Understanding IgE Biology

了解 IgE 生物学

• 批准号: 10375189
• 负责人: Duane R. Wesemann
• 金额: $ 68.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375189
• 关键词: Affinity; Allergens; Allergic; Allergic Disease; Allergic inflammation; Alternative Splicing; Anaphylaxis; Anatomic Models; Antibodies; Antigens; Apoptosis; B-Cell Antigen Receptor; B-Lymphocytes; Basophils; Biological; Biology; Bone Marrow; Bone Marrow Aspiration; Cell Degranulation; Cell Lineage; Cell Surface Receptors; Cell Survival; Cell surface; Cells; Complex; Data; Development; Distal; Evolution; Food; Gene Expression Profiling; Geography; Health; Heavy-Chain Immunoglobulins; Human; Human Volunteers; Hypersensitivity; IgE; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Individual; Inflammation; Inflammation Mediators; Interleukin-13; Interleukin-4; Knowledge; Lead; Literature; Location; Longevity; Mediating; Membrane; Memory; Memory B-Lymphocyte; Messenger RNA; Mission; Mus; Nature; Pathogenesis; Patients; Pattern; Peripheral; Plants; Plasma Cells; Plasmablast; Play; Process; Production; Property; Proteins; Public Health; RNA Splicing; Research; Role; Signal Transduction; Site; Source; Stimulus; Structure of germinal center of lymph node; Surface; Surface Immunoglobulins; Systemic disease; Testing; Tissues; United States National Institutes of Health; Variant; Work; antigen binding; base; cytokine; deep sequencing; density; disability; experimental study; genetic manipulation; insight; mast cell; mouse model; pathogen; receptor density; response; transcriptomics

Project Summary IgE-mediated allergic disease is a growing problem. The pathogenesis of allergic disease requires that immunoglobulin (Ig) E (IgE) molecules be produced against what are otherwise usually innocuous substances. Upon activation in the setting of cytokines such as IL-4 or IL-13, B cells can undergo IgH CSR to IgE. IgE secreted from B lineage cells can, in the presence of cognate antigen, activate mast cells and basophils to release potent inflammatory mediators. While IgE responses can lead to protective immunity as a part of a specialized responses to multicellular pathogens or other noxious threats, they also underlie allergic disease. Allergic disease can be manifest by localized inflammation, or by multiorgan involvement, including deadly systemic anaphylactic reactions via IgE-sensitized mast cell degranulation. Thus, the production and dissemination of IgE play a significant role in dictating the strength and extent of tissue mast cell sensitization. It is therefore critical to understand not only how B cell IgE production and maturation is controlled, but also the principles underlying distribution of IgE from point of origin to distal sites throughout the body. The overall objective of this application is to understand biological aspects of IgE production and dissemination and to gain insights into how this is influenced in allergic disease. Emerging literature and preliminary data from the applicant suggest a general hypothesis that biological constraints cooperate to restrict IgE dissemination under homeostatic conditions, and that accumulation of bone marrow IgE long-lived plasma cells is an aberrancy underlying systemic manifestations of allergic disease. This hypothesis will be tested by pursuing three specific aims, which are: 1) to determine the mechanisms of IgE expression dynamics on IgE B cells; 2) to elucidate mechanisms underlying IgE distribution from point of origin to effector sites; and 3) to characterize IgE plasma cells in allergic patients. Under the first aim, IgE mRNA splicing and IgE surface density will be genetically perturbed to examine the hypothesis that splice bias-mediated dilute IgE BCR density limits independent IgE GC B cell evolution potential. Under the second aim, models of anatomic location-specific allergic challenge will be deployed to examine the degree to which IgE distribution is locally biased, and the role of naïve bystander B cells in this process. Under the third aim, bone marrow aspirations from healthy and allergic individuals will be obtained for IgH isotype-resolved deep sequencing as well as single cell transcriptomics to elucidate the cellular sources and biological properties of IgE in patients with long-standing severe allergies. This contribution is significant because it is expected to elucidate a more complete picture of how IgE responses are regulated. Ultimately, such knowledge has the potential to inform the development of new strategies that will help to reduce the growing problem of allergic disease.

项目摘要 IgE介导的过敏性疾病是一个日益严重的问题。过敏性疾病的发病机理要求 免疫球蛋白（Ig）E（IgE）分子是针对通常是无害物质的。 在激活IL-4或IL-13等细胞因子的情况下，B细胞会经历IGE CSR到IgE。 Ige 从B谱系细胞分泌的可以在存在同源抗原的情况下激活肥大细胞和嗜碱性粒细胞 释放潜在的炎症介体。虽然IgE的反应可以导致保护性免疫 对多细胞病原体或其他有害威胁的专门反应也是过敏性疾病的基础。 过敏性疾病可以通过局部感染或多机器人参与来表现，包括致命 通过对IgE敏感的肥大细胞脱粒的全身过敏反应。那，生产和 IgE的传播在决定组织肥大细胞敏感性的强度和程度方面起着重要作用。 因此，至关重要的是，不仅了解B细胞IgE的产生和成熟是如何控制的，而且还要 IgE从原点到整个身体远端位点的原理。总体 该应用的目的是了解IgE生产和传播的生物学方面并获得 洞察这是如何影响过敏性疾病的。新兴文学和初步数据 申请人提出了一个普遍的假设，即生物学约束合作以限制IgE传播 稳态条件以及骨髓的积累长期浆细胞是一种异常 过敏性疾病的潜在系统表现。该假设将通过追求三个特定的特定来检验 目的是：1）确定IgE B细胞上IgE表达动力学的机制； 2）阐明 IgE分布从原点到效应位点的机制； 3）表征IgE等离子体 过敏患者的细胞。在第一个目标下，IgE mRNA剪接和IgE表面密度通常是 扰动以检查剪接偏置介导的稀释的IgE BCR密度独立的假设 GC B细胞演化潜力。在第二个目标下，解剖特定位置过敏挑战的模型 将部署以检查IgE分布在局部偏见的程度以及幼稚的作用 在此过程中，旁观者B细胞。在第三个目标下，健康和过敏性的骨髓质量 对于IGH同种型分解的深度测序以及单细胞转录组学将获得个体 阐明了长期严重过敏的患者IgE的细胞来源和生物学特性。 这项贡献很重要，因为有望阐明IgE如何更完整的情况 响应受到调节。最终，这种知识有可能告知新的发展 将有助于减少过敏性疾病日益严重的问题的策略。