Chylomicrons promote intestinal absorption and systemic dissemination of dietary

描述（由申请人提供）：在西方社会，食物过敏的发病率呈上升趋势。常见的食物过敏包括牛奶、鸡蛋、大豆和花生过敏，尤其是后者可能是致命的。当膳食过敏原接触到肠道或其他组织肥大细胞表面的IgE分子时，就会发生过敏反应。因此，有理由认为肠道对过敏原的吸收是有害的。然而，肠道对过敏原和一般膳食抗原的吸收也是诱导广泛的全身免疫耐受（“口服耐受”）所必需的，这可以防止食物过敏，甚至可以用于治疗食物过敏。由此可见，抗原吸收机制在食物过敏的发病机制中起着至关重要的作用。不幸的是，目前对食物抗原穿过肠上皮的机制以及它们随后如何在体内运输知之甚少。大多数膳食蛋白质，包括大多数已知的过敏原，都具有乳化特性，这预示着它们对乳糜微粒等脂蛋白颗粒表现出亲和力。这些大的乳剂颗粒通过肠系膜淋巴和血液运输膳食长链甘油三酯（LCT，“脂肪”）。如果膳食抗原与乳糜微粒结合，它们将被运送到乳糜微粒靶组织，如肠系膜淋巴结（MLN）。膳食抗原转运到MLN可以促进对抗原的口服耐受，因为这是这些淋巴结中常见的免疫反应。因此，乳糜微粒依赖性抗原吸收被假设为促进口服耐受性。大多数主食，包括那些含有过敏原的食物，如牛奶、鸡蛋、大豆和花生，也含有大量的LCT，这意味着抗原摄入后会分泌乳糜微粒。我们假设饮食抗原的肠道吸收和全身运输是通过与乳糜微粒分泌相关发生的。更具体地说，我们假设1.)饮食抗原与肠上皮细胞（IEC）内新形成的乳糜微粒颗粒结合，并与新生乳糜微粒一起分泌到肠系膜淋巴中，2.)饮食抗原与乳糜微粒一起通过肠系膜淋巴，通过MLN进入血液，3.)乳糜微粒依赖性抗原吸收促进口服耐受。这些假设得到了用一种典型食物过敏原卵清蛋白（OVA）在小鼠身上获得的初步数据的支持，但未来的实验也将研究花生过敏原。我们拟在R21基金申请中详细研究其吸收机制，并探索新型乳糜微粒途径的免疫调节作用。这些研究确定了食物抗原吸收的潜在机制，并为优化抗原递送到肠道和外周免疫系统提供了机制框架，预计将对食物过敏研究产生重大影响。

DESCRIPTION (provided by applicant): The incidence of food allergies is on the rise in Western societies. Common food allergies include milk-, egg-, soy and peanut allergy, and especially the latter can be fatal. An allergic response occurs when the dietary allergen gains access to IgE molecules on the surface of Mast cells in the intestine or in other tissues. It is therefore reasonable to assume that intestinal absorption of the allergens is detrimental. However, intestinal absorption of the allergen, and of dietary antigens in general, is also required for the induction of broad systemic immunological tolerance ("oral tolerance"), which prevents food allergies and may even be used to treat food allergies. It appears thus that the mechanism of antigen absorption plays a crucial role in the pathogenesis of food allergies. Unfortunately, relatively little is currently known on the mechanism by which food antigens cross the intestinal epithelium, and how they are subsequently transported through the body. Most dietary proteins, including most known allergens, have emulsifying properties, which predicts that they show affinity for lipoprotein particles, such as chylomicrons. These large emulsion particles transport dietary long-chain triglycerides (LCT, "fat") through mesenteric lymph and blood. If dietary antigens are bound to chylomicrons, they would then be transported to chylomicron target tissues, such as mesenteric lymph nodes (MLN). Transport of dietary antigens to MLN could promote oral tolerance to the antigen, since this is the common immune response in these lymph nodes. Thus, chylomicron-dependent antigen absorption is hypothesized to promote oral tolerance. Most food staples, including those with allergens such as milk, eggs, soybeans and peanuts, also contain significant amounts of LCT, meaning that antigen ingestion is followed by chylomicron secretion. We hypothesize that intestinal absorption and systemic transport of dietary antigens occurs through association with chylomicron secretion. More specifically, we hypothesize that 1.) dietary antigens associate with newly formed chylomicron particles within intestinal epithelial cells (IEC) and are secreted into mesenteric lymph in association with nascent chylomicrons, 2.) dietary antigens are transported in association with chylomicrons through mesenteric lymph, via MLN, into blood, 3.) chylomicron-dependent antigen absorption promotes oral tolerance.These hypotheses are supported by preliminary data obtained with a prototypical food allergen, ovalbumin (OVA), in mice, but future experiments will also study peanut allergens. We propose to study the absorption mechanism in detail in this R21 grant application, and to explore immune modulating effects of the novel chylomicron pathway. These studies are expected to significantly impact food allergy research, since they define the underlying mechanism of dietary antigen absorption and provide the mechanistic framework for optimization of antigen delivery to the intestinal and peripheral immune system.