Regulation of IgE and Atopic Itch

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PROJECT SUMMARY The current paradigm of allergic inflammation asserts that allergen crosslinking of FcεR1-bound to allergen- specific IgE leads to mast cell and basophil degranulation and release of effector molecules like histamine and leukotrienes. AD is a classic allergic disorder like asthma and food allergy and the most common chronic illness of childhood and is often a lifelong disease1. However, the specific role of IgE in AD pathogenesis is not well characterized and controversial2,3. In 2021, the Kim lab showed that IgE-mediated mast cell stimulation triggers histamine-induced itch in the steady state. Intriguingly, under AD-like conditions, IgE triggers basophils to elicit non-histaminergic itch through the mediator leukotriene C4 (LTC4). Patients with AD demonstrated increased IgE reactivity and basophil activation in association with acute itch flares4. In parallel, our studies demonstrated for the first time that IgE glycosylation, and specifically sialic acid, is a determinant of IgE pathogenicity. Increased sialic acid content of IgE resulted in more significantly mast cell degranulation in both murine and human models5. Our studies raised the possibility that pathogenicity of IgE can be variably regulated to control cellular responses through alterations in glycosylation. Taken together with the variations in IgE cellular interactions in steady state and AD-associated itch demonstrated by Dr. Kim's group, our central hypothesis is that unique IgE glycosylation patterns result in enhanced mast cell-mediated itch in the steady state, while also promoting basophil-mediated acute itch flares in AD. We will test our central hypothesis and attain the objective of the application by pursuing the following three specific aims: 1) Do different glycoforms of IgE mediate itch in the steady state?; 2) Does AD-associated inflammation result in the production of different glycoforms of IgE?; 3) Identify itch-specfic IgE glycosylation patterns in human AD. The role of specific IgE glycosylation in contributing to itch in AD is unknown and regulation of these processes is poorly defined. The work from this proposal will allow us to pursue our long-term goal of establishing how IgE glycosylation and basophils can be targeted to yield innovative treatments for itch and AD. The overall objective of our proposal is to test the mechanisms by which IgE glycosylation affects mast cell and basophil activation, respectively, contributing to the development of different forms of itch. There is an urgent need to decrypt the role of IgE glycosylation in AD in an effort to yield more effective therapies for AD-associated itch. These studies will have impact beyond AD to diseases in which IgE and itch are implicated including allergic contact dermatitis, bullous pemphigoid, and chronic spontaneous urticaria among others with shared mast cell and/or basophil pathologies.