Understanding IgE Biology

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B细胞IgE的产生和成熟是如何被控制的，而且要了解IgE的产生和成熟是如何被控制的。 IgE从起源点到全身远端部位的分布原理。整体 本申请的目的是了解IgE产生和传播的生物学方面， 了解这在过敏性疾病中的影响。新出现的文献和初步数据 申请人提出了一个一般性假设，即生物学约束条件协同作用， 稳态条件下，骨髓IgE长寿浆细胞的积累是一种异常 过敏性疾病的潜在全身表现。这一假设将通过以下三个具体的测试来检验： 目的是：1）确定IgE B细胞表达IgE的动力学机制; 2）阐明 IgE从起源点到效应位点分布的潜在机制;和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表面密度将在遗传学上被确定。 为了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性激发模型 将部署检查IgE分布局部偏倚的程度，以及幼稚型IgE的作用。 旁观者B细胞参与了这个过程。在第三个目标下，健康和过敏的骨髓穿刺 将获得个体用于IgH同种型分辨深度测序以及单细胞转录组学， 阐明长期严重过敏患者中IgE的细胞来源和生物学特性。 这一贡献是重要的，因为它有望阐明一个更完整的画面，如何IgE 反应是有规律的。最终，这些知识有可能为新的发展提供信息， 这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.