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

Pro-Type 2 杯状细胞抗原在食品致敏和反应中的传代

• 批准号: 10752964
• 负责人: SIMON Patrick HOGAN
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-04 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752964
• 关键词: Ablation; Adjuvant; Adult; Affect; Allergic; Allergic Reaction; Allergy to peanuts; American; Anaphylaxis; Antigen-Presenting Cells; Antigens; Basophils; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Communication; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Cholera Toxin; Clinical; Complex; Development; Exposure to; FDA approved; Food; Food Hypersensitivity; Frequencies; Funding; Gastrointestinal tract structure; Genes; Genetic; Goblet Cells; Human; IL18 gene; IgE; Immune; Immune Tolerance; Immunologics; Individual; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Knowledge; Lamina Propria; Link; Mechanics; Mediating; Milk; Modeling; Molecular; Mus; Nuts; Oral; Organism; Organoids; Outcome; Pathogenicity; Pattern; Phenotype; Population; Prevalence; Prevention; Process; Production; Property; Proto-Oncogene Protein c-kit; Reaction; Reporter; Role; Sesame - dietary; Shellfish; Signal Induction; Signal Pathway; Signal Transduction; Skin; Skin injury; Small Intestines; System; T cell response; TSLP gene; Technology; Testing; Th2 Cells; Therapeutic; Trees; Tropism; Visit; Wheat; conditioning; crosslink; cytokine; dietary; economic cost; egg; filaggrin; food allergen; food antigen; food avoidance; gastrointestinal; imprint; intestinal epithelium; mast cell; mouse model; recruit; response; skin barrier; soy; therapeutic target; two photon microscopy

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.

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-4 R 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-4 R 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ILC 2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; SA 2）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CD 4 + Th 2 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。

项目成果

Dysregulation of intestinal epithelial CFTR-dependent Cl- ion transport and paracellular barrier function drives gastrointestinal symptoms of food-induced anaphylaxis in mice.

肠上皮 CFTR 依赖性氯离子转运和细胞旁屏障功能的失调导致小鼠食物诱发过敏反应的胃肠道症状。

• DOI: 10.1038/s41385-020-0306-6
• 发表时间: 2021
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Yamani,Amnah;Wu,David;Ahrens,Richard;Waggoner,Lisa;Noah,TaekoK;Garcia-Hernandez,Vicky;Ptaschinski,Catherine;Parkos,CharlesA;Lukacs,NicholasW;Nusrat,Asma;Hogan,SimonP
• 通讯作者: Hogan,SimonP

Eosinophilic esophagitis: Immune mechanisms and therapeutic targets.

• DOI: 10.1111/cea.14196
• 发表时间: 2022-10
• 期刊: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.

IL-4-BATF信号直接调节IL-9在实验食品过敏中产生粘膜肥大细胞（MMC9）功能。

• DOI: 10.1016/j.jaci.2020.08.043
• 发表时间: 2021-01
• 期刊: The Journal of allergy and clinical immunology
• 作者: Tomar S;Ganesan V;Sharma A;Zeng C;Waggoner L;Smith A;Kim CH;Licona-Limón P;Reinhardt RL;Flavell RA;Wang YH;Hogan SP
• 通讯作者: Hogan SP

Uridine diphosphate-glucose/P2Y14R axis is a nonchemokine pathway that selectively promotes eosinophil accumulation.

尿苷二磷酸-葡萄糖/P2Y14R轴是选择性促进嗜酸性粒细胞积累的非趋化因子途径。

• DOI: 10.1172/jci147735
• 发表时间: 2021
• 期刊: The Journal of clinical investigation
• 作者: Foster,PaulS;Tay,HockL;Hogan,SimonP
• 通讯作者: Hogan,SimonP