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SARS\u2010CoV\u20102 anti\u2010spike antibodies of the IgG isotype are known to strongly contribute to this hyperinflammation by overactivation of alveolar macrophages. However, while the pathogenic function of IgG has been extensively studied, very little is known about the function of IgA, the most abundant immunoglobulin isotype in the airways. Although IgA is generally considered noninflammatory, in this study, we show that anti\u2010spike IgA induces pronounced proinflammatory responses. We demonstrate that stimulation of macrophages with anti\u2010spike IgA immune complexes in combination with a viral stimulus amplifies proinflammatory cytokine production. This IgA\u2010induced inflammation is particularly driven by IgA2, the IgA subclass that is increased in the plasma of severely ill COVID\u201019 patients. We identified that IgA2\u2010induced inflammation is predominantly dependent on Fc\u03b1RI\u2010Syk signaling. Mechanistically, IgA2\u2010induced inflammation is linked to enhanced glycolysis and altered mitochondrial function, indicating subclass\u2010specific immunometabolic reprogramming. Taken together, these data indicate a pathogenic role for IgA2 in severe COVID\u201019 and highlight its signaling cascades and metabolic pathways as potential druggable targets to counteract hyperinflammation in severe coronavirus infections, such as COVID\u201019, SARS, MERS, and potential future outbreaks.<\/jats:p>","DOI":"10.1002\/eji.70068","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T04:43:47Z","timestamp":1759812227000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Anti\u2010SARS\u2010CoV\u20102 Spike IgA2 Induces Inflammation by Human Macrophages"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-7795","authenticated-orcid":false,"given":"Lynn","family":"Mes","sequence":"first","affiliation":[{"name":"Center for Infection and Molecular Medicine Amsterdam University Medical Center (UMC) University of Amsterdam Amsterdam The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-371X","authenticated-orcid":false,"given":"Jennifer","family":"Veth","sequence":"additional","affiliation":[{"name":"Center for Infection and Molecular Medicine Amsterdam University Medical Center (UMC) University of Amsterdam Amsterdam The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Van Coillie","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunohematology Sanquin Research  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jim B. 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