TY - JOUR
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
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 - Haerynck, Filomeen
AU - Dalmau, David
AU - Martinez-Picado, Javier
AU - Brodin, Petter
AU - Nussenzweig, Michel C.
AU - Boisson-Dupuis, Stéphanie
AU - Rodríguez-Gallego, Carlos
AU - Vogt, Guillaume
AU - Mogensen, Trine H.
AU - Oler, Andrew J.
AU - Gu, Jingwen
AU - Burbelo, Peter D.
AU - Cohen, Jeffrey I.
AU - Biondi, Andrea
AU - Bettini, Laura Rachele
AU - D'Angio, Mariella
AU - Bonfanti, Paolo
AU - Rossignol, Patrick
AU - Mayaux, Julien
AU - Rieux-Laucat, Frédéric
AU - Husebye, Eystein S.
AU - Fusco, Francesca
AU - Ursini, Matilde Valeria
AU - Imberti, Luisa
AU - Sottini, Alessandra
AU - Paghera, Simone
AU - Quiros-Roldan, Eugenia
AU - Rossi, Camillo
AU - Castagnoli, Riccardo
AU - Montagna, Daniela
AU - Licari, Amelia
AU - Marseglia, Gian Luigi
AU - Duval, Xavier
AU - Ghosn, Jade
AU - Tsang, John S.
AU - Goldbach-Mansky, Raphaela
AU - Kisand, Kai
AU - Lionakis, Michail S.
AU - Puel, Anne
AU - Zhang, Shen-Ying
AU - Holland, Steven M.
AU - Gorochov, Guy
AU - Jouanguy, Emmanuelle
AU - Rice, Charles M.
AU - Cobat, Aurélie
AU - Notarangelo, Luigi D.
AU - Abel, Laurent
AU - Su, Helen C.
AU - Casanova, Jean-Laurent
AU - HGID-Lab
AU - NIAID-USUHS Covid Study Group
AU - Covid Clinicians
AU - COVID-Storm Clinicians
AU - Imagine Covid Group
AU - French Covid Cohort Study
AU - The Milieu Intérieur Consortium
AU - COV-Contact-Cohort
AU - Amsterdam UMC COVID-19 Biobank
AU - Covid Human Genetic Effort
PY - 2020
DA - September
TI - Autoantibodies against type I IFNs in patients with life-threatening COVID-19
JO - Science
VL - 370
IS - 6515
DO - https://doi.org/10.1126/science.abd4585
AB - 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).
PB - American Association for the Advancement of Science
UR - https://www.research.ed.ac.uk/en/publications/f55c9dc6-7f66-4fc1-8b17-76efb9eb9c66
KW - Coronavirus (COVID-19)
ER