Philipp Starkl1,2,3, Nicolas Gaudenzio3,4, Thomas Marichal3,5, Laurent L Reber3,4, Riccardo Sibilano3,6, Martin L Watzenboeck7, Frédéric Fontaine2, André C Mueller2, Mindy Tsai3,6, Sylvia Knapp1,2, Stephen J Galli3,6,8. 1. Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. 2. CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. 3. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. 4. Toulouse Institute for Infectious and Inflammatory Diseases, INSERM UMR1291, CNRS, UMR5051, University of Toulouse III, Toulouse, France. 5. GIGA-Research and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium. 6. Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Stanford, CA, USA. 7. Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. 8. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Abstract
BACKGROUND: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE-related 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-mediated BV detoxification. METHODS: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. RESULTS: Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. CONCLUSIONS: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.
BACKGROUND: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE-related 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-mediated BV detoxification. METHODS: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. RESULTS: Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. CONCLUSIONS: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.
Authors: Marcus Maurer; Jochen Wedemeyer; Martin Metz; Adrian M Piliponsky; Karsten Weller; Devavani Chatterjea; David E Clouthier; Masashi M Yanagisawa; Mindy Tsai; Stephen J Galli Journal: Nature Date: 2004-11-14 Impact factor: 49.962
Authors: Manuela B Pucca; Felipe A Cerni; Isadora S Oliveira; Timothy P Jenkins; Lídia Argemí; Christoffer V Sørensen; Shirin Ahmadi; José E Barbosa; Andreas H Laustsen Journal: Front Immunol Date: 2019-09-06 Impact factor: 7.561