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Novel Roles of IgE Glycosylation in Anaphylaxis

IgE 糖基化在过敏反应中的新作用

基本信息

批准号：
10084262
负责人：
Robert McCullough Anthony
金额：
$ 49.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084262
关键词：
Affect Affinity Allergens Allergic Allergic Disease Allergic inflammation Anaphylaxis Anti-Inflammatory Agents Antibodies Antigens Asparagine Attenuated Basophils Binding Biological Markers Biology Biophysics Cell Count Cells Cellular Immunology Clinical Data Development Disease Epitopes Excision Food Gene Expression Glycobiology Goals Human Hypersensitivity IgE IgE Receptors Immune response Immunoglobulin G Immunology Individual Inflammation Insect Proteins Knowledge Lectin Link Location Mannose Mannosidase Maps Mediating Mediator of activation protein Mission Modification Molecular Immunology Outcome Pathogenicity Pathway interactions Pattern Play Polysaccharides Population Positioning Attribute Post-Translational Protein Processing Public Health Regulation Research Role Sialic Acids Signal Transduction Signaling Protein Site Structure Symptoms Systemic Lupus Erythematosus Testing United States National Institutes of Health anti-IgE base biomarker discovery crosslink glycosylation helminth infection in vivo innovation mast cell new therapeutic target novel novel marker novel therapeutic intervention novel therapeutics prevent receptor receptor binding sialylation sugar translational impact

项目摘要

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. !

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。是可能有多种因素造成，包括过敏原的IgE亲和力或表位多样性的差异，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。 !