@article{Bastard_P-2020_214398,
title = {Autoantibodies against type I IFNs in patients with life-threatening COVID-19},
author = {Bastard, P. and Rosen, L. and Zhang, Q. and Michailidis, E. and Hoffmann, H. and Zhang, Y. and Dorgham, K. and Philippot, Q. and Rosain, J. and Béziat, V. and Manry, J. and Shaw, E. and Haljasmägi, L. and Peterson, P. and Lorenzo, L. and Bizien, L. and Trouillet-Assant, S. and Dobbs, K. and de Jesus, A. and Belot, A. and Kallaste, A. and Catherinot, E. and Tandjaoui-Lambiotte, Y. and Le Pen, J. and Kerner, G. and Bigio, B. and Seeleuthner, Y. and Yang, R. and Bolze, A. and Spaan, A. and Delmonte, O. and Abers, M. and Aiuti, A. and Casari, G. and Lampasona, V. and Piemonti, L. and Ciceri, F. and Bilguvar, K. and Lifton, R. and Vasse, M. and Smadja, D. and Migaud, M. and Hadjadj, J. and Terrier, B. and Duffy, D. and Quintana-Murci, L. and van de Beek, D. and Roussel, L. and Vinh, D. and Tangye, S. and Haerynck, F. and Dalmau, D. and Martinez-Picado, J. and Brodin, P. and Nussenzweig, M. and Boisson-Dupuis, S. and Rodríguez-Gallego, C. and Vogt, G. and Mogensen, T. and Oler, A. and Gu, J. and Burbelo, P. and Cohen, J. and Biondi, A. and Bettini, L. and D'Angio, M. and Bonfanti, P. and Rossignol, P. and Mayaux, J. and Rieux-Laucat, F. and Husebye, E. and Fusco, F. and Ursini, M. and Imberti, L. and Sottini, A. and Paghera, S. and Quiros-Roldan, E. and Rossi, C. and Castagnoli, R. and Montagna, D. and Licari, A. and Marseglia, G. and Duval, X. and Ghosn, J. and Tsang, J. and Goldbach-Mansky, R. and Kisand, K. and Lionakis, M. and Puel, A. and Zhang, S. and Holland, S. and Gorochov, G. and Jouanguy, E. and Rice, C. and Cobat, A. and Notarangelo, L. and Abel, L. and Su, H. and Casanova, J. and HGID-Lab and NIAID-USUHS Covid Study Group and Covid Clinicians and COVID-Storm Clinicians and Imagine Covid Group and French Covid Cohort Study and The Milieu Intérieur Consortium and COV-Contact-Cohort and Amsterdam UMC COVID-19 Biobank and Covid Human Genetic Effort},
month = {sep},
year = {2020},
abstract = {INTRODUCTION 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 &lt; 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals (P &lt; 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).},
volume = {370},
issue = {6515},
journal = {Science},
publisher = {American Association for the Advancement of Science},
url = {https://doi.org/10.1126/science.abd4585},
}
