Understanding IgE Biology

了解 IgE 生物学

• 批准号: 10396243
• 负责人: Duane R. Wesemann
• 金额: $ 30万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396243
• 关键词: Affinity; Allergens; Allergic; Allergic Disease; Allergic inflammation; Alternative Splicing; Anaphylaxis; Anatomic Models; Antibodies; Antigens; Apoptosis; Asthma; B-Cell Antigen Receptor; B-Lymphocytes; Basophils; Biological; Biology; Bone Marrow; Bone Marrow Aspiration; Cell Degranulation; Cell Lineage; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Complex; Data; Development; Distal; Food; Food Hypersensitivity; Gene Expression Profiling; Geography; Health; Heavy-Chain Immunoglobulins; Human; Human Volunteers; Hypersensitivity; IgE; Immunity; Immunoglobulin Class Switching; 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; Surface; Surface Immunoglobulins; Systemic disease; Testing; Tissues; United States National Institutes of Health; Variant; Work; Yang; antigen binding; base; cytokine; deep sequencing; density; disability; experimental study; genetic manipulation; insight; mast cell; 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 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 LLPCs 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 cell function; 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 mRNA production away from the mIg splice variant (i.e. the BCR variant) restricts the number and longevity IgE expressing cells, thus constraining IgE secretion largely to the insult site. 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 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 免疫球蛋白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制要求 免疫球蛋白(Ig)E(IgE)分子可以对抗通常无害的物质。 当B细胞在IL-4或IL-13等细胞因子的作用下被激活时，B细胞可以经历高CSR到IgE。免疫球蛋白 B系细胞分泌的物质可以在同种抗原存在的情况下激活肥大细胞和嗜碱性粒细胞 释放有效的炎症介质。虽然免疫球蛋白E应答可以导致保护性免疫，作为 除了对多细胞病原体或其他有害威胁的专门反应外，它们也是过敏性疾病的基础。 过敏性疾病可表现为局部炎症，或多器官受累，包括致命的 IgE致敏的肥大细胞脱颗粒引起的全身过敏反应。因此，生产和生产 IgE的扩散在决定组织肥大细胞致敏的强度和程度方面起着重要作用。 因此，不仅要了解B细胞IgE的产生是如何控制的，而且要了解其原理 免疫球蛋白E从起始点到全身远端的潜在分布。这样做的总体目标是 应用是了解免疫球蛋白E产生和传播的生物学方面，并获得对 这在过敏性疾病中是如何受到影响的。来自申请者的新兴文献和初步数据表明 生物约束在体内平衡条件下协同抑制IgE传播的一般假说 条件下，骨髓中IgE LLPC的积聚是一种系统性的异常 过敏性疾病的表现。这个假设将通过追求三个具体目标来检验，这三个目标是：1) 确定IgE表达动力学对IgE B细胞功能的影响机制：2)阐明机制 基础的免疫球蛋白E分布从起始点到效应部位；和3)表征免疫球蛋白E浆细胞 过敏症患者。在第一个目标下，IgE mRNA剪接和IgE表面密度将受到遗传扰动 检验远离MiG剪接变异体(即BCR变异体)的信使核糖核酸产生受到限制的假设 表达IgE的细胞的数量和寿命，从而在很大程度上限制了IgE的分泌到损伤部位。在……下面 第二个目标，将部署解剖位置特定过敏挑战的模型来检查程度 IgE分布局部偏向，以及B细胞在这一过程中的作用。在第三个目标下，骨头 来自健康和过敏个体的骨髓愿望将被获取用于IgH同型解析的深度 测序和单细胞转录，以阐明细胞来源和生物学特性 长期严重过敏患者的免疫球蛋白E。这一贡献意义重大，因为预计它将 更全面地阐明免疫球蛋白E反应是如何被调节的。归根结底，这种知识具有 为新战略的发展提供信息的潜力，这些战略将有助于减少日益严重的过敏问题 疾病。