Autoantibodies against type I IFNs in patients with critical influenza pneumonia

Qian Zhang; Andrés Pizzorno; Lisa Miorin; Paul Bastard; Adrian Gervais; Tom Le Voyer; Lucy Bizien; Jeremy Manry; Jérémie Rosain; Quentin Philippot; Kelian Goavec; Blandine Padey; Anastasija Cupic; Emilie Laurent; Kahina Saker; Martti Vanker; Karita Särekannu; Tamara García-Salum; Marcela Ferres; Nicole Le Corre; Javier Sánchez-Céspedes; María Balsera-Manzanero; Jordi Carratala; Pilar Retamar-Gentil; Gabriela Abelenda-Alonso; Adoración Valiente; Pierre Tiberghien; Marie Zins; Stéphanie Debette; Isabelle Meyts; Filomeen Haerynck; Riccardo Castagnoli; Luigi D. Notarangelo; Luis I. Gonzalez-Granado; Nerea Dominguez-Pinilla; Evangelos Andreakos; Vasiliki Triantafyllia; Carlos Rodríguez-Gallego; Jordi Solé-Violán; José Juan Ruiz-Hernandez; Felipe Rodríguez de Castro; José Ferreres; Marisa Briones; Joost Wauters; Lore Vanderbeke; Simon Feys; Chen Yen Kuo; Wei Te Lei; Cheng Lung Ku; Galit Tal; Amos Etzioni; Suhair Hanna; Thomas Fournet; Jean Sebastien Casalegno; Gregory Queromes; Laurent Argaud; Etienne Javouhey; Manuel Rosa-Calatrava; Elisa Cordero; Teresa Aydillo; Rafael A. Medina; Kai Kisand; Anne Puel; Emmanuelle Jouanguy; Laurent Abel; Aurélie Cobat; Sophie Trouillet-Assant; Adolfo García-Sastre; Jean Laurent Casanova

doi:10.1084/jem.20220514

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

Qian Zhang, Andrés Pizzorno, Lisa Miorin, Paul Bastard, Adrian Gervais, Tom Le Voyer, Lucy Bizien, Jeremy Manry, Jérémie Rosain, Quentin Philippot, Kelian Goavec, Blandine Padey, Anastasija Cupic, Emilie Laurent, Kahina Saker, Martti Vanker, Karita Särekannu, Tamara García-Salum, Marcela Ferres, Nicole Le CorreJavier Sánchez-Céspedes, María Balsera-Manzanero, Jordi Carratala, Pilar Retamar-Gentil, Gabriela Abelenda-Alonso, Adoración Valiente, Pierre Tiberghien, Marie Zins, Stéphanie Debette, Isabelle Meyts, Filomeen Haerynck, Riccardo Castagnoli, Luigi D. Notarangelo, Luis I. Gonzalez-Granado, Nerea Dominguez-Pinilla, Evangelos Andreakos, Vasiliki Triantafyllia, Carlos Rodríguez-Gallego, Jordi Solé-Violán, José Juan Ruiz-Hernandez, Felipe Rodríguez de Castro, José Ferreres, Marisa Briones, Joost Wauters, Lore Vanderbeke, Simon Feys, Chen Yen Kuo, Wei Te Lei, Cheng Lung Ku, Galit Tal, Amos Etzioni, Suhair Hanna, Thomas Fournet, Jean Sebastien Casalegno, Gregory Queromes, Laurent Argaud, Etienne Javouhey, Manuel Rosa-Calatrava, Elisa Cordero, Teresa Aydillo, Rafael A. Medina, Kai Kisand, Anne Puel, Emmanuelle Jouanguy, Laurent Abel, Aurélie Cobat, Sophie Trouillet-Assant, Adolfo García-Sastre, Jean Laurent Casanova

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

2 Scopus citations

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.

Original language	English
Article number	e20220514
Journal	Journal of Experimental Medicine
Volume	219
Issue number	11
DOIs	https://doi.org/10.1084/jem.20220514
State	Published - 7 Nov 2022

Access to Document

10.1084/jem.20220514

Cite this

Zhang, Q., Pizzorno, A., Miorin, L., Bastard, P., Gervais, A., Le Voyer, T., Bizien, L., Manry, J., Rosain, J., Philippot, Q., Goavec, K., Padey, B., Cupic, A., Laurent, E., Saker, K., Vanker, M., Särekannu, K., García-Salum, T., Ferres, M., ... Casanova, J. L. (2022). Autoantibodies against type I IFNs in patients with critical influenza pneumonia. Journal of Experimental Medicine, 219(11), [e20220514]. https://doi.org/10.1084/jem.20220514

@article{8ba6159be5a84b97910d053dca3116aa,

title = "Autoantibodies against type I IFNs in patients with critical influenza pneumonia",

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{\textquoteright} 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.",

author = "Qian Zhang and Andr{\'e}s Pizzorno and Lisa Miorin and Paul Bastard and Adrian Gervais and {Le Voyer}, Tom and Lucy Bizien and Jeremy Manry and J{\'e}r{\'e}mie Rosain and Quentin Philippot and Kelian Goavec and Blandine Padey and Anastasija Cupic and Emilie Laurent and Kahina Saker and Martti Vanker and Karita S{\"a}rekannu and Tamara Garc{\'i}a-Salum and Marcela Ferres and Corre, {Nicole Le} and Javier S{\'a}nchez-C{\'e}spedes and Mar{\'i}a Balsera-Manzanero and Jordi Carratala and Pilar Retamar-Gentil and Gabriela Abelenda-Alonso and Adoraci{\'o}n Valiente and Pierre Tiberghien and Marie Zins and St{\'e}phanie Debette and Isabelle Meyts and Filomeen Haerynck and Riccardo Castagnoli and Notarangelo, {Luigi D.} and Gonzalez-Granado, {Luis I.} and Nerea Dominguez-Pinilla and Evangelos Andreakos and Vasiliki Triantafyllia and Carlos Rodr{\'i}guez-Gallego and Jordi Sol{\'e}-Viol{\'a}n and Ruiz-Hernandez, {Jos{\'e} Juan} and {de Castro}, {Felipe Rodr{\'i}guez} and Jos{\'e} Ferreres and Marisa Briones and Joost Wauters and Lore Vanderbeke and Simon Feys and Kuo, {Chen Yen} and Lei, {Wei Te} and Ku, {Cheng Lung} and Galit Tal and Amos Etzioni and Suhair Hanna and Thomas Fournet and Casalegno, {Jean Sebastien} and Gregory Queromes and Laurent Argaud and Etienne Javouhey and Manuel Rosa-Calatrava and Elisa Cordero and Teresa Aydillo and Medina, {Rafael A.} and Kai Kisand and Anne Puel and Emmanuelle Jouanguy and Laurent Abel and Aur{\'e}lie Cobat and Sophie Trouillet-Assant and Adolfo Garc{\'i}a-Sastre and Casanova, {Jean Laurent}",

note = "Funding Information: SINOVAC outside the submitted work. P. Retamar-Gentil reported personal fees from Merck outside the submitted work. I. Meyts reported grants from CSL-Behring outside the submitted work. E. Andreakos reported grants from Janssen Pharmaceuticals during the conduct of the study. J. Wauters reported grants and personal fees from Pfizer and Gilead outside the submitted work. L. Vanderbeke reported grants from Research Foundation Flanders and non-financial support from Pfizer outside the submitted work. S. Feys reported grants from Pfizer outside the submitted work. J. Casalegno reported “other” from Pfizer and grants from Sanofi outside the submitted work. M. Rosa-Calatrava reported a patent to WO2016/146836 licensed (Signia Therapeutics), a patent to WO2017/174593 licensed (Signia Therapeutics), and a patent to WO2019/224489 licensed (Signia Therapeutics); and is the co-founder of Signia Therapeutics SAS. S. Trouillet-Assant reported non-financial support from BioM{\'e}rieux outside the submitted work. A. Garcia-Sastre reported “other” from Vivaldi Biosciences, Pagoda, Contrafect, Vaxalto, Accurius, Curelab oncology, and Curelab veterinary; personal fees from Avimex, 7Hills, Esperovax, Pfizer, Farmak, Applied Biological Laboratories, Paratus, Pharmamar, Pfizer, and Synairgen; grants from Pfizer, Pharmamar, Blade Therapeutics, Avimex, Accurius, Dyna-vax, Kenall Manufacturing, ImmunityBio, Nanocomposix, Merck, Model Medicines, Atea Pharma, Shenwa Biosciences, Johnson & Johnson, 7 Hills, Hexamer, N-fold LLC, and Applied Biological Laboratories outside the submitted work; in addition, A. Garcia-Sastre had a patent for influenza virus vaccines and uses thereof issued; and invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. J. Casanova reported a patent to PCT/US2021/ 042741 pending. No other disclosures were reported. Funding Information: We thank Dr. Cato Jacobs for her contribution to the sampling of UZLeuven patients in Belgium. 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{\textquoteright}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{\textquoteright}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 solidarit{\'e} pour l{\textquoteright}enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Sci-ence, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), REACTing-INSERM, and the Universit{\'e} Paris Cit{\'e}. This work was partly supported by the Center for Research on Influenza Pathogenesis and Transmis-sion, 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. Garc{\'i}a-Sastre and R.A. Medina, and by NIAID grant U19AI142733 and U19AI168631 to A. Garc{\'i}a-Sastre. Work in the Medina laboratory was also supported by the PIA ACT 1408, FONDECYT 1161971 and 1212023 grants from Agencia Nacional de Investigaci{\'o}n y De-sarrollo of Chile. The VirPath team is supported by INSERM REACTing (Research & Action Emerging Infectious Diseases), CNRS, and M{\'e}rieux 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. Rodr{\'i}guez-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, Fundaci{\'o}n MAPFRE Guanarteme, Sociedad Espa{\~n}ola de Neumolog{\'i}a y Cirug{\'i}a Tor{\'a}cica and Cab-ildo Insular de Tenerife (CGIEU0000219140 and “Apuestas, cient{\'i}ficas del Instituto Tecnol{\'o}gico y de Energ{\'i}as 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). 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 In-stituto de Salud Carlos III, Subdirecci{\'o}n General de Redes y Centros de Investigaci{\'o}n Cooperativa, Ministerio de Ciencia, Innovaci{\'o}n y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009); cofinanced by European Regional Development Fund “A way to achieve Eu-rope”; Operative Program Intelligence Growth 2014-2020 (CB21/13/00006) also was supported by CIBER-Consorcio Centro de Investigaci{\'o}n Biom{\'e}dica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaci{\'o}n and Uni{\'o}n Europea–Next Generation EU and Consejer{\'i}a de Econom{\'i}a, Conocimiento, Empresas y Universidad, Secretar{\'i}a General de Universidades, Investigaci{\'o}n y Tecnolog{\'i}a, Junta de Andaluc{\'i}a, 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. Author contributions: Q. Zhang, A. Pizzorno, L. Miorin, P. Funding Information: 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{\textquoteright}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{\textquoteright}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 solidarit{\'e} pour l{\textquoteright}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 Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), REACTing-INSERM, and the Universit{\'e} Paris Cit{\'e}. 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. Garc{\'i}a-Sastre and R.A. Medina, and by NIAID grant U19AI142733 and U19AI168631 to A. Garc{\'i}a-Sastre. Work in the Medina laboratory was also supported by the PIA ACT 1408, FONDECYT 1161971 and 1212023 grants from Agencia Nacional de Investigaci{\'o}n y De-sarrollo of Chile. The VirPath team is supported by INSERM REACTing (Research & Action Emerging Infectious Diseases), CNRS, and M{\'e}rieux 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. Rodr{\'i}guez-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, Fundaci{\'o}n MAPFRE Guanarteme, Sociedad Espa{\~n}ola de Neumolog{\'i}a y Cirug{\'i}a Tor{\'a}cica and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas, cient{\'i}ficas del Instituto Tecnol{\'o}gico y de Energ{\'i}as Renovables para colaborar en la lucha contra la COVID-19”). E. Andreakos is supported by the Hellenic Foundation for Research and Funding Information: Innovation (INTERFLU, no. 1574). 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 In-stituto de Salud Carlos III, Subdirecci{\'o}n General de Redes y Centros de Investigaci{\'o}n Cooperativa, Ministerio de Ciencia, Innovaci{\'o}n 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 Investigaci{\'o}n Biom{\'e}dica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaci{\'o}n and Uni{\'o}n Europea–Next Generation EU and Consejer{\'i}a de Econom{\'i}a, Conocimiento, Empresas y Universidad, Secretar{\'i}a General de Universidades, Investigaci{\'o}n y Tecnolog{\'i}a, Junta de Andaluc{\'i}a, 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. Publisher Copyright: {\textcopyright} 2022 Zhang et al.",

year = "2022",

month = nov,

day = "7",

doi = "10.1084/jem.20220514",

language = "English",

volume = "219",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "11",

}

Zhang, Q, Pizzorno, A, Miorin, L, Bastard, P, Gervais, A, Le Voyer, T, Bizien, L, Manry, J, Rosain, J, Philippot, Q, Goavec, K, Padey, B, Cupic, A, Laurent, E, Saker, K, Vanker, M, Särekannu, K, García-Salum, T, Ferres, M, Corre, NL, Sánchez-Céspedes, J, Balsera-Manzanero, M, Carratala, J, Retamar-Gentil, P, Abelenda-Alonso, G, Valiente, A, Tiberghien, P, Zins, M, Debette, S, Meyts, I, Haerynck, F, Castagnoli, R, Notarangelo, LD, Gonzalez-Granado, LI, Dominguez-Pinilla, N, Andreakos, E, Triantafyllia, V, Rodríguez-Gallego, C, Solé-Violán, J, Ruiz-Hernandez, JJ, de Castro, FR, Ferreres, J, Briones, M, Wauters, J, Vanderbeke, L, Feys, S, Kuo, CY, Lei, WT, Ku, CL, Tal, G, Etzioni, A, Hanna, S, Fournet, T, Casalegno, JS, Queromes, G, Argaud, L, Javouhey, E, Rosa-Calatrava, M, Cordero, E, Aydillo, T, Medina, RA, Kisand, K, Puel, A, Jouanguy, E, Abel, L, Cobat, A, Trouillet-Assant, S, García-Sastre, A & Casanova, JL 2022, 'Autoantibodies against type I IFNs in patients with critical influenza pneumonia', Journal of Experimental Medicine, vol. 219, no. 11, e20220514. https://doi.org/10.1084/jem.20220514

TY - JOUR

T1 - Autoantibodies against type I IFNs in patients with critical influenza pneumonia

AU - Zhang, Qian

AU - Pizzorno, Andrés

AU - Miorin, Lisa

AU - Bastard, Paul

AU - Gervais, Adrian

AU - Le Voyer, Tom

AU - Bizien, Lucy

AU - Manry, Jeremy

AU - Rosain, Jérémie

AU - Philippot, Quentin

AU - Goavec, Kelian

AU - Padey, Blandine

AU - Cupic, Anastasija

AU - Laurent, Emilie

AU - Saker, Kahina

AU - Vanker, Martti

AU - Särekannu, Karita

AU - García-Salum, Tamara

AU - Ferres, Marcela

AU - Corre, Nicole Le

AU - Sánchez-Céspedes, Javier

AU - Balsera-Manzanero, María

AU - Carratala, Jordi

AU - Retamar-Gentil, Pilar

AU - Abelenda-Alonso, Gabriela

AU - Valiente, Adoración

AU - Tiberghien, Pierre

AU - Zins, Marie

AU - Debette, Stéphanie

AU - Meyts, Isabelle

AU - Haerynck, Filomeen

AU - Castagnoli, Riccardo

AU - Notarangelo, Luigi D.

AU - Gonzalez-Granado, Luis I.

AU - Dominguez-Pinilla, Nerea

AU - Andreakos, Evangelos

AU - Triantafyllia, Vasiliki

AU - Rodríguez-Gallego, Carlos

AU - Solé-Violán, Jordi

AU - Ruiz-Hernandez, José Juan

AU - de Castro, Felipe Rodríguez

AU - Ferreres, José

AU - Briones, Marisa

AU - Wauters, Joost

AU - Vanderbeke, Lore

AU - Feys, Simon

AU - Kuo, Chen Yen

AU - Lei, Wei Te

AU - Ku, Cheng Lung

AU - Tal, Galit

AU - Etzioni, Amos

AU - Hanna, Suhair

AU - Fournet, Thomas

AU - Casalegno, Jean Sebastien

AU - Queromes, Gregory

AU - Argaud, Laurent

AU - Javouhey, Etienne

AU - Rosa-Calatrava, Manuel

AU - Cordero, Elisa

AU - Aydillo, Teresa

AU - Medina, Rafael A.

AU - Kisand, Kai

AU - Puel, Anne

AU - Jouanguy, Emmanuelle

AU - Abel, Laurent

AU - Cobat, Aurélie

AU - Trouillet-Assant, Sophie

AU - García-Sastre, Adolfo

AU - Casanova, Jean Laurent

N1 - Funding Information: SINOVAC outside the submitted work. P. Retamar-Gentil reported personal fees from Merck outside the submitted work. I. Meyts reported grants from CSL-Behring outside the submitted work. E. Andreakos reported grants from Janssen Pharmaceuticals during the conduct of the study. J. Wauters reported grants and personal fees from Pfizer and Gilead outside the submitted work. L. Vanderbeke reported grants from Research Foundation Flanders and non-financial support from Pfizer outside the submitted work. S. Feys reported grants from Pfizer outside the submitted work. J. Casalegno reported “other” from Pfizer and grants from Sanofi outside the submitted work. M. Rosa-Calatrava reported a patent to WO2016/146836 licensed (Signia Therapeutics), a patent to WO2017/174593 licensed (Signia Therapeutics), and a patent to WO2019/224489 licensed (Signia Therapeutics); and is the co-founder of Signia Therapeutics SAS. S. Trouillet-Assant reported non-financial support from BioMérieux outside the submitted work. A. Garcia-Sastre reported “other” from Vivaldi Biosciences, Pagoda, Contrafect, Vaxalto, Accurius, Curelab oncology, and Curelab veterinary; personal fees from Avimex, 7Hills, Esperovax, Pfizer, Farmak, Applied Biological Laboratories, Paratus, Pharmamar, Pfizer, and Synairgen; grants from Pfizer, Pharmamar, Blade Therapeutics, Avimex, Accurius, Dyna-vax, Kenall Manufacturing, ImmunityBio, Nanocomposix, Merck, Model Medicines, Atea Pharma, Shenwa Biosciences, Johnson & Johnson, 7 Hills, Hexamer, N-fold LLC, and Applied Biological Laboratories outside the submitted work; in addition, A. Garcia-Sastre had a patent for influenza virus vaccines and uses thereof issued; and invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. J. Casanova reported a patent to PCT/US2021/ 042741 pending. No other disclosures were reported. Funding Information: We thank Dr. Cato Jacobs for her contribution to the sampling of UZLeuven patients in Belgium. 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 Sci-ence, 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 Transmis-sion, 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 De-sarrollo 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 Cab-ildo 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). 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 In-stituto 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 Eu-rope”; 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. Author contributions: Q. Zhang, A. Pizzorno, L. Miorin, P. Funding Information: 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 De-sarrollo 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 Funding Information: Innovation (INTERFLU, no. 1574). 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 In-stituto 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. Publisher Copyright: © 2022 Zhang et al.

PY - 2022/11/7

Y1 - 2022/11/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85136198376&partnerID=8YFLogxK

U2 - 10.1084/jem.20220514

DO - 10.1084/jem.20220514

M3 - Article

C2 - 36112363

AN - SCOPUS:85136198376

VL - 219

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 11

M1 - e20220514

ER -

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

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