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Recent research supports the <jats:italic>toxin hypothesis<\/jats:italic>, showing that MCs and IgE\u2010related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC\u2010mediated BV detoxification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We applied <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> fluorescence microscopyimaging, and flow cytometry, fibroblast\u2010based toxicity assays and mass spectrometry to investigate IgE\u2010mediated detoxification of BV cytotoxicity by mouse and human MCs <jats:italic>in vitro<\/jats:italic>. Pharmacologic strategies to interfere with MC\u2010derived heparin and proteases helped to define the importance of specific detoxification mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Venom\u2010specific IgE increased the degranulation and cytokine responses of MCs to BV <jats:italic>in vitro<\/jats:italic>. Passive serum sensitization enhanced MC degranulation <jats:italic>in vivo<\/jats:italic>. IgE\u2010activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin\u2010related interference with toxicity. Mediators released by IgE\u2010activated human MCs efficiently degraded multiple BV toxins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin\u2010neutralizing activity to MC\u2010derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.14852","type":"journal-article","created":{"date-parts":[[2021,4,11]],"date-time":"2021-04-11T10:54:27Z","timestamp":1618138467000},"page":"499-512","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["IgE antibodies increase honeybee venom responsiveness and detoxification efficiency of mast cells"],"prefix":"10.1111","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-129X","authenticated-orcid":false,"given":"Philipp","family":"Starkl","sequence":"first","affiliation":[{"name":"Laboratory of Infection Biology Department of Medicine I Medical University of Vienna Vienna Austria"},{"name":"CeMM \u2010 Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria"},{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Gaudenzio","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"},{"name":"Toulouse Institute for Infectious and Inflammatory Diseases INSERM UMR1291, CNRS, UMR5051, University of Toulouse III Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Marichal","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"},{"name":"GIGA\u2010Research and Faculty of Veterinary Medicine University of Liege Liege Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3384-6769","authenticated-orcid":false,"given":"Laurent L.","family":"Reber","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"},{"name":"Toulouse Institute for Infectious and Inflammatory Diseases INSERM UMR1291, CNRS, UMR5051, University of Toulouse III Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Sibilano","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"},{"name":"Sean N. 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