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， 食物过敏（每个教室大约2个），每年的经济成本约为250亿美元。目前有 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 更好地理解食物过敏的免疫机制和信号通路， 保证允许开发新的有效和安全的治疗方法8。 在过去的资助期间，我们的团队确定了"典型的"杯状细胞抗原通道（GAP）， 将饮食抗原递送至离散的免疫学小生境并将抗原呈递细胞（APC）与 致耐受特性以促进免疫耐受。此外，我们发现食物过敏的情况 与改变的肠道抗原通道模式和景观有关。这些IL-13/IL-4R β依赖性 诱导IgE-MC反应需要"非典型"抗原传代。 在初步的研究中，我们证明了IL-13/IL-4R β信号通路的系统激活， 足以促进Sl前2型GC亚群的生长，其表达与以下相关的基因： 饮食抗原识别和独特的前2型炎性表型，并形成抗原通道。 引人注目的是，我们提供了皮肤屏障破坏和前2型细胞因子产生之间的联系， 肠IL-13产生ILC2细胞和胃肠抗原传代景观从"典型"到"典型"的转变， "非典型"抗原传代。目前的知识差距是亲2型GC对食品的要求 过敏原通过并将过敏性炎症反应导向肠道（过敏性肠道向性）和引发 食物反应性。 我们假设SI前2型GC作为非经典抗原通道，驱动过敏性肠道嗜性， 和对食物的临床反应。为了验证我们的假设，我们提出了三个具体的目标（SA）：SA 1）定义角色 在GI前2型GC抗原传代形成中的全身性2型信号; SA2）定义GI前2型GC抗原传代形成中的作用 2过敏性肠道嗜性和SA中的GC抗原传代3）确定GI前2型GC抗原的要求 食物反应性中的过敏性肠道向性。关于预期成果，研究报告 预期SA 1中提出的方法可证明GI前2型GC抗原传代; SA 2证明GI 前2型GC将抗原导向致敏LP-DC群体并募集食物抗原特异性CD4 + Th2 细胞对胃肠道的反应和SA 3）确定过敏性肠道嗜性中对GI pro-type 2 GC的需求， 临床反应性 成功完成拟议的研究将为我们提供一个新的和实质性的出发点， 目前对饮食食物过敏原通过的潜在分子机制的理解， 肠上皮支持GI pro-type 2 GCs在过敏性肠道向性和食物反应性中的关键作用 并保证前2型GC的治疗靶向以预防食物过敏反应。

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.