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，它们必须首先穿过 排列在胃肠道中的单层柱状上皮细胞。我们最近发现， 发生易化的抗原取样机制，由此肠腔中的IgE与抗原结合， 通过低亲和力IgE受体CD23作为复合物运输穿过上皮。这些抗原IgE 然后复合物可以作用于效应细胞如肥大细胞，导致脱粒和正常细胞的改变。 肠、肺或皮肤的生理学。此外，我们已经表明，食物过敏的受试者有 粪便中可检测到的CD23和食物特异性IgE水平，而非特应性对照则不能。我们假设 CD23介导的摄取机制是食物过敏的病理生理学中的关键步骤， 粪便中CD23和IgE的出现可能是食物过敏性疾病的有用的非侵入性生物标志物。 在这些拟议的实验中，我们将研究粪便CD23作为食物过敏生物标志物的用途。 我们将测量一组110名牛奶致敏个体的粪便CD 23，并确定粪便CD 23是否与 与临床上对牛奶的反应有关。我们将纵向跟踪这组牛奶致敏个体 并确定粪便CD23在疾病自然史中的相关性。最后，我们将 确定口服免疫治疗是否与索莱尔（奥马珠单抗）影响粪便CD 23水平。 在接下来的一系列实验中，我们将确定上皮CD23在肿瘤病理生理学中的作用。 实验性食物过敏我们已经表明，CD23的触发导致炎症反应， 人类肠上皮细胞，我们将确定负责这一信号传导机制 activation.此外，我们将构建表达人CD23、人FcDRI、人CD24和人CD25的三重转基因小鼠， 和人IgE来测试CD23在抗原取样、过敏反应和过敏原诱导的炎症中的作用 in vivo.

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.