, 2.44 MBLicence: CC BY

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Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H.-H., Zhang, Y., Dorgham, K., Philippot, Q., Rosain, J., Béziat, V., Manry, J., Shaw, E., Haljasmägi, L., Peterson, P., Lorenzo, L., Bizien, L., Trouillet-Assant, S., Dobbs, K., de Jesus, A. A., ... Bruijning-Verhagen, P. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 370(6515), Article eabd4585. https://doi.org/10.1126/science.abd4585

@article{96aad4332dc3490889c6a616751f197c,

title = "Autoantibodies against type I IFNs in patients with life-threatening COVID-19",

abstract = "Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. 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.",

keywords = "Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing/blood, Asymptomatic Infections, Autoantibodies/blood, Betacoronavirus, COVID-19, Case-Control Studies, Coronavirus Infections/immunology, Critical Illness, Female, Humans, Immunoglobulin G/blood, Interferon Type I/immunology, Interferon alpha-2/immunology, Male, Middle Aged, Pandemics, Pneumonia, Viral/immunology, SARS-CoV-2",

author = "Paul Bastard and Rosen, \{Lindsey B\} and Qian Zhang and Eleftherios Michailidis and Hans-Heinrich Hoffmann and Yu Zhang and Karim Dorgham and Quentin Philippot and J{\'e}r{\'e}mie Rosain and Vivien B{\'e}ziat and J{\'e}r{\'e}my Manry and Elana Shaw and Liis Haljasm{\"a}gi and P{\"a}rt Peterson and Lazaro Lorenzo and Lucy Bizien and Sophie Trouillet-Assant and Kerry Dobbs and \{de Jesus\}, \{Adriana Almeida\} and Alexandre Belot and Anne Kallaste and Emilie Catherinot and Yacine Tandjaoui-Lambiotte and \{Le Pen\}, Jeremie and Gaspard Kerner and Benedetta Bigio and Yoann Seeleuthner and Rui Yang and Alexandre Bolze and Spaan, \{Andr{\'a}s N\} and Delmonte, \{Ottavia M\} and Abers, \{Michael S\} and Alessandro Aiuti and Giorgio Casari and Vito Lampasona and Lorenzo Piemonti and Fabio Ciceri and Kaya Bilguvar and Lifton, \{Richard P\} and Marc Vasse and Smadja, \{David M\} and M{\'e}lanie Migaud and J{\'e}rome Hadjadj and Benjamin Terrier and Darragh Duffy and Lluis Quintana-Murci and \{van de Beek\}, Diederik and Lucie Roussel and Vinh, \{Donald C\} and Tangye, \{Stuart G\} and P. Bruijning-Verhagen",

note = "Funding Information: We thank the patients, their families, and healthy donors for placing their trust in us. We thank the French Incontinentia pigmenti association for their help and support. We thank Y. Nemirovskaya, D. Papandrea, M. Woollett, D. Liu, C. Rivalain, and C. Patissier for administrative assistance; D. Kapogiannis (National Institute on Aging) for providing healthy donor samples; and S. Xirasager, J. Barnett, X. Cheng, S. Weber, J. Danielson, B. Garabedian, and H. Matthews for their assistance in this study. We also thank R. Apps, B. Ryan, and Y. Belkaid of the CHI for their assistance. We thank the CRB-Institut J{\'e}r{\^o}me Lejeune, CRB-BioJeL, Paris, France, for their assistance. We thank M. C. Garc{\'i}a Guerrero; I. Erkizia; E. Grau; M. Massanella from IrsiCaixa AIDS Research Institute, Badalona, Spain; and J. Guitart from the Department of Clinical Genetics, University Hospital Germans Trias i Pujol, Badalona, Spain, for providing samples. We also thank J. Dalmau from IrsiCaixa for assistance. Funding: 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, 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 solidarit{\'e} pour l'enfance, the SCOR Corporate Foundation for Science, the Institut Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (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). The Milieu Int{\'e}rieur Consortium was supported by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Milieu Int{\'e}rieur grant (ANR-10-LABX-69-01) (primary investigators: L.Q.-M. and D.Du.). The Simoa experiment was supported by the PHRC-20-0375 COVID-19 grant “DIGITAL COVID” (primary investigator: G.G.). S.G.T. is supported by a Leadership 3 Investigator Grant awarded by the National Health and Medical Research Council of Australia and a COVID19 Rapid Response Grant awarded by UNSW Sydney. C.R.-G. and colleagues 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) and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas cient{\'i}ficas del ITER para colaborar en la lucha contra la COVID-19”). S.T.-A. and A.B. were supported by ANR-20-COVI-0064 (primary investigator: A.Be.). This work is supported by the French Ministry of Health “Programme Hospitalier de Recherche Clinique Inter regional 2013,” by the Contrat de Plan Etat-Lorraine and FEDER Lorraine, and by a public grant overseen by the French National Research Agency (ANR) as part of the second Investissements d'Avenir program FIGHT-HF (reference no. ANR-15-RHU-0004) and by the French PIA project “Lorraine Universit{\'e} d'Excellence” (reference no. ANR-15-IDEX-04-LUE) (45); and biobanking is performed by the Biological Resource Center Lorrain BB-0033-00035. This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology; by a grant from the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to F.R.-L.); and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1; a George Mason University Fast Grant; and the G. Harold and Leila Y. Mathers Charitable Foundation. The Amsterdam UMC Covid-19 Biobank was supported by grants from the Amsterdam Corona Research Fund, the Dr. C.J. Vaillant Fund, and the Netherlands Organization for Health Research and Development [ZonMw; NWO-Vici-Grant (grant no. 918·19·627 to D.v.d.B.)]. This work was also supported by the Division of Intramural Research of the National Institute of Dental Craniofacial Research and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e comorbidita”). The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. J.H. holds an Institut Imagine M.D.-Ph.D. fellowship from the Fondation Bettencourt Schueller. J.R. is supported by the INSERM Ph.D. program (“poste d'accueil Inserm”). P.Ba. was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the M.D.-Ph.D. program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). We thank the Association “Turner et vous” for their help and support. Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. D.C.V. is supported by the Fonds de la recherche en sant{\'e} du Qu{\'e}bec clinician-scientist scholar program. K.K. was supported by the Estonian Research Council grant PUT1367. We thank the GENCOVID Multicenter Study (https://sites.google.com/dbm.unisi.it/ gen-covid). We thank the NIAID Office of Cyber Infrastructure and Computational Biology, Bioinformatics and Computational Biosciences Branch (contract no. HHSN316201300006W/ HHSN27200002 to MSC, Inc.), the Operations Engineering Branch for developing the HGRepo system to enable streamlined access to the data, and the NCI Advanced Biomedical Computational Science (ABCS) for data transformation support. Biomedical Advanced Research and Development Authority was supported under contract no. HHSO10201600031C (to J.H.). Financial support was provided by the National Institute of Allergy and Infectious Diseases (NIAID) K08AI135091; the Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; and the American Academy of Allergy Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",

year = "2020",

month = oct,

day = "23",

doi = "10.1126/science.abd4585",

language = "English",

volume = "370",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6515",

}

Bastard, P, Rosen, LB, Zhang, Q, Michailidis, E, Hoffmann, H-H, Zhang, Y, Dorgham, K, Philippot, Q, Rosain, J, Béziat, V, Manry, J, Shaw, E, Haljasmägi, L, Peterson, P, Lorenzo, L, Bizien, L, Trouillet-Assant, S, Dobbs, K, de Jesus, AA, Belot, A, Kallaste, A, Catherinot, E, Tandjaoui-Lambiotte, Y, Le Pen, J, Kerner, G, Bigio, B, Seeleuthner, Y, Yang, R, Bolze, A, Spaan, AN, Delmonte, OM, Abers, MS, Aiuti, A, Casari, G, Lampasona, V, Piemonti, L, Ciceri, F, Bilguvar, K, Lifton, RP, Vasse, M, Smadja, DM, Migaud, M, Hadjadj, J, Terrier, B, Duffy, D, Quintana-Murci, L, van de Beek, D, Roussel, L, Vinh, DC, Tangye, SG & Bruijning-Verhagen, P 2020, 'Autoantibodies against type I IFNs in patients with life-threatening COVID-19', Science, vol. 370, no. 6515, eabd4585. https://doi.org/10.1126/science.abd4585

TY - JOUR

T1 - Autoantibodies against type I IFNs in patients with life-threatening COVID-19

AU - Bastard, Paul

AU - Rosen, Lindsey B

AU - Zhang, Qian

AU - Michailidis, Eleftherios

AU - Hoffmann, Hans-Heinrich

AU - Zhang, Yu

AU - Dorgham, Karim

AU - Philippot, Quentin

AU - Rosain, Jérémie

AU - Béziat, Vivien

AU - Manry, Jérémy

AU - Shaw, Elana

AU - Haljasmägi, Liis

AU - Peterson, Pärt

AU - Lorenzo, Lazaro

AU - Bizien, Lucy

AU - Trouillet-Assant, Sophie

AU - Dobbs, Kerry

AU - de Jesus, Adriana Almeida

AU - Belot, Alexandre

AU - Kallaste, Anne

AU - Catherinot, Emilie

AU - Tandjaoui-Lambiotte, Yacine

AU - Le Pen, Jeremie

AU - Kerner, Gaspard

AU - Bigio, Benedetta

AU - Seeleuthner, Yoann

AU - Yang, Rui

AU - Bolze, Alexandre

AU - Spaan, András N

AU - Delmonte, Ottavia M

AU - Abers, Michael S

AU - Aiuti, Alessandro

AU - Casari, Giorgio

AU - Lampasona, Vito

AU - Piemonti, Lorenzo

AU - Ciceri, Fabio

AU - Bilguvar, Kaya

AU - Lifton, Richard P

AU - Vasse, Marc

AU - Smadja, David M

AU - Migaud, Mélanie

AU - Hadjadj, Jérome

AU - Terrier, Benjamin

AU - Duffy, Darragh

AU - Quintana-Murci, Lluis

AU - van de Beek, Diederik

AU - Roussel, Lucie

AU - Vinh, Donald C

AU - Tangye, Stuart G

AU - Bruijning-Verhagen, P.

N1 - Funding Information: We thank the patients, their families, and healthy donors for placing their trust in us. We thank the French Incontinentia pigmenti association for their help and support. We thank Y. Nemirovskaya, D. Papandrea, M. Woollett, D. Liu, C. Rivalain, and C. Patissier for administrative assistance; D. Kapogiannis (National Institute on Aging) for providing healthy donor samples; and S. Xirasager, J. Barnett, X. Cheng, S. Weber, J. Danielson, B. Garabedian, and H. Matthews for their assistance in this study. We also thank R. Apps, B. Ryan, and Y. Belkaid of the CHI for their assistance. We thank the CRB-Institut Jérôme Lejeune, CRB-BioJeL, Paris, France, for their assistance. We thank M. C. García Guerrero; I. Erkizia; E. Grau; M. Massanella from IrsiCaixa AIDS Research Institute, Badalona, Spain; and J. Guitart from the Department of Clinical Genetics, University Hospital Germans Trias i Pujol, Badalona, Spain, for providing samples. We also thank J. Dalmau from IrsiCaixa for assistance. Funding: 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, 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). The Milieu Intérieur Consortium was supported by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Milieu Intérieur grant (ANR-10-LABX-69-01) (primary investigators: L.Q.-M. and D.Du.). The Simoa experiment was supported by the PHRC-20-0375 COVID-19 grant “DIGITAL COVID” (primary investigator: G.G.). S.G.T. is supported by a Leadership 3 Investigator Grant awarded by the National Health and Medical Research Council of Australia and a COVID19 Rapid Response Grant awarded by UNSW Sydney. C.R.-G. and colleagues 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) and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). S.T.-A. and A.B. were supported by ANR-20-COVI-0064 (primary investigator: A.Be.). This work is supported by the French Ministry of Health “Programme Hospitalier de Recherche Clinique Inter regional 2013,” by the Contrat de Plan Etat-Lorraine and FEDER Lorraine, and by a public grant overseen by the French National Research Agency (ANR) as part of the second Investissements d'Avenir program FIGHT-HF (reference no. ANR-15-RHU-0004) and by the French PIA project “Lorraine Université d'Excellence” (reference no. ANR-15-IDEX-04-LUE) (45); and biobanking is performed by the Biological Resource Center Lorrain BB-0033-00035. This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology; by a grant from the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to F.R.-L.); and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1; a George Mason University Fast Grant; and the G. Harold and Leila Y. Mathers Charitable Foundation. The Amsterdam UMC Covid-19 Biobank was supported by grants from the Amsterdam Corona Research Fund, the Dr. C.J. Vaillant Fund, and the Netherlands Organization for Health Research and Development [ZonMw; NWO-Vici-Grant (grant no. 918·19·627 to D.v.d.B.)]. This work was also supported by the Division of Intramural Research of the National Institute of Dental Craniofacial Research and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e comorbidita”). The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. J.H. holds an Institut Imagine M.D.-Ph.D. fellowship from the Fondation Bettencourt Schueller. J.R. is supported by the INSERM Ph.D. program (“poste d'accueil Inserm”). P.Ba. was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the M.D.-Ph.D. program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). We thank the Association “Turner et vous” for their help and support. Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. D.C.V. is supported by the Fonds de la recherche en santé du Québec clinician-scientist scholar program. K.K. was supported by the Estonian Research Council grant PUT1367. We thank the GENCOVID Multicenter Study (https://sites.google.com/dbm.unisi.it/ gen-covid). We thank the NIAID Office of Cyber Infrastructure and Computational Biology, Bioinformatics and Computational Biosciences Branch (contract no. HHSN316201300006W/ HHSN27200002 to MSC, Inc.), the Operations Engineering Branch for developing the HGRepo system to enable streamlined access to the data, and the NCI Advanced Biomedical Computational Science (ABCS) for data transformation support. Biomedical Advanced Research and Development Authority was supported under contract no. HHSO10201600031C (to J.H.). Financial support was provided by the National Institute of Allergy and Infectious Diseases (NIAID) K08AI135091; the Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; and the American Academy of Allergy Publisher Copyright: © 2020 American Association for the Advancement of Science. All rights reserved.

PY - 2020/10/23

Y1 - 2020/10/23

N2 - Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. 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.

AB - Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Neutralizing/blood

KW - Asymptomatic Infections

KW - Autoantibodies/blood

KW - Betacoronavirus

KW - COVID-19

KW - Case-Control Studies

KW - Coronavirus Infections/immunology

KW - Critical Illness

KW - Female

KW - Humans

KW - Immunoglobulin G/blood

KW - Interferon Type I/immunology

KW - Interferon alpha-2/immunology

KW - Male

KW - Middle Aged

KW - Pandemics

KW - Pneumonia, Viral/immunology

KW - SARS-CoV-2

UR - https://www.scopus.com/pages/publications/85094096675

U2 - 10.1126/science.abd4585

DO - 10.1126/science.abd4585

M3 - Article

C2 - 32972996

SN - 0036-8075

VL - 370

JO - Science

JF - Science

IS - 6515

M1 - eabd4585

ER -

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

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