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A role for glycolipids and unconventional T cell subsets in alpha-gal allergy

糖脂和非常规 T 细胞亚群在 α-gal 过敏中的作用

基本信息

批准号：
10627911
负责人：
Onyinye I Iweala
金额：
$ 19.83万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627911
关键词：
Adult Allergic Allergic Reaction Anaphylaxis Antibodies Antigens Appearance Area Arthritis Automobile Driving Basic Science Basophils Binding Biology Carbohydrates Cell surface Cells Cellular biology Circulation Complex Conceptions Consumption Cytotoxic T-Lymphocytes Data Development Disease Effector Cell Environment Epithelium Epitopes Exposure to Food Food Hypersensitivity Foundations Frequencies Funding Mechanisms Future Gene Expression Generations Glycolipids Goals Government Agencies Grant Histamine Hour Human Hypersensitivity IgE IgE Receptors Immediate hypersensitivity Immune Immune response Immunology Individual Ingestion Knowledge Leukotrienes Link Lipids Liver Lymphocyte Meat Mediating Mediator Medicine Mentors Mentorship Molecular Mucosal Immunity Mucous Membrane North Carolina Oligosaccharides Organ Outcome Pathogenesis Patients Phase Phenotype Plasma Population Privatization Process Proteins Reaction Reporting Research Research Personnel Role Running Secondary to Severities Signal Transduction Skin Surface Symptoms Syndrome T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Thinness Ticks Tissues Training Translational Research Universities Up-Regulation Vision allergic response alpha-gal syndrome career cytokine effective therapy experience fatty acid metabolism food allergen galactosyl-(1-3)galactose in vivo interest knowledge base lipid metabolism mast cell medical schools member metabolic profile novel particle prevent professor response skills tenure track theories therapeutic target tick bite translational research program trend

项目摘要

Project Summary/Abstract This proposal seeks to expand our understanding of the mechanisms driving alpha-gal syndrome (AGS) and to provide a strong foundation for the applicant, Dr. Onyinye Iweala, to build an independent basic and translational research career. The candidate is an Assistant Professor of Medicine, tenure track, at the University of North Carolina-Chapel Hill (UNC) School of Medicine and a member of the Thurston Arthritis Research Center and the UNC Food Allergy Initiative. The proposed project expands on her previous training in mucosal immunology, weaving together the fields of mucosal immunity with glycolipid biology and allergic effector cell biology in the context of a paradigm-shifting food allergy. Through formal coursework outlined in the proposal and with help from her mentorship team, led by primary mentors Scott Commins and Wesley Burks, the candidate will develop the technical and administrative skills needed to run a successful basic and translational research enterprise. In the process, she will develop a unique skillset that will enhance her ability to compete successfully for R01 grants and comparable funding mechanisms available through government agencies and private foundations. AGS is an exciting area of food allergy ripe for discovery. By studying this condition, the candidate will cultivate her interest in mucosal immunity and develop new expertise in glycolipid biology during her transition from a mentored to an independent investigator. Alpha-gal syndrome, characterized by delayed allergic responses to red meat (mammalian meat), is a novel allergic condition associated with tick bites and specific IgE antibody to the oligosaccharide galactose-α-1,3- galactose (alpha-gal). Alpha-gal food allergy challenges the current paradigm for food allergy because reactions are usually delayed, appearing >2 hours following meat ingestion; IgE antibodies are against a carbohydrate rather than a protein; and the allergy can develop in adulthood after many years of safely tolerating red meat. The lipid content of ingested meat appears to impact reaction consistency and severity, leading many to theorize that alpha-gal in glycolipid form is a critical driver of symptoms in this allergy. However, no one has shown that alpha-gal-specific (s)IgE can bind alpha-gal glycolipids or that alpha-gal glycolipids can activate allergic effector cells. Innate or unconventional T lymphocyte populations, specifically CD1d-restricted invariant natural killer T (iNKT) cells, bind glycolipid antigens complexed with CD1d and direct immune responses to lipid. Yet, the extent to which this T cell population drives alpha-gal allergy remains unexplored. Our preliminary results suggest that alpha-gal-sIgE binds mammalian glycolipids and that alpha-gal glycolipids can activate basophils sensitized with plasma containing alpha-gal-sIgE. Moreover, activated circulating CD1d-restricted NKT cells are detectable in alpha-gal allergic subjects. Thus, we hypothesize that alpha-gal glycolipids are critical to the pathogenesis of alpha-gal syndrome, through CD1d-mediated interactions with unconventional T cells and through IgE-Fc epsilon receptor (FcRI)-mediated interactions with allergic effector cells.

项目总结/摘要该提案旨在扩大我们对α-半乳糖综合征（AGS）驱动机制的理解并为申请人Onyinye Iweala博士提供坚实的基础，以建立一个独立的基础和翻译研究生涯该候选人是该大学终身教职医学助理教授北卡罗来纳州教堂山医学院（North Carolina Chapel Hill School of Medicine）和瑟斯顿关节炎研究中心的成员和抗过敏食物倡议组织拟议的项目扩大了她以前在粘膜方面的培训免疫学，将粘膜免疫领域与糖脂生物学和过敏效应细胞结合在一起食物过敏的范式转变背景下的生物学。通过提案中概述的正式课程在她的导师团队的帮助下，由主要导师Scott Commins和Wesley Burks领导，候选人将发展所需的技术和管理技能，以成功地运行一个基本的和翻译研究企业。在此过程中，她将培养独特的技能，增强她的竞争能力成功地获得R 01赠款和通过政府机构提供的类似供资机制，私人基金会。AGS是一个令人兴奋的食物过敏领域，等待发现。通过研究这种情况，候选人将培养她对粘膜免疫的兴趣，并在糖脂生物学方面发展新的专业知识。她从一名受指导的调查员转变为一名独立调查员。 α-半乳糖综合征的特征是对红肉（哺乳动物肉）的迟发性过敏反应，与蜱叮咬和寡糖半乳糖-α-1，3-特异性IgE抗体相关的过敏性疾病半乳糖（α-gal）。α-半乳糖食物过敏挑战了目前的食物过敏范式，通常延迟，在摄入肉类后>2小时出现; IgE抗体针对碳水化合物而不是一种蛋白质;在安全地耐受红肉多年之后，这种过敏会在成年期发展。摄入肉类的脂质含量似乎会影响反应的一致性和严重性，导致许多人认为糖脂形式的α-半乳糖是这种过敏症症状的关键驱动因素。然而，没有人表明， α-gal特异性IgE可结合α-gal糖脂或α-gal糖脂可激活过敏效应物细胞先天或非常规T淋巴细胞群，特别是CD 1d限制性不变的自然杀伤T细胞（iNKT）细胞结合与CD 1d复合的糖脂抗原并指导对脂质的免疫应答。然而，这种T细胞群驱动α-gal过敏的原因仍然未被探索。我们的初步结果表明， α-gal-sIgE结合哺乳动物糖脂，α-gal糖脂可激活用α-gal-sIgE致敏的嗜碱性粒细胞。含有α-半乳糖-sIgE的血浆。此外，活化的循环CD 1d限制性NKT细胞在对α-半乳糖过敏的人因此，我们假设α-半乳糖苷脂在糖尿病的发病机制中是至关重要的。 α-半乳糖综合征，通过CD 1d介导的与非常规T细胞的相互作用和通过IgE-Fc免疫受体（Fc β RI）介导的与过敏效应细胞的相互作用。