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

项目概要/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 翻译研究生涯候选人是一名医学助理教授，终身教职，在大学 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。在这个过程中，她将发展出一套独特的技能，这将增强她的竞争能力 成功地获得R01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。 她从一个有指导的调查员转变为一个独立调查员 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CD1d限制性不变的自然杀伤T细胞 （iNKT）细胞结合与CD1d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CD1d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。

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.