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 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制要求， 免疫球蛋白（IG）E（IgE）分子是针对通常无害的物质产生的。 在细胞因子如IL-4或IL-13的环境中活化后，B细胞可经历IgH CSR至IgE。IgE 在同源抗原存在下，从B谱系细胞分泌的CD 4 + T细胞可以激活肥大细胞和嗜碱性粒细胞， 释放强有力的炎症介质。虽然IgE反应可以导致保护性免疫， 它们对多细胞病原体或其他有害威胁的特殊反应，也是过敏性疾病的基础。 过敏性疾病可以表现为局部炎症，或多器官受累，包括致命的 通过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 IgE的扩散在决定组织肥大细胞致敏的强度和程度方面起重要作用。 因此，不仅要了解如何控制B细胞IgE的产生，而且要了解其原理， IgE从起源点到全身远端部位的潜在分布。本报告的总体目标 应用的目的是了解IgE产生和传播的生物学方面，并深入了解 这在过敏性疾病中是如何影响的。来自申请人的新兴文献和初步数据表明 一个普遍的假设，即生物约束合作，以限制IgE传播下稳态 条件下，和骨髓IgE LLPC的积累是一个异常的基础系统性 过敏性疾病的表现。这一假设将通过追求三个具体目标来检验，这三个目标是： 确定IgE表达动力学对IgE B细胞功能的机制; 2）阐明机制 从起源点到效应位点的潜在IgE分布;以及3）表征在免疫缺陷病毒中的IgE浆细胞。 过敏患者在第一个目标下，IgE mRNA剪接和IgE表面密度将受到遗传干扰， 检查mRNA产生远离mIg剪接变体（即BCR变体）限制的假设 表达IgE的细胞的数量和寿命，从而将IgE分泌主要限制在损伤部位。下 第二个目标，将部署解剖位置特异性过敏性激发模型，以检查 IgE的分布是局部偏向的，以及B细胞在这一过程中的作用。在第三个目标下，骨头 将从健康和过敏个体获得骨髓抽吸物，用于IgH同种型分辨的深 测序以及单细胞转录组学，以阐明细胞来源和生物学特性， 长期严重过敏患者的IgE。这一贡献意义重大，因为预计 阐明了一个更完整的图片IgE反应是如何调节。最终，这些知识 潜在的通知新战略的发展，这将有助于减少日益严重的问题，过敏 疾病