Autoantibodies against type I IFNs in patients with critical influenza pneumonia

• Type of Material: Article
• Authors: Tamara Garcia, Emory University; Qian Zhang, Rockefeller University; Andrés Pizzorno, Université Claude Bernard Lyon 1; Lisa Miorin, Icahn School of Medicine at Mount Sinai; Paul Bastard, Rockefeller University; Adrian Gervais, Necker Hospital for Sick Children; Tom Le Voyer, Necker Hospital for Sick Children; Lucy Bizien, Necker Hospital for Sick Children; Jeremy Manry, Necker Hospital for Sick Children; Jérémie Rosain, Necker Hospital for Sick Children; Quentin Philippot, Necker Hospital for Sick Children; Kelian Goavec, Necker Hospital for Sick Children; Blandine Padey, Signia Therapeut SAS; Anastasija Cupic, Icahn School of Medicine at Mount Sinai; Emilie Laurent, Université Claude Bernard Lyon 1; Kahina Saker, Lyon Sud Hospital; Martti Vanker, University of Tartu; Karita Särekannu, University of Tartu; Tamara García-Salum, Pontificia Universidad Católica de Chile; Marcela Ferres, Pontificia Universidad Católica de Chile; Nicole Le Corre, Pontificia Universidad Católica de Chile; Javier Sánchez-Céspedes, Instituto de Salud Carlos III, Madrid; María Balsera-Manzanero, Instituto de Salud Carlos III, Madrid; Jordi Carratala, Instituto de Salud Carlos III, Madrid; Pilar Retamar-Gentil, Instituto de Salud Carlos III, Madrid; Gabriela Abelenda-Alonso, Bellvitge University Hospital; Adoración Valiente, Instituto de Salud Carlos III, Madrid; Pierre Tiberghien, Etablissement Francais Sang; Marie Zins, Universite Paris Saclay; Stéphanie Debette, University of Bordeaux; Isabelle Meyts, Katholieke University Leuven; Filomeen Haerynck, Ghent University Hospital; Riccardo Castagnoli, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Luigi D Notarangelo, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Luis I Gonzalez-Granado, Complutense University of Madrid; Nerea Dominguez-Pinilla, University Hospital 12 October; Evangelos Andreakos, Academy of Athens; Vasiliki Triantafyllia, Academy of Athens; Carlos Rodríguez-Gallego, Canarian Health System; Jordi Solé-Violán, Univ Fernando Pessoa Canarias; José Juan Ruiz-Hernandez, Canarian Health System; Felipe Rodríguez de Castro, Canarian Health System; José Ferreres, Hospital Clínico de Valencia; Marisa Briones, Hospital Clínico y Universitario de Valencia; Joost Wauters, University Hospital Leuven; Lore Vanderbeke, University Hospital Leuven; Simon Feys, University Hospital Leuven; Chen-Yen Kuo, Chang Gung University; Wei-Te Lei, Chang Gung University; Cheng-Lung Ku, Chang Gung University; Galit Tal, Rambam Health Care Campus; Amos Etzioni, Rambam Health Care Campus; Suhair Hanna, Rambam Health Care Campus; Thomas Fournet, Université de Franche-Comté; Jean-Sebastian Casalegno, Hospices Civils de Lyon; Gregory Queromes, Universite Claude Bernard Lyon 1; Laurent Argaud, Edouard Herriot Hospital; Etienne Javouhey, Hopital Femme Mère Enfant; Manuel Rosa-Calatrava, Université Claude Bernard Lyon 1; Elisa Cordero, Instituto de Salud Carlos III; Teresa Aydillo, Icahn School of Medicine at Mount Sinai; Rafael A Medina, Icahn School of Medicine at Mount Sinai; Kai Kisand, University of Tartu; Anne Puel, Rockefeller University; Emmanuelle Jouanguy, Rockefeller University; Laurent Abel, Rockefeller University; Aurélie Cobat, Rockefeller University; Sophie Trouillet-Assant, Universite Claude Bernard Lyon 1; Adolfo García-Sastre, Icahn School of Medicine at Mount Sinai; Jean-Laurent Casanova, Rockefeller University
• Language: English
• Date: 2022-09-16
• Publisher: ROCKEFELLER UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Zhang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20220514
• Title of Journal or Parent Work: JOURNAL OF EXPERIMENTAL MEDICINE
• Volume: 219
• Issue: 11
• Grant/Funding Information: P. Bastard was supported by the French Foundation for Medical Research (EA20170638020) and by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009); cofinanced by European Regional Development Fund “A way to achieve Europe”; Operative Program Intelligence Growth 2014-2020 (CB21/13/00006) also was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea–Next Generation EU and Consejería de Economía, Conocimiento, Empresas y Universidad, Secretaría General de Universidades, Investigación y Tecnología, Junta de Andalucía, Spain (P18-RT-3320). I. Meyts is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies, a CSL-Behring Research Grant, KU Leuven C1 grant C16/18/007, a VIB GC PID Grant, Fonds Wetenschappelijk Onderzoek grants G0C8517N, G0B5120N, and G0E8420N, and the Jeffrey Modell Foundation. Open Access funding provided by Rockefeller University.; 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 and R01AI163029), the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1 TR001866), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, 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 (EQU201903007798), the ANRS-COV05, ANR-RHU program ANR-21-RHUS-08, ANR GENVIR (ANR-20-CE93-003), ANR GenMISC (ANR-21-COVR-0039), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the Square Foundation, Grandir–Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the Université Paris Cité. This work was partly supported by the Center for Research on Influenza Pathogenesis and Transmission, a National Institute of Allergy and Infectious Diseases (NIAID)–funded Center of Excellence for Influenza Research and Response (contract no. 75N93021C00014), and the FLUOMICS Consortium (NIH-NIAID grant U19AI135972) to both A. García-Sastre and R.A. Medina, and by NIAID grant U19AI142733 and U19AI168631 to A. García-Sastre.; Work in the Medina laboratory was also supported by the PIA ACT 1408, FONDECYT 1161971 and 1212023 grants from Agencia Nacional de Investigación y Desarrollo of Chile. The VirPath team is supported by INSERM REACTing (Research & Action Emerging Infectious Diseases), CNRS, and Mérieux Research grants. B. Padey is supported by an ANRT CIFRE PhD scholarship. For the Lyon cohort, specimen collection and study was supported by a grant from the French Ministry of Health PHRC-I 2013 ANTIGRIPPE. C. Rodríguez-Gallego and colleagues were supported by the Instituto de Salud Carlos III (COV20_01333, COV20_01334, and PI12/01565, Spanish Ministry for Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE), Grupo DISA, Fundación MAPFRE Guanarteme, Sociedad Española de Neumología y Cirugía Torácica and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas, científicas del Instituto Tecnológico y de Energías Renovables para colaborar en la lucha contra la COVID-19”). E. Andreakos is supported by the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574)
• Keywords: Medicine, Research & Experimental; INTERFERON; DETERMINANTS; INFECTION; Research & Experimental Medicine; MYASTHENIA-GRAVIS PATIENTS; Immunology; IMMUNITY; SEVERE COVID-19; Science & Technology; NEUTRALIZING ANTIBODIES; ALPHA; Life Sciences & Biomedicine; BURDEN; ALLELES
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6–73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients’ autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10−5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10−10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.