Project 2: Innate Immune Pathways in Food-induced Anaphylaxis

点击翻译按钮获取中文摘要

SUMMARY – Project 2 Food allergy is mediated by IgE triggering of mast cells and basophils. We found that peanut-specific IgE and basophil activation test could distinguish allergic from sensitized individuals, but had no utility in predicting reaction severity during double blind placebo controlled food challenges (DBPCFC). Distinguishing mild from potentially severe reactions would be of major clinical benefit. Transcriptional profiling identified a neutrophil signature that was associated not only with reactions to peanut, but also with severity of reactions. Flow cytometry profiling identified a significant increase in circulating neutrophils post-challenge, and preliminary data shows a change in neutrophil phenotype consistent with activation. Although neutrophils have been shown to be activated by IgG-allergen complexes, it is unlikely that there would be significant immune complex formation due to the low dose of peanut exposure. Neutrophils have been shown to be responsive to serotonin metabolites, and in preliminary data we demonstrate that activation of whole blood with peanut induces serotonin release. Human mast cells (and potentially basophils) produce low levels of serotonin, but platelets are a major source of serotonin in the circulation and can release it upon activation. We have previously shown that platelets form complexes with basophils in blood from peanut allergic individuals upon exposure to peanut. We hypothesize that basophil-platelet complexes are responsible for the release of serotonin, which then activates neutrophils in the context of food allergy. We will test this hypothesis with three specific aims. The first aim will use spectral flow cytometry and RNA sequencing to examine neutrophil and other innate immune activation during DBPCFC. The second aim will examine the release of serotonin and serotonin metabolites during reactions and test the role of serotonin and metabolites in neutrophil activation. The third aim will examine the contribution of basophil platelet complexes to the production of serotonin in response to peanut exposure. Successful completion of these aims will reveal novel innate immune mechanisms of severe reactions to peanut, leading the way to new interventions for the prevention of severe peanut allergy.