Intestinal epithelial immunological responses and food allergen sampling

项目摘要 食物过敏的发病率迅速增加，是过敏反应的最常见原因。虽然显著 在我们对树突状细胞参与的潜在免疫途径的理解方面已经取得了进展， (DC)食物过敏原的呈递，CD 4 + Th 2库的发展，以及IgE-MC依赖性的 虽然食物过敏原的传递过程是一个效应过程，但很少有人关注食物过敏原的传递过程 穿过胃肠道上皮并将这些过敏原呈递给免疫区室。 我们最近报道了1）幼稚小鼠小肠（SI）中的杯状细胞（GC）可以作为管道 并允许食物过敏原穿过肠上皮（IE）层并呈递给SI 固有层免疫区室（称为杯状细胞抗原通道; GAP）13; 2）食物过敏小鼠 利用不同的IE转运机制，包括SI绒毛和隐窝GC、肠内分泌细胞和Paneth 将食物过敏原穿过肠上皮层（称为分泌性上皮抗原）的细胞 传代; SAP）24和3）IE细胞衍生的前2型细胞因子如TSLP、IL-25和IL-33的关键作用 在小鼠食物诱发过敏反应的发展中14. 在一系列的初步研究中，我们将这些观察结果联系起来，证明诱导SAP和 食物过敏原在鼠肠上皮细胞中的摄取导致促过敏细胞因子IL-10的表达， 33和采用人肠类器官（HIO）移植模型系统证明， 在人类中，GAP和SAP是保守的。 目前的知识缺口是分泌性肠上皮细胞摄取食物过敏原的特异性 可能存在导致修饰抗原的IE的环境触发编程 通道模式（GAP与SAP）; SAP摄取食物过敏原与表达之间的关系 前2型细胞因子在人体组织。我们假设SAP是食物过敏原 被引导穿过肠上皮，促进前2型细胞因子的产生， 成分和功能受环境触发因素的调节。 在目的I中，我们将定义参与食物过敏原传代的SI分泌细胞谱系以及 食物过敏原通道模式和Aim II的环境触发因素，定义了转录炎症 食物过敏原摄取后人类肠上皮细胞的特征。相对于预期 结果，目标I中提出的研究预计将确定不同的SI上皮特异性 食物过敏原运输过程以及它们如何受到环境触发因素的影响，以及Aim II中的那些 预期揭示前Th 2细胞因子产生与S1肠道对食物过敏原的摄取之间的联系。 上皮细胞，并定义抗原通道的促变应性转录炎症特征。 总的来说，这些研究将阐明新的IE限制的过程，通过这些过程，食物过敏原被采样， 人SI区室;将食物过敏原摄取与pro-Type 2细胞因子产生联系起来，并鉴定不同的 食物过敏原摄取受FA状态影响的SIIE途径。

Project Summary Food allergy is rapidly increasing in prevalence and is the most common cause of anaphylaxis. While significant progress has been made in our understanding of the underlying immunologic pathways involved in dendritic cell (DC) presentation of food allergens, the development of the CD4+ Th2 repertoire, and the IgE-MC–dependent effector processes, there has been little attention to the processes underlying the passage of food allergens across the GI epithelium and presentation of these allergens to the immune compartment. We have recently reported 1) that goblet cells (GCs) in the small intestine (SI) of naïve mice can act as a conduit and permit the passage of food allergens across the intestinal epithelial (IE) layer and presentation to the SI lamina propria immune compartment (termed Goblet cell antigen passages; GAPs)13; 2) that food allergic mice utilize a different IE transport mechanism involving SI villus and crypt GCs, enteroendocrine cells, and Paneth cells that passage food allergens across the intestinal epithelial layer (termed secretory epithelial antigen passages; SAPs)24 and 3) a critical role for IE cell-derived pro-Type 2 cytokines such as TSLP, IL-25 and IL-33 in the development of food-induced anaphylaxis in mice14. In a series of preliminary studies, we interconnect these observations demonstrating that induction of SAPs and uptake of food allergens in murine intestinal epithelial cells leads to expression of the pro-allergic cytokine, IL- 33 and employing a human intestinal organoid (HIO) transplant model system demonstrate that the molecular processes, GAPs and SAPs are conserved in humans. The current gap in knowledge is the specificity of food allergen uptake by secretory intestinal epithelial cell lineages; the potential existence of environmental trigger programming of IEs which leads to modified antigen passage patterning (GAPs vs SAPs); and the relationship between food allergen uptake by SAPs and expression of pro-Type 2 cytokines in human tissue. We hypothesize that SAPs are a mechanism by which food allergens are channeled across the intestinal epithelium, promote the production of pro-Type 2 cytokines and whose composition and function are modulated by environmental triggers. In Aim I we will define the SI secretory cell lineages involved in food allergen passages and the impact of environmental triggers on food allergen passage patterning and Aim II, define the transcriptional inflammatory signature of human intestinal epithelial cells following food allergen uptake. With respect to the expected outcomes, the studies proposed in Aim I are expected to identify the involvement of distinct SI epithelial-specific food allergen transport processes and how they are influenced by environmental triggers, and those in Aim II are expected to reveal a link between pro-Th2 cytokine production and food allergen uptake by SI intestinal epithelial cells and define the pro-allergic transcriptional inflammatory signature of antigen passages. Collectively, these studies will illuminate new IE-restricted processes by which food allergens are sampled by the human SI compartment; link food allergen uptake with pro-Type 2 cytokine production and identify divergent pathways of SI IEs food allergen uptake that are influenced by FA status.