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.

项目概要 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而产生的。 在 IL-4 或 IL-13 等细胞因子激活后，B 细胞可以经历 IgH CSR 转化为 IgE。免疫球蛋白E B 谱系细胞分泌的 B 谱系细胞在存在同源抗原的情况下可以激活肥大细胞和嗜碱性粒细胞 释放强效炎症介质。虽然 IgE 反应可以导致保护性免疫，作为免疫反应的一部分 它们是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全身过敏反应。因此，生产和 IgE 的传播在决定组织肥大细胞致敏的强度和程度方面发挥着重要作用。 因此，不仅了解 B 细胞 IgE 的产生和成熟是如何控制的，而且了解 B 细胞 IgE 的产生和成熟也至关重要。 IgE 从起源点到全身远端部位分布的基本原理。整体 该应用的目的是了解 IgE 产生和传播的生物学方面，并获得 深入了解这对过敏性疾病的影响。新兴文献和初步数据 申请人提出了一个一般性假设，即生物约束在条件下协同限制 IgE 传播 稳态条件下，骨髓 IgE 长寿命浆细胞的积累是一种异常 过敏性疾病的潜在全身表现。这个假设将通过追求三个具体的 目标是： 1) 确定 IgE B 细胞上 IgE 表达动态的机制； 2）阐明 IgE 从起始点到效应位点分布的机制； 3) 表征 IgE 血浆 过敏患者的细胞。在第一个目标下，IgE mRNA 剪接和 IgE 表面密度将在遗传上 不安地检验剪接偏倚介导的稀释 IgE BCR 密度限制独立 IgE 的假设 GC B细胞进化潜力。在第二个目标下，解剖位置特异性过敏挑战模型 将被部署来检查 IgE 分布局部偏差的程度，以及 naïve 的作用 B细胞是这个过程的旁观者。在第三个目标下，健康和过敏者的骨髓穿刺 将获得个体进行 IgH 同种型解析深度测序以及单细胞转录组学，以 阐明长期严重过敏患者 IgE 的细胞来源和生物学特性。 这一贡献意义重大，因为它有望更全面地阐明 IgE 如何 反应受到监管。最终，这些知识有可能为新的开发提供信息 有助于减少日益严重的过敏性疾病问题的策略。