Molecular basis for the regulation of IgE class switch recombination by IL-21 and STAT3

项目概要/摘要 变态反应性疾病的发病率在现代化社会中一直在稳步增加，并代表了一种新的疾病。 重大公共卫生问题。过敏反应的主要触发因素之一是由IgE抗体介导的 对过敏原成分有特异性。这些IgE抗体由终末分化的IgE血浆分泌 细胞，其来源于已经历类别转换重组为IgE的B细胞。最近 技术进步使得能够直接研究小鼠和人中表达IgE的B细胞。一 流行的范例是，类转换重组IgE发生在2型免疫的背景下， 反应，如过敏性疾病模型和寄生虫感染，而类转换重组IgE 在针对病毒和细菌的1型免疫反应中是不利的。然而，我们发现，IgE类 开关重组在大多数类型的免疫应答下被细胞因子IL-21广泛抑制， 通过B细胞中的IL-21受体和STAT 3起作用。本研究的总体目标是确定 IL-21-STAT 3轴负调节IgE类别转换重组的分子基础。的 本研究的具体目标是：1）表征IL-21调节IgE类的分子机制 转换重组和2）鉴定参与调节IgE类别转换重组的新基因。 这些研究的结果将帮助我们了解IgE的初始类别转换是如何调节的，从而 让我们深入了解过敏性致敏是如何在分子水平上发生的。

Project Summary/Abstract The incidence of allergic diseases has been steadily increasing in modernized societies and represents a major public health problem. One of the main triggers of allergic responses is mediated by IgE antibodies specific for allergen components. These IgE antibodies are secreted by terminally differentiated IgE plasma cells, which are derived from B cells that have undergone class switch recombination to IgE. Recent technological advances have enabled the direct study of IgE-expressing B cells in mice and humans. A prevailing paradigm is that class switch recombination to IgE occurs in the context of type 2 immune responses, such as allergic disease models and parasitic infection, whereas class switch recombination to IgE is disfavored under type 1 immune responses to viruses and bacteria. We have found, however, that IgE class switch recombination is broadly restrained under most types of immune responses by the cytokine IL-21, acting through the IL-21 receptor and STAT3 in B cells. The overall objective of this study is to determine the molecular basis by which the IL-21-STAT3 axis negatively regulates IgE class switch recombination. The specific goals of this study are to: 1) characterize the molecular mechanism by which IL-21 regulates IgE class switch recombination and 2) identify new genes involved in the regulation of IgE class switch recombination. The results from these studies will help us understand how the initial class switch to IgE is regulated, thereby giving us insights into how allergic sensitization occurs at a molecular level.