Understanding IgE Biology

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的产生和成熟是如何控制的，而且还要了解B细胞IgE的生成和成熟是如何控制的。 免疫球蛋白E从起始点到全身远端分布的基本原理。整体而言 这项应用的目的是了解IgE产生和传播的生物学方面，并获得 洞察这一点在过敏性疾病中是如何受到影响的。新兴文献和来自 申请人提出了一个普遍的假设，即在以下情况下，生物制约因素共同作用来限制IgE的传播 动态平衡条件下，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。这一假设将通过追求三个具体的 目的：1)确定IgE B细胞上IgE表达动力学的机制；2)阐明 从起始点到效应部位的IgE分布的潜在机制；以及3)表征IgE血浆的特征 过敏患者体内的细胞。在第一个目标下，IgE mRNA剪接和IgE表面密度将在遗传上 对剪接偏差介导的稀释型IgE bcr密度限制独立IgE的假设感到不安 GC B细胞的进化潜能。在第二个目标下，解剖位置特异性过敏挑战的模型 将被部署来检查IgE分布在多大程度上偏向本地，以及幼稚的角色 旁观者B细胞在这一过程中。在第三个目标下，健康和过敏患者的骨髓愿望 将获得个体用于免疫球蛋白同型分辨的深度测序以及单细胞转录以 阐明长期严重变态反应患者中IgE的细胞来源和生物学特性。 这一贡献意义重大，因为它有望更完整地阐明IgE如何 反应是受监管的。归根结底，这样的知识有可能为新的 将有助于减少日益严重的过敏性疾病问题的战略。

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.