TSLP, IL-9-producing mucosal mast cells, and allergic inflammation

特应性皮炎的发生和发病机制被认为是发展的第一步。 其他过敏性疾病，如哮喘；这种疾病的进展也被称为“特应性进行曲”。当前 知识无法解释为什么过敏性炎症仅限于某些人的一种组织，而它 进展到涉及其他个体的额外组织。越来越明显的是， 疾病进展要比过敏反应复杂得多。TSLP是必要和充分的 然而，在小鼠模型3-5中，特应性进行症是TSLP促进过敏的机制基础 疾病进展尚不清楚。我们最近发表了我们的发现，描述了一种新的肠道种群 产生高水平IL-9、IL-13和肥大细胞蛋白酶1的小鼠粘膜肥大细胞(MMC9) 我们已发表和未发表的研究表明：(1)MMC9在 免疫幼稚的小鼠，但在摄入TSLP诱导的AD小鼠的肠道中积累 食物抗原；(2)在AD小鼠摄入食物抗原后的肺中发现MMC9。 存在与哮喘的呼吸道炎症特征有关；(3)MMC9的消融导致 减弱CD4+TH2免疫反应和抵抗形成哮喘样呼吸道炎症；(4) 人类体内存在MMC9样细胞，MMC9标志物的表达水平与共病相关 过敏性疾病；(5)摄食后小鼠肠上皮细胞IL-33表达增强 (6)IL-33诱导纯化的小鼠MMC9产生更高水平的IL-9和IL-13。总而言之， 这些令人兴奋的发现表明，MMC9在胃肠道的诱导可能是一个关键的细胞检查点， 将皮肤中TSLP的产生与肺部哮喘的发展联系起来，即过敏性疾病的进展。我们的 中心假说是表皮TSLP启动的CD4+TH2免疫反应推动MMC9的发育 胃肠道(GI)和肠上皮源性IL-33(由摄入的食物抗原诱导) 进而放大MMC9功能和气道MMC9蓄积，促进过敏性哮喘。这一假设是 具有高度的临床相关性。这项应用将对公共卫生产生重大影响。通过提议的目标， 我们将(1)阐明促进MMC9细胞发育和扩增的机制；(2) 阐明MMC9在共病变态反应性疾病发病机制中的作用；(4)描述免疫学 预测疾病从AD发展到哮喘的生物标志物；以及(4)提供机制数据，将 能够设计治疗干预措施，以防止过敏性疾病的进展。

The development and pathogenesis of atopic dermatitis is thought to be the first step in the path to develop other allergic diseases, such as asthma; the disease progression also known as the “atopic march”. Current knowledge cannot explain why allergic inflammation is restricted to one tissue in some individuals, while it progresses to involve additional tissues in other individuals. It is increasingly evident that the mechanisms of disease progression are far more complex than allergic sensitization. TSLP is necessary and sufficient for the atopic march in mouse models3-5, however, the mechanisms underpinnings TSLP's contribution to allergic disease progression is not clear. We recently published our findings describing a novel population of intestinal mucosal mast cells (MMC9) in mice that produce high levels of IL-9, IL-13, and mast cell proteases 1 (chymase) and 6 (tryptase)6. Our published and unpublished studies demonstrate: (1) MMC9s are scarce in immunologically naïve mice, but accumulate in the gut of mice with TSLP-induced AD following ingestion of food antigens; (2) MMC9 are found in the lungs of AD mice following ingestion of food antigens and their presence is associated with airway inflammation characteristic of asthma; (3) ablation of MMC9s results in attenuated CD4+TH2 immune responses and resistance to develop asthma-like airway inflammation; (4) MMC9-like cells are present in humans and expression levels of MMC9 markers are associated with co-morbid allergic disease; (5) IL-33 expression is induced in mouse intestinal epithelium following ingestion of food antigens; and (6) IL-33 induces purified murine MMC9s to produce higher levels of IL-9 and IL-13. Collectively, these exciting findings suggest that MMC9 induction in GI tract may serve as a key cellular checkpoint that bridges TSLP production in the skin to asthma development in the lung, i.e. allergic disease progression. Our central hypothesis is that epidermal TSLP-initiated CD4+TH2 immune responses drive MMC9 development in the gastrointestinal (GI) tract and that intestinal epithelial-derived IL-33 (induced by ingested food antigens) then amplifies MMC9 function and airway MMC9 accumulation to promote allergic asthma. This hypothesis is highly clinically relevant. This application will have significant public health impact. Through the proposed aims, we will (1) elucidate the mechanisms that promote the development and expansion of MMC9 cells; (2) elucidate the role of MMC9 in the pathogenesis of co-morbid allergic disease; (4) delineate immunologic biomarkers that predict disease progression from AD to asthma; and (4) provide mechanistic data that will enable the design of therapeutic interventions to prevent the progression of allergic disorders.