Cellular and molecular mechanisms of IgE cell memory in allergic responses

项目总结： 免疫球蛋白E抗体是过敏反应的重要介质。少量过敏原特异性IgE可导致 过敏反应危及生命，但过敏反应可以通过非特异性或低亲和力的IgE来预防。 因此，了解控制高亲和力和低亲和力IgE产生的机制是 最重要的是开发靶向治疗。我们实验室以前的工作证明了 免疫球蛋白E细胞不遵循经典的分化途径，这种途径已被很好地描述为免疫球蛋白细胞。免疫球蛋白 生发中心细胞是暂时性的和凋亡性的，不能产生长寿的浆细胞和功能性的IgE 存储单元。然而，高亲和力的IgE可以通过IgG1细胞向IgE的顺序转换而产生。 维持免疫球蛋白E反应记忆的机制还知之甚少。长期抗体 反应，通常是那些涉及免疫球蛋白抗体的反应，由重新激活的记忆B细胞维持 在再次暴露于抗原时，以及长期存活的浆细胞。可见，免疫球蛋白E的记忆机制 响应必须是唯一的，并且不同于对免疫球蛋白的记忆。在本应用程序中，我们将解决长期持续的 记忆反应中高亲和力和低亲和力IgE的细胞来源问题。最终，我们想要 了解怎样才能产生致病的IgE，并定义过程中可能遵循的步骤 治疗性干预。

Project Summary: IgE antibodies are essential mediators of allergic reactions. Small amounts of allergen-specific IgE can cause life-threatening anaphylaxis, but anaphylaxis can be prevented by non-specific or low affinity IgE. Understanding the mechanisms that control the production of high affinity and low affinity IgE is thus of outmost importance for the development targeted therapies. Previous work from our laboratory demonstrated that IgE cells do not follow the classical differentiation pathway that has been well described for IgG cells. IgE germinal center cells are transient and apoptotic, and fail to generate long lived plasma cells and functional IgE memory cells. Nevertheless, high affinity IgE can be generated by the sequential switching of IgG1 cells to IgE. The mechanisms that maintain the memory of IgE responses are poorly understood. Long-term antibody responses, typically those involving IgG antibodies, are maintained by memory B cells that are reactivated upon re-exposure to antigen, and by long lived plasma cells. It is clear that the mechanisms of memory of IgE responses must be unique and different from IgG memory. In this application, we will address the long-lasting question of the cellular origin of high and low affinity IgE in memory responses. Ultimately we want to understand what it takes to make pathogenic IgE, and define steps in the process that could be amenable to therapeutic intervention.