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

项目摘要/摘要 在现代化社会中，过敏性疾病的发病率一直在稳步上升，这代表着一种 重大的公共卫生问题。过敏反应的主要诱因之一是由IgE抗体介导的 专门针对过敏原成分。这些IgE抗体是由终末分化的IgE血浆分泌的 B细胞经类切换重组为IgE后的细胞。近期 技术进步使在小鼠和人类中直接研究表达IgE的B细胞成为可能。一个 流行的模式是在2型免疫的背景下发生类切换到IgE的重组 反应，如过敏性疾病模型和寄生虫感染，而类切换到IgE重组 在对病毒和细菌的1型免疫反应下是不受欢迎的。然而，我们发现，IgE类 开关重组在大多数类型的免疫反应中都受到细胞因子IL-21的广泛抑制， 通过B细胞中的IL-21受体和STAT3发挥作用。这项研究的总体目标是确定 IL-21-STAT3轴负性调节IgE类开关重组的分子基础。这个 本研究的具体目标是：1)研究IL-21调节IgE类的分子机制 2)发现参与调节IgE类开关重组的新基因。 这些研究的结果将帮助我们理解最初的班级向IgE的转换是如何调节的，从而 让我们深入了解过敏敏化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.