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In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti\u2013severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti\u2013IFN-\u03b1 antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti\u2013IFN-\u03b1 autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti\u2013SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti\u2013IFN-\u03b1 autoantibodies followed the peak of host IFN-\u03b1 production and waned with disease recovery, revealing a regulated balance between IFN-\u03b1 and anti\u2013IFN-\u03b1 response. In contrast, systemic IgG1 anti\u2013IFN-\u03b1 autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti\u2013IFN-\u03b1 in the immunopathology of COVID-19 and suggest that anti\u2013IFN-\u03b1 autoantibodies may serve a homeostatic function to regulate host IFN-\u03b1 after viral infection in the respiratory mucosa.<\/jats:p>","DOI":"10.1126\/scitranslmed.adq1789","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T13:58:18Z","timestamp":1730901498000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":17,"title":["Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-8045","authenticated-orcid":true,"given":"Benjamin R.","family":"Babcock","sequence":"first","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Kosters","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7905-8306","authenticated-orcid":true,"given":"Devon J.","family":"Eddins","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9647-2473","authenticated-orcid":true,"given":"Maria Sophia Baluyot","family":"Donaire","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases &amp; 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