Epithelial CD23 in Cow Milk Allergy:Role in Pathogenesis and Function as a Diseas

为了让食物过敏原在全身引发过敏反应，它们必须首先通过 胃肠道中排列的单层柱状上皮细胞。我们最近展示了一种 简化的抗原采样机制发生在肠腔中的IgE与抗原结合并可以 通过低亲和力的IgE受体CD23以复合体的形式通过上皮运输。这些抗原-lge 然后，复合体可以作用于肥大细胞等效应细胞，导致脱颗粒和正常 肠道、肺或皮肤的生理学。此外，我们还表明，对食物过敏的受试者 粪便中可检测到的CD23和食物特异性IgE水平，而非特应性对照组则不能。我们假设 CD23介导的摄取机制是食物过敏病理生理学中的关键一步，以及 粪便中CD23和IgE的出现可能是一种有用的非侵入性食物过敏性疾病的生物标志物。 在这些拟议的实验中，我们将研究粪便CD23作为食物过敏的生物标记物的用途。 我们将检测110名牛奶致敏个体的粪便CD23，并确定粪便CD23是否 与临床对牛奶的反应性有关。我们将对这群牛奶敏感者进行纵向追踪 并确定粪便CD23在疾病自然病程中的关联性。最后，我们会 确定口服免疫疗法加或不加索莱尔(奥马珠单抗)是否影响粪便CD23水平。 在接下来的一系列实验中，我们将确定上皮CD23在糖尿病的病理生理学中的作用。 实验性食物过敏。我们已经证明，CD23的触发通过以下方式导致炎症反应 人类肠道上皮细胞，我们将确定导致这一现象的信号机制 激活。此外，我们还将构建一种表达人CD23、人FcDRI、 和人IgE来测试CD23在抗原采样、过敏反应和过敏原诱导的炎症中的作用 在活体内。

In order for food allergens to initiate an allergic response throughout the body, they must first traffic across the single layer of columnar epithelial cells that line the gastrointestinal tract. We have recently shown that a facilitated antigen sampling mechanism occurs whereby IgE in the intestinal lumen binds to antigens and can be trafficked as a complex across the epithelium by the low-affinity IgE receptor CD23. These antigen-lgE complexes can then act of effector cells such as mast cells, leading to degranulation and alteration of normal physiology of the gut, lung, or skin. In addition, we have shown that subjects with food allergy have detectable CD23 and food-specific IgE levels in the stool, which non-atopic controls do not. We hypothesize that the CD23-mediated uptake mechanism is a critical step in the pathophysiology of food allergy, and appearance of CD23 and IgE in the stool may be a useful non-invasive biomarker of food allergic disease. In these proposed experiments, we will examine the use of stool CD23 as a biomarker in food allergy. We will measure stool CD23 in a group of 110 milk-sensitized individuals and determine if stool CD23 is associated with clinical reactivity to milk. We will follow this group of milk-sensitized individuals longitudinally and determine the association of stool CD23 in the natural history of the disease. And finally, we will determine if oral immunotherapy with or without Xolair (omalizumab) affects the level of stool CD23. In the next series of experiments, we will determine the role of epithelial CD23 in the pathophysiology of experimental food allergy. We have shown that triggering of CD23 leads to an inflammatory response by human intestinal epithelial cells, and we will determine the signaling mechanisms responsible for this activation. In addition, we will construct a triple transgenic mouse expressing human CD23, human FcDRI, and human IgE to test the role of CD23 in antigen sampling, anaphylaxis, and allergen-induced inflammation in vivo.