Peanut Glycolipid Antigens Activate Natural Killer T Cells Causing Severe Allergy

描述(由申请人提供)： 该项目的长期目标是更好地定义花生过敏原，并确定导致花生过敏高发的花生特性，以及花生过敏未能随着时间的推移而解决的原因，并解释花生诱发过敏反应严重发作的不成比例数量。我们假设花生含有脂类和脂类-碳水化合物复合体，它们激活天然免疫机制，提供佐剂作用，从而极大地增强花生特异性适应性免疫反应。我们将研究花生的脂类复合体，以及它们激活自然杀伤T(NKT)细胞的能力，已知NKT细胞对糖脂产生反应，并对适应性免疫和炎症性疾病(如传染病、自身免疫、癌症和哮喘)做出重大贡献。我们之前已经证明，粘膜部位的NKT细胞在呼吸道炎症和哮喘的发生发展中发挥关键作用。此外，我们还发现，来自神经鞘氨醇单胞菌的糖脂可以直接激活肺NKT细胞，诱导呼吸道炎症和气道高反应性，这是哮喘的主要特征。这些结果表明，粘膜组织中的NKT细胞可能对含有糖脂的微生物和植物产品等物质产生反应，NKT细胞可能在调节粘膜组织对环境糖脂的许多免疫反应中发挥先前未被怀疑但却至关重要的作用。虽然目前已知只有少数糖脂可以激活NKT细胞，但我们认为一些食物，如花生，可能含有能够刺激NKT细胞的糖脂，导致天然和适应性粘膜免疫反应的激活。因此，我们建议从花生中提纯并鉴定能直接激活NKT细胞的糖脂。我们认为花生糖脂可以激活NKT细胞，从而激活先天免疫机制，从而极大地增强对花生的适应性免疫。我们将研究小鼠系统，以及来自正常和花生过敏个体的人类细胞，检查体外和体内反应。我们正在与一位杰出的脂质生物化学家合作，并拥有丰富的人类和小鼠NKT细胞工作经验。此外，我们已经有令人兴奋的初步数据表明，纯化的花生糖脂确实可以激活NKT细胞，这表明我们的假设是正确的，我们的研究是可行的，并可能产生重要的新信息。我们相信，我们的研究可能会极大地扩大对发生在粘膜部位的免疫反应类型的基本了解，以及花生等食物如何诱导导致食物过敏的免疫反应。

DESCRIPTION (provided by applicant): The long-term goal of this project is to better define peanut allergens, and to identify the properties of peanuts that result in the high prevalence of peanut sensitization, the failure of peanut allergy to resolve over time, and explain the disproportionate number of severe episodes of peanut induced anaphylaxis. We hypothesize that peanuts contain lipid and lipid-carbohydrate complexes that activate innate immune mechanisms, providing adjuvant effects, which greatly enhance peanut specific adaptive immune responses. We will examine lipid complexes from peanuts, and their capacity to activate natural killer T (NKT) cells, which are known to respond to glycolipids and to contribute significantly to adaptive immunity and to inflammatory diseases such as infectious diseases, autoimmunity, cancer and asthma. We have previously shown that NKT cells at mucosal sites play a critical role in the development of airway inflammation and asthma. In addition, we have shown that glycolipids from the bacterial species Sphingomonas can directly activate pulmonary NKT cells and induce airway inflammation and airway hyper-reactivity, a cardinal feature of asthma. These results suggest that NKT cells in mucosal tissues may respond to agents such as microbes and plant products containing glycolipids, and that NKT cells could play a previously unsuspected but critical role in regulating many immune responses in mucosal tissues to environmental glycolipids. Although only a few glycolipids are currently known to activate NKT cells, we believe that some foods, such as peanuts, may contain glycolipids that can stimulate NKT cells, resulting in the activation of innate and adaptive mucosal immune responses. We therefore propose to purify and identify glycolipids from peanuts that can directly activate NKT cells. We believe that peanut glycolipids can activate NKT cells, thereby activating innate immune mechanisms that then greatly enhance adaptive immunity to peanuts. We will study murine systems, as well as human cells from normal and peanut allergic individuals, examining both in vitro and in vivo responses. We are working with an outstanding lipid biochemist, and have extensive experience working with human and murine NKT cells. Moreover, we already have exciting preliminary data demonstrating that purified peanut glycolipids can indeed activate NKT cells, suggesting that our hypothesis is correct, and that our studies are feasible and likely to generate important new information. We believe that our studies are likely to greatly expand the fundamental understanding of the types of immune responses that occur at mucosal sites, and how foods, such as peanuts, can induce immune responses that result in food allergy.