Novel Roles of IgE Glycosylation in Anaphylaxis

项目摘要/摘要。 目前尚不清楚为什么一些患有过敏原特异性IgE的人会患上过敏，而另一些人则不会。它是 可能是多种因素造成的，包括过敏原的IgE亲和力或表位多样性的差异 细胞数量、FcεRI表达水平、Syk信号、变应原特异性免疫球蛋白抗体和抗免疫球蛋白E抗体。 另一个尚未考虑的因素是糖基化对IgE的贡献。我们的长期目标是 了解抗体的糖基化如何调节，以及如何被免疫反应调节。我们的中央 假说是，IgE效应器的功能受不同位置的糖链的不同调节。 事实上，本申请中显示的初步数据支持了这一点。其背后的理论基础 建议的研究是，了解特定的IgE多糖对过敏性炎症的贡献将 使新的和创新的过敏疗法成为可能。我们将测试我们的中心假设，从而实现 本申请的目的通过追求以下三个特定目的：1)确定IgE多糖 FcεRI结合的要求；2)确定唾液酸如何调节Ig E介导的过敏反应；3)检查 体内IgE糖基化的调节。使用生物物理学、细胞和分子相结合的方法 免疫学和糖生物学，我们将确定多糖是Ig E-FcεRI相互作用的必需品，定义了一种新的 抗过敏途径，建立致病的IgE糖基化模式，减轻过敏反应 调节IgE多聚糖。除了能够发现标记导致过敏的IgE的生物标记物外， 这里的研究可能会导致确定过敏性疾病的新治疗靶点。最后，这些 研究将对包括系统性红斑狼疮在内的与IgE有关的疾病产生过敏以外的影响 红斑狼疮(SLE)和蠕虫感染。 好了！

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. !