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

• 批准号: 10055102
• 负责人: Onyinye I Iweala
• 金额: $ 20.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10055102
• 关键词: Adult; Allergic; Allergic Reaction; Anaphylaxis; Antibodies; Antigens; Appearance; Area; Arthritis; Automobile Driving; Basic Science; Basophils; Binding; Biology; Blood Circulation; Carbohydrates; Cell surface; Cells; Cellular biology; Complex; Conceptions; Consumption; Cytotoxic T-Lymphocytes; Data; Development; Disease; Effector Cell; Environment; Epithelial; Epithelium; Epitopes; Exposure to; Food; Food Hypersensitivity; Foundations; Frequencies; Funding Mechanisms; Future; Galactose; 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 of activation protein; 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-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; therapeutic target; tick bite; translational research program; trend

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.

项目摘要/摘要 这项建议旨在扩大我们对阿尔法-半乳糖综合征(Ags)发病机制的理解。 并为申请人Onyinye Iweala博士建立独立的基础和 翻译研究生涯。候选人是该大学医学助理教授，终身教职 北卡罗来纳-教堂山(UNC)医学院教授，瑟斯顿关节炎研究中心成员 和北卡罗来纳大学的食物过敏倡议。拟议中的项目是对她以前在粘膜方面的培训的扩展。 免疫学，将粘膜免疫领域与糖脂生物学和过敏效应细胞编织在一起 改变范式的食物过敏背景下的生物学。通过建议书中概述的正式课程作业 在她由主要导师斯科特·康明斯和韦斯利·伯克斯领导的导师团队的帮助下， 候选人将开发成功运行基础和翻译所需的技术和管理技能 研究企业。在这个过程中，她将发展一套独特的技能，这将增强她的竞争能力 成功获得R01赠款和可通过政府机构和 私人基金会。AGS是一个令人兴奋的食物过敏领域，发现的时机已经成熟。通过对这种情况的研究， 候选人将培养她对粘膜免疫的兴趣，并在糖脂生物学方面开发新的专业知识 她从一名有指导的人转变为一名独立调查员。 阿尔法-盖尔综合征的特征是对红肉(哺乳动物肉)的迟发性过敏反应，是一种新的 与扁虱叮咬和低聚半乳糖-α-1，3-Ig E抗体相关的变态反应 半乳糖(α-半乳糖)。阿尔法半食物过敏挑战目前食物过敏的范例，因为反应 通常是延迟的，在摄入肉类后2小时出现；IgE抗体是针对碳水化合物的 而不是蛋白质；在安全耐受红肉多年后，过敏症可能会在成年后发展。 摄入肉类的脂肪含量似乎会影响反应的一致性和严重性，这导致许多人提出了理论 糖脂形式的α-半乳糖是这种过敏症状的关键驱动因素。然而，没有人表现出这一点 α-半乳糖特异性(S)免疫球蛋白能与α-半乳糖结合或α-半乳糖能激活过敏效应 细胞。先天或非常规T淋巴细胞群，特别是CD1d限制性不变自然杀伤T细胞 (INKT)细胞，结合糖脂抗原与CD1d络合，直接免疫应答脂质。然而，这一程度 这种T细胞群导致阿尔法-半乳糖过敏的机制尚不清楚。我们的初步结果表明 α-Gal-sIgE与哺乳动物糖脂结合，α-Gal糖脂可激活致敏的嗜碱性粒细胞 血浆中含有α-半乳糖-sIgE。此外，激活的循环CD1d限制的NKT细胞在 阿尔法女孩过敏的受试者。因此，我们假设α-半乳糖脂在糖尿病的发病机制中起关键作用。 通过CD1d介导的与非常规T细胞的相互作用和通过IgE-Fc epsilon 受体(FcRI)介导的与过敏效应细胞的相互作用。