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|Title:||ROLE OF IL-1α IN IgG1 MEDIATED ANAPHYLAXIS|
|Department:||Medical Sciences (Molecular Virology and Immunology Program)|
|Abstract:||BACKGROUND: There is growing evidence indicating that skin can be an initiating site for allergic sensitization to peanut. Additionally, anaphylaxis can also be mediated by IgG1 and macrophages, known as the alternative pathway. In this setting, the allergen binds to serum IgG1 forming immune complexes which can bind to macrophages, basophils and neutrophils and cause the release of anaphylactic mediators. METHODS: The model of epicutaneous sensitization used in this study relied on tape stripping the skin followed by direct application of peanut. Knockout mice and/or antibody neutralization studies were used to characterize anaphylaxis in this model. For the in vitro experiments, we used either peritoneal or bone marrow derived macrophages. We also collected samples from mice undergoing anaphylaxis at different time points to measure mediators involved. RESULTS: We found that anaphylaxis in this model of epicutaneous sensitization was dependent on IgG1, macrophages and PAF but not IgE, mast cells, basophils, neutrophils, monocytes and histamine. Additionally, IL-1α was critically required for anaphylaxis. Interestingly, this role was intracellular as both anti-IL-1α treatment and a deficiency in IL-1R failed to prevent anaphylaxis. Using macrophage cultures, we found that the activity of cPLA2, the enzyme responsible for PAF production, was intact in the absence of IL-1α. Likewise, the activity of PAF-AH, the enzyme that degrades PAF, was also unaffected in IL-1α-/- mice. We also showed that PAF signalling was intact in IL-1α-/- mice. Lastly, we showed that MDR1, the transporter for PAF was not critical for anaphylaxis in this model. CONCLUSION: We developed a model of skin sensitization in which anaphylaxis was driven by IgG1, macrophages and PAF. We identified intracellular IL-1α as a critical component of the alternative pathway of anaphylaxis. We also showed that this effect is not related to defects in PAF metabolism or signalling. This allows us to direct the focus on other pathways affected by IL-1α in our future studies.|
|Appears in Collections:||Open Access Dissertations and Theses|
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