Regulation of IgE and Atopic Itch

IgE 和特应性瘙痒的调节

• 批准号: 10707185
• 负责人: Michelle E Conroy
• 金额: $ 64.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707185
• 关键词: Acute; Address; Affect; Affinity; Allergens; Allergic; Allergic Contact Dermatitis; Allergic inflammation; Antibodies; Asthma; Atopic Dermatitis; Basophils; Binding; Bullous Pemphigoid; Cell Degranulation; Cell surface; Childhood; Chronic; Chronic Disease; Development; Disease; Disease remission; Flare; Food Hypersensitivity; Foundations; Glycobiology; Goals; Histamine; Human; IgE; Immunology; Inflammation; Knowledge; Leukotriene C4; Leukotrienes; Mediating; Mediator; Mission; Mus; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Process; Production; Pruritus; Public Health; Regulation; Relapse; Role; Sampling; Severities; Sialic Acids; Skin; Testing; Time; United States National Institutes of Health; Urticaria; Variant; Work; crosslink; effective therapy; environmental allergen; glycosylation; human model; in vivo; innovation; mast cell; mouse model; novel marker; novel therapeutics; pyroglyphid; receptor; response; sialylation; sugar

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.

项目摘要 当前的过敏性注射范式断言，FcεR1结合到过敏原的过敏原交联 特定的IgE导致肥大细胞和嗜碱性粒细胞退化以及效应分子（例如组胺和）的释放 白细胞。广告是一种经典的过敏症，例如哮喘和食物过敏，也是最常见的慢性疾病 童年时期，通常是终身疾病1。但是，IgE在AD发病机理中的具体作用不太好 表征和有争议2,3。在2021年，Kim Lab表明IgE介导的肥大刺激触发器 组胺引起的瘙痒处于稳定状态。有趣的是，在类似AD的条件下，IgE触发了嗜碱性粒细胞 通过介体白三烯C4（LTC4）的非希斯明能瘙痒。广告患者显示出增加 与急性瘙痒相关的IgE反应性和嗜碱性激活4。同时，我们的研究表明 第一次，IgE糖基化，特别是唾液酸，是IgE致病性的确定。 IgE的唾液酸含量增加导致鼠和 人类模型5。我们的研究提出了可以将IgE致病性多样化以控制的可能性 通过改变糖基化的细胞反应。与IgE细胞中的变化在一起 Kim博士的组以稳定状态和广告相关的相互作用的相互作用，我们的中心假设是 独特的IgE糖基化模式可在稳态下增强肥大细胞介导的瘙痒，同时也 在AD中促进粒细胞介导的急性瘙痒。我们将检验我们的中心假设并实现目标 通过追求以下三个特定目的来应用：1）在 稳定状态？ 2）与广告相关的注射会导致产生不同的糖基型IgE？ 3）确定人类AD中的瘙痒性IgE糖基化模式。特定IgE糖基化在 在AD中造成瘙痒是未知的，这些过程的调节定义很差。这项工作 提案将使我们能够实现我们的长期目标，以建立IgE糖基化和嗜碱性粒细胞如何 针对瘙痒和广告产生创新的治疗方法。我们建议的总体目的是测试 IgE糖基化分别影响肥大细胞和嗜碱性激活的机制，有助于 不同形式的瘙痒的发展。迫切需要解密IgE糖基化在AD中的作用 为了产生与广告相关瘙痒的更有效疗法。这些研究将超越广告影响 暗示IgE和瘙痒的疾病，包括过敏性接触性皮炎，大胆的Pemphigoid和 慢性赞助的荨麻疹等具有共有肥大细胞和/或嗜碱性病理学。