Pro-Type 2 Goblet Cell Antigen Passages in Food Sensitization and Reactivity

项目摘要 美国疾病控制和预防中心估计，多达600万美国儿童患有 食物过敏(每个教室大约有2个)，每年的经济成本约为250亿美元。目前，有以下几种 FDA批准的食物过敏治疗选择有限，避免食物仍然是唯一安全的选择。一个 更好地理解食物过敏的免疫机制和信号通路是显而易见的 允许开发新的有效和安全的治疗方法8。 在上一次资助期间，我们的团队确定了起作用的“规范”杯状细胞抗原通道(GAP) 将饮食抗原输送到离散的免疫利基并印记抗原提呈细胞(APC) 提高免疫耐受性的致耐受特性。此外，我们还表明，食物过敏的情况 与肠道抗原通道模式和景观的改变有关。这些IL-13/IL-4R依赖 诱导IgE-MC反应需要“非规范”的抗原传代。 在初步研究中，我们证明了IL-13/IL-4R信号通路的系统性激活是 足以促进SI PRO-2型GC亚群的生长，这些亚群表达与 食物中的抗原识别和一种独特的前2型炎症表型，并形成抗原通道。 值得注意的是，我们提供了皮肤屏障的破坏和前2型细胞因子产生之间的联系 肠道产生IL-13的ILC2细胞和胃肠道抗原通路格局的转变 “非规范”的抗原传代。目前的知识差距是亲2类GC对食物的要求 过敏原通路和引导肠道过敏性炎症反应(过敏性肠道嗜性)和启动 对于食物的反应性。 我们假设SI PRO-2型GC作为非规范的抗原通路，驱动过敏肠道嗜性 以及临床对食物的反应性。为了检验我们的假设，我们提出了三个具体目标(SA)；SA1)定义角色 系统的2型信号在胃肠道前2型GC-抗原传代形成中的作用；SA2)定义胃肠道前型的作用 2过敏性肠嗜性和SA3)决定了GI前-2型GC抗原的需求 食物反应性中的过敏性肠道嗜好性。关于预期结果，这些研究 在SA1中提出的建议有望证明GI亲2型GC抗原传代；SA2证明GI 亲2型GC直接抗原致敏LP-DC群体并募集食物抗原特异性的CD4+Th2 对胃肠道和SA3的细胞反应)确定胃肠道嗜好性中对GI前2型GC的需求和 临床反应性。 成功完成拟议的研究将为我们提供一个新的实质性起点 目前对膳食食物过敏原途径的潜在分子机制的理解 肠道上皮细胞在胃肠道嗜性和食物反应性中的关键作用 并保证前2型GC的治疗靶点，以防止食物过敏反应。

Project Summary The U.S. Center for Disease Control and Prevention estimates of up to 6 million American children with food allergies (roughly 2 in every classroom) at an economic cost of ~$25 billion per year. Currently, there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of new effective and safe therapies8. Over the last funded period our team identified “canonical” goblet cell antigen passages (GAPs) that act to deliver dietary antigens to discrete immunological niches and imprint antigen presenting cells (APCs) with tolerogenic properties to promote immune tolerance. Furthermore, we showed that the food allergic condition was associated with altered gut antigen passage patterning and landscape. These IL-13/IL-4R-dependent “non-canonical” antigen passages were required for induction of IgE-MC reactions. In preliminary studies we demonstrate that systemic activation of the IL-13/IL-4R-signaling pathway is sufficient to promote the outgrowth of SI pro-type-2 GC subpopulation, which express genes associated with dietary antigen recognition and a distinct pro-type-2 inflammatory phenotype and form antigen passages. Strikingly, we provide a link between disruption of skin barrier and pro-Type 2 cytokine production with increased gut IL-13-producing ILC2 cells and a shift in gastrointestinal antigen passage landscape from the “canonical” to “non-canonical” antigen passages. The current gap in knowledge is the requirement of pro-type-2 GCs to food allergen passage and directing the allergic inflammatory response to the gut (allergic gut tropism) and priming for food reactivity. We hypothesize that SI pro-type 2 GCs act as non-canonical antigen passages, drive allergic gut tropism and clinical reactivity to foods. To test our hypothesis, we propose three specific Aims (SA); SA1) Define the role of systemic Type-2 signals in GI pro-type 2 GC-antigen passage formation; SA2) Define the role of GI pro-type 2 GC antigen passages in allergic gut tropism and SA3) Define the requirement of GI pro-type 2 GC antigen passage-induced allergic gut tropism in food reactivity. With respect to the expected outcomes, the studies proposed in SA1 are expected to demonstrate GI pro-type 2 GC antigen passages; SA2 demonstrate that GI pro-type 2 GCs direct antigens to sensitizing LP-DC populations and recruit the food antigen-specific CD4+ Th2 cell response to GI tract and SA3) identify the requirement for GI pro-type 2 GCs in allergic gut tropism and clinical reactivity. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms of dietary food allergen passage across the intestinal epithelium underpinning a critical role for GI pro-type 2 GCs in allergic gut tropism and food reactivity and warrant therapeutic targeting of pro-type 2 GCs for prevention of food allergic reactions.