Regulation of IgE and Atopic Itch

IgE 和特应性瘙痒的调节

• 批准号: 10584784
• 负责人: Michelle E Conroy
• 金额: $ 66.23万
• 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/10584784
• 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; Flare; Food Hypersensitivity; Foundations; Glycobiology; Goals; Histamine; Human; IgE; Immunology; Inflammation; Knowledge; Leukotriene C4; Leukotrienes; Mediating; Mediator of activation protein; 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; in vivo; innovation; mast cell; mouse model; novel marker; novel therapeutics; pyroglyphid; receptor; response; 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 目前过敏性炎症的研究范式认为，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颗粒和释放效应分子如组胺， 白三烯AD是一种典型的过敏性疾病，与哮喘和食物过敏一样，是最常见的慢性疾病 这是一种儿童疾病，通常是一种终身疾病1。但IgE在AD发病机制中的特异性作用尚不清楚 有争议的和有争议的2，3。2021年，Kim实验室显示IgE介导的肥大细胞刺激触发了 稳定状态下组胺引起的瘙痒有趣的是，在AD样条件下，IgE触发嗜碱性粒细胞引起 通过介体白三烯C4（LTC 4）的非组胺能瘙痒。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。同时，我们的研究表明， 第一次发现IgE糖基化，特别是唾液酸，是IgE致病性的决定因素。 IgE的唾液酸含量增加导致小鼠和小鼠中肥大细胞脱颗粒更显著， 人体模型5.我们的研究提出了IgE的致病性可以通过间接调节来控制的可能性。 通过改变糖基化的细胞反应。结合IgE细胞内 Kim博士的小组证明了稳态和AD相关瘙痒的相互作用，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，同时还 促进AD中嗜碱性粒细胞介导的急性瘙痒发作。我们将检验我们的中心假设， 通过追求以下三个具体目标来实现本申请的目的：1）IgE的不同糖型是否介导瘙痒， 稳定状态？2)AD相关炎症是否导致IgE不同糖型的产生？ 3)鉴定人类AD中瘙痒特异性IgE糖基化模式。特异性IgE糖基化在免疫调节中的作用 导致AD瘙痒的原因尚不清楚，并且这些过程的调节也不清楚。从这个工作 这项提案将使我们能够追求我们的长期目标，即确定IgE糖基化和嗜碱性粒细胞如何能够被 针对瘙痒和AD的创新疗法。我们建议的总体目标是测试 IgE糖基化分别影响肥大细胞和嗜碱性粒细胞活化的机制， 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 以获得更有效的治疗AD相关瘙痒的方法。这些研究将产生超越AD的影响 涉及IgE和瘙痒的疾病，包括变应性接触性皮炎、大疱性类天疱疮和 慢性自发性荨麻疹，其中包括共同的肥大细胞和/或嗜碱性粒细胞病理。