Regulation of IgE responses by B cell receptor signaling

项目摘要/摘要 过敏性疾病，包括哮喘、过敏性鼻炎和食物过敏，在#年一直在稳步增加。 发病率高，对儿童的影响也不成比例。暴露在空气中可迅速引发过敏反应 一种过敏原，与肥大细胞和嗜碱性粒细胞上的IgE抗体结合；然后这些细胞脱颗粒并释放 强有力的促炎调停剂。如果这种反应是系统性的，也就是所谓的过敏反应，它可能是生命- 具有威胁性。然而，尽管IgE在过敏性疾病中很重要，但调节 表达Ige的B细胞仍不清楚。最近的技术进步使直接检测和检测 在小鼠中观察到IgE+B细胞，发现IgE+B细胞经历了一个流产的生发中心期，并且 容易分化成短暂的浆细胞。IgE+B细胞的这些特性抑制了IgE 因此，这可能有助于预防健康个体的过敏和过敏反应。近期 研究表明，小鼠IgE+B细胞的明显特征在很大程度上是由于其表达 膜上的IgE B细胞受体，与其他同型相比，具有微弱的慢性信号活性。 这项研究的总体目标是确定B细胞受体信号如何调节IgE+B细胞反应 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细胞受体信号调节IgE浆细胞反应的机制，2) 描述B细胞受体信号在生发中心的IgE+B细胞动力学中的作用，以及3) 确定人IgE B细胞受体是否以类似于小鼠IgE B细胞的方式调节IgE反应 感受器。这些研究的结果将帮助我们了解免疫球蛋白E介导的过敏反应 都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. .