Novel Roles of IgE Glycosylation in Anaphylaxis

项目概要/摘要。 目前尚不清楚为什么有些过敏原特异性IgE的人患有过敏症，而其他人则没有。是 可能有多种因素起作用，包括IgE亲和力的差异或过敏原的表位多样性，肥大 细胞数量、FcεRI表达水平、Syk信号传导、过敏原特异性IgG抗体和抗IgE抗体。 尚未考虑的另外因素是糖基化对IgE的贡献。我们的长期目标是 了解抗体的糖基化是如何调节的，以及如何被免疫反应所调节。我们的中央 一种假说是IgE效应子功能由不同位置的确定聚糖差异调节。 实际上，这得到了本申请中所示的初步数据的支持。这是一个基本的理由， 一项被提议的研究是，了解特异性IgE聚糖对过敏性炎症的作用， 使新的和创新的过敏疗法。我们将测试我们的中心假设，从而达到 通过追求以下三个具体目标来实现本申请的目的：1）定义IgE聚糖 FcεRI结合的要求; 2）确定唾液酸如何调节IgE介导的过敏反应; 3）检查 体内IgE糖基化的调节。利用结合生物物理学、细胞和分子的方法 免疫学和糖生物学，我们将确定IgE-FcεRI相互作用所必需的聚糖， 抗过敏途径，建立致病性IgE糖基化模式，并通过 调节IgE聚糖。除了能够发现标记引起过敏的IgE的生物标志物外， 这里的研究将潜在地导致鉴定过敏性疾病的新的治疗靶点。最后这些 研究将对IgE参与的疾病产生超越过敏的影响，包括系统性狼疮 红斑狼疮（SLE）和蠕虫感染。 !

Project Summary/Abstract. It is not clear why some individuals with allergen-specific IgE suffer from allergies, while others do not. It is likely that multiple factors contribute, including differences in IgE affinity or epitope diversity for allergens, mast cell numbers, FcεRI expression levels, Syk signaling, allergen-specific IgG antibodies, and anti-IgE antibodies. An addition factor that has not been considered is the contribution of glycosylation to IgE. Our long-term goal is to understand how glycosylation of antibodies regulates, and is regulated, by immune responses. Our central hypothesis is that IgE effector function is regulated differentially by defined glycans at distinct positions. Indeed, this is supported by preliminary data shown in this application. The rationale that underlies the proposed research is that understanding the contribution of specific IgE glycans to allergic inflammation will enable new and innovative allergic therapies. We will test our central hypothesis and, thereby, attain the objective of this application by pursuing the following three specific aims: 1) Define the IgE glycan requirements for FcεRI binding; 2) Determine how sialic acid regulates IgE-mediated anaphylaxis; 3) Examine the regulation of IgE glycosylation in vivo. Using an approach that combines biophysics, cellular and molecular immunology, and glycobiology, we will determine glycans a essential for IgE-FcεRI interactions, define a novel anti-anaphylactic pathway, establish pathogenic IgE glycosylation patterns, and attenuate anaphylaxis by modulating IgE glycans. In addition to enabling discovery of biomarkers marking allergy-causing IgE, the studies here will potentially result in identification of novel therapeutic targets for allergic disease. Finally, these studies will have impact beyond allergy in diseases in which IgE is involved, including systemic lupus erythematosus (SLE) and helminth infection. !