Cellular and molecular mechanisms of IgE cell memory in allergic responses

项目摘要： IgE抗体是过敏反应的基本介质。少量的过敏原特异性IgE可导致 危及生命的过敏反应，但过敏反应可以通过非特异性或低亲和力IgE预防。 因此，了解控制高亲和力和低亲和力IgE产生的机制是重要的。 对靶向治疗的发展至关重要。我们实验室以前的工作表明， IgE细胞并不遵循IgG细胞已充分描述的经典分化途径。IgE 生发中心细胞是短暂的和凋亡的，不能产生长寿命的浆细胞和功能性IgE 记忆细胞然而，高亲和力IgE可以通过IgG1细胞向IgE的顺序转换来产生。 维持IgE反应记忆的机制知之甚少。长期抗体 免疫应答，通常是那些涉及IgG抗体的应答，是由被重新激活的记忆B细胞维持的 在再次暴露于抗原时，以及通过长寿命的浆细胞。很明显，IgE的记忆机制 应答必须是唯一的，并且不同于IgG记忆。在本申请中，我们将解决长期存在的 记忆反应中高和低亲和力IgE的细胞起源问题。最终我们希望 了解如何制造致病性IgE，并确定过程中可能适用的步骤 治疗干预

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.