TY - JOUR
T1 - Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19
AU - UCSF COMET consortium
AU - van der Wijst, Monique G.P.
AU - Vazquez, Sara E.
AU - Hartoularos, George C.
AU - Bastard, Paul
AU - Grant, Tianna
AU - Bueno, Raymund
AU - Lee, David S.
AU - Greenland, John R.
AU - Sun, Yang
AU - Perez, Richard
AU - Ogorodnikov, Anton
AU - Ward, Alyssa
AU - Mann, Sabrina A.
AU - Lynch, Kara L.
AU - Yun, Cassandra
AU - Havlir, Diane V.
AU - Chamie, Gabriel
AU - Marquez, Carina
AU - Greenhouse, Bryan
AU - Lionakis, Michail S.
AU - Norris, Philip J.
AU - Dumont, Larry J.
AU - Kelly, Kathleen
AU - Zhang, Peng
AU - Zhang, Qian
AU - Gervais, Adrian
AU - Le Voyer, Tom
AU - Whatley, Alexander
AU - Si, Yichen
AU - Byrne, Ashley
AU - Combes, Alexis J.
AU - Rao, Arjun Arkal
AU - Song, Yun S.
AU - Fragiadakis, Gabriela K.
AU - Kangelaris, Kirsten
AU - Calfee, Carolyn S.
AU - Erle, David J.
AU - Hendrickson, Carolyn
AU - Krummel, Matthew F.
AU - Woodruff, Prescott G.
AU - Langelier, Charles R.
AU - Casanova, Jean Laurent
AU - Derisi, Joseph L.
AU - Anderson, Mark S.
AU - Ye, Chun Jimmie
AU - Abe-Jones, Yumiko
AU - Alvarenga, Bonny
AU - Asthana, Saurabh
AU - Beagle, Alexander
AU - Gonzalez, Ana
N1 - Funding Information:
This study was performed with support from the National Institute of Allergy and Infectious Diseases (NIAID)?sponsored Immunophenotyping Assessment in a COVID-19 Cohort Network (NIAID grant U19 AI1077439 to D.J.E.). This work was supported by grants from the Dutch Research Council (NWO-Veni 192.029 to M.G.P.v.d.W.), the NSF under the Graduate Research Fellowship Program (1650113 to G.C.H.), the National Institute of Diabetes, Digestive and Kidney Diseases (1F30DK123915-01 to S.E.V.), the Chan Zuckerberg Biohub, the NIAID (5PO1AI118688-04 to M.S.A.), and the National Heart, Lung and Blood Institute (R35 HL140026 to C.S.C.). J.R.G. was supported by the Veteran Affairs Office of Research and Development CSR&D section (IK2CX001034) and the National Heart Lung and Blood Institute (HL151552). M.S.L. was supported by the Division of Intramural Research of the NIH. T.G. was supported by the PhD Program in Bioinformatics at UCSF. A. Whatley and Y.S.S. were supported, in part, by NIH grant R35-GM134922 and the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the U.S. Department of Energy Office of Science and the National Nuclear Security Administration. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the NIH (R01AI088364 to J.-L.C.), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866 to Q.Z.), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University (to Q.Z.), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956 to J.-L.C.), the French National Research Agency (ANR) under the ?Investments for the Future? program (ANR-10-IAHU-01 to J.-L.C.), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID to J.-L.C.), the French Foundation for Medical Research (FRM) (EQU201903007798 to J.-L.C.), the FRM and ANR GENCOVID project, ANRS-COV05 (to J.-L.C.), the Square Foundation (to J.-L.C.), Grandir?Fonds de solidarit? pour l?enfance (to J.-L.C.), the SCOR Corporate Foundation for Science (to J.-L.C.), Institut National de la Sant? et de la Recherche M?dicale (INSERM), and the University of Paris. The work was supported, in part, by the Intramural Research Program of the NIAID, NIH. P.B. and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). C.J.Y. is further supported by NIH grants R01AR071522, R01AI136972, and U01HG012192 and the Chan Zuckerberg Initiative and is an investigator at the Chan Zuckerberg Biohub and a member of the Parker Institute for Cancer Immunotherapy (PICI). This work was partially funded by Genentech (COMET Plus, TSK-020586 to UCSF COMET consortium).
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/9/22
Y1 - 2021/9/22
N2 - Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
AB - Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
U2 - 10.1126/scitranslmed.abh2624
DO - 10.1126/scitranslmed.abh2624
M3 - Article
C2 - 34429372
AN - SCOPUS:85117152301
SN - 1946-6234
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 612
M1 - eabh2624
ER -