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.

项目概要 目前过敏性炎症的范例断言 FcεR1 与过敏原结合的过敏原交联 特异性 IgE 导致肥大细胞和嗜碱性粒细胞脱粒并释放效应分子，如组胺和 白三烯。 AD 是一种典型的过敏性疾病，如哮喘和食物过敏，也是最常见的慢性疾病 童年时期的疾病，通常是一种终生疾病1。然而，IgE在AD发病机制中的具体作用尚不清楚 特征和争议2,3。 2021 年，Kim 实验室表明 IgE 介导的肥大细胞刺激会触发 稳定状态下组胺引起的瘙痒。有趣的是，在类似 AD 的条件下，IgE 会触发嗜碱性粒细胞 通过介质白三烯 C4 (LTC4) 产生非组胺能瘙痒。 AD 患者表现出增加 IgE 反应性和嗜碱性粒细胞活化与急性瘙痒发作相关4。与此同时，我们的研究表明 首次证明 IgE 糖基化，特别是唾液酸，是 IgE 致病性的决定因素。 IgE 唾液酸含量的增加导致小鼠和小鼠的肥大细胞脱粒更加显着。 人体模型5.我们的研究提出了一种可能性，即可以通过不同方式调节 IgE 的致病性来控制 通过改变糖基化来调节细胞反应。结合细胞 IgE 的变化 Kim 博士的团队证明了稳态和 AD 相关瘙痒之间的相互作用，我们的中心假设是 独特的 IgE 糖基化模式导致稳定状态下肥大细胞介导的瘙痒增强，同时也 促进嗜碱性粒细胞介导的 AD 急性瘙痒发作。我们将检验我们的中心假设并实现目标 通过追求以下三个具体目标来研究该应用程序：1) IgE 的不同糖型是否介导瘙痒 稳定状态？ 2) AD 相关炎症是否会导致不同糖型 IgE 的产生？ 3) 识别人类 AD 中瘙痒特异性 IgE 糖基化模式。特异性 IgE 糖基化的作用 导致 AD 瘙痒的因素尚不清楚，并且这些过程的调节也不清楚。作品从这里 该提案将使我们能够实现我们的长期目标，即确定 IgE 糖基化和嗜碱性粒细胞如何 旨在开发针对瘙痒和 AD 的创新疗法。我们提案的总体目标是测试 IgE 糖基化分别影响肥大细胞和嗜碱性粒细胞活化的机制，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 努力为 AD 相关瘙痒提供更有效的治疗方法。这些研究的影响将超越AD 与 IgE 和瘙痒有关的疾病，包括过敏性接触性皮炎、大疱性类天疱疮和 慢性自发性荨麻疹等具有共同的肥大细胞和/或嗜碱性粒细胞病理学。