Regulation of IgE responses by B cell receptor signaling

项目总结/摘要 过敏性疾病，包括哮喘、过敏性鼻炎和食物过敏，在美国一直在稳步增加。 发病率和对儿童影响不成比例。过敏反应可在暴露于 一种与肥大细胞和嗜碱性粒细胞上的IgE抗体结合的过敏原，这些细胞然后去免疫并释放 强效促炎介质。如果这种反应是全身性的，称为过敏反应，它可能是生命- 威胁。然而，尽管IgE在过敏性疾病中的重要性，但调节IgE的内在机制仍然存在。 表达IgE的B细胞仍不清楚。最近的技术进步使得直接检测和 使小鼠中的IgE+ B细胞可视化，揭示了IgE+ B细胞经历了一个流产的生发中心期， 倾向于分化成短命的浆细胞。IgE+ B细胞的这些特性抑制IgE 因此可以帮助保护健康个体免受过敏和过敏反应。最近 研究表明，小鼠IgE+ B细胞的独特特征主要是由于表达 膜IgE B细胞受体，与其他同种型相比，其具有弱的慢性信号传导活性。 本研究的总体目标是确定B细胞受体信号传导如何调节IgE+ B细胞应答 以及这些发现是否适用于人类B细胞。本研究的具体目标是：（1） 阐明B细胞受体信号传导调节IgE浆细胞应答的机制，2） 表征B细胞受体信号传导在衰老中心IgE+ B细胞动力学中的作用，和3） 确定人IgE B细胞受体是否以与小鼠IgE B细胞类似的方式调节IgE应答 受体。这些研究的结果将帮助我们了解IgE介导的过敏反应是如何有效的， 是在分子水平上控制的。 .

Project Summary/Abstract Allergic diseases, including asthma, allergic rhinitis, and food allergy, have been steadily increasing in incidence and disproportionately affect children. Allergic responses can be triggered rapidly upon exposure to an allergen that binds to IgE antibodies on mast cells and basophils; these cells then degranulate and release potent pro-inflammatory mediators. If this response occurs systemically, known as anaphylaxis, it can be life- threatening. However, despite the importance of IgE in allergic disease, the intrinsic mechanisms that regulate IgE-expressing B cells remain unclear. Recent technical advances have made it possible to directly detect and visualize IgE+ B cells in mice, revealing that IgE+ B cells undergo an abortive germinal center phase and are predisposed to differentiate into short-lived plasma cells. These properties of IgE+ B cells restrain IgE responses and therefore may help protect against allergy and anaphylaxis in healthy individuals. Recent studies have demonstrated that the distinct features of mouse IgE+ B cells are largely due to the expression of the membrane IgE B cell receptor, which has weak, chronic signaling activity compared with other isotypes. The overall objective of this study is to determine how B cell receptor signaling regulates IgE+ B cell responses in mice and whether these findings are applicable to human B cells. The specific goals of this study are to 1) elucidate the mechanisms by which B cell receptor signaling regulates IgE plasma cell responses, 2) to characterize the role of B cell receptor signaling in the dynamics of IgE+ B cells in germinal centers, and 3) to determine whether human IgE B cell receptors regulate IgE responses in a similar fashion to mouse IgE B cell receptors. The results from these studies will help us understand how potent IgE-mediated allergic responses are controlled at a molecular level. .