Innate Immune Regulation of Skin Inflammation

项目摘要/摘要 特应性皮炎(AD)是一种慢性、复发性皮肤病，影响10%-20%的儿童和1%-3%的成年人 据估计，仅在美国，每年的直接医疗成本就超过30亿美元。广告与 以细胞因子表达增加为特征的辅助性T细胞2型(TH2)细胞反应的发展 白介素4、白介素5、白介素13。此外，有益共生细菌组成的变化 社区与TH2细胞因子相关炎症的易感性增加有关， 这表明微生物信号可能对阿尔茨海默病等疾病产生重大影响。尽管我们 增加对促进过敏性炎症的因素、细胞和分子的了解 调节阿尔茨海默病发展的机制仍然不清楚。在最近的研究中，我发现了一个 健康人中存在的未被识别的第2组固有淋巴样细胞(ILC2s) 并在AD患者的皮损皮肤中富含。ILC2缺乏对各种已被描述的细胞的标记 T细胞、B细胞、树突状细胞、巨噬细胞、自然杀伤细胞和粒细胞等类型，因此 被称为血统阴性(LIN-)。然而，它们确实表达CD25和IL-33R等标志物和 在上皮细胞衍生的细胞因子胸腺的刺激下，可以产生TH2细胞相关的细胞因子 基质淋巴生成素(TSLP)、IL-25或IL-33。利用AD的小鼠模型，我发现TSLP是 在皮肤中诱导ILC2所需的，以及这些由TSLP诱导的ILC2对 缺乏T和B细胞的小鼠的AD样病的发生。此外，当TSLP引发的ILC2 转移到自然野生型小鼠中，AD样疾病和适应性TH2细胞反应随之而来。这些研究 提出了TSLP诱导的皮肤相关ILC2是AD样进展所必需的假说 它们可能直接影响淋巴细胞充足的宿主中的TH2细胞反应。这一假设 构成目标1的基础，该目标将解决皮肤相关的ILC2如何影响AD样疾病和TH2细胞 小鼠的反应以及人类皮肤驻留的ILC2如何影响患者的AD。在新的预赛中 研究，我还发现，通过广泛的治疗，共生细菌的枯竭或故意改变- 光谱抗生素(ABX)导致皮肤中TSLP表达增加和ILC2数量增加- 引流淋巴结，引发共生细菌可能影响TSLP诱导的ILC2的假说 对AD的反应和易感性。这一假设构成了目标2的基础，目标2将解决如何 共生细菌的改变可能调节ILC2反应和小鼠AD样炎症。这些目标 将利用我在Artis实验室可用的智力和科学资源来解决，小说 与TSLP相关的试剂和宾夕法尼亚大学的灵生小鼠设施。作为董事会认证的 皮肤科医生和宾夕法尼亚大学翻译研究硕士项目的学生，我将直接 利用我的临床和翻译技能完成这个项目的翻译方面。

PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is a chronic, relapsing skin disease that affects 10-20% of children and 1-3% of adults and is estimated to cost over $3 billion a year in direct medical costs in the US alone. AD is associated with the development of T helper type 2 (TH2) cell responses characterized by increased expression of the cytokines interleukin (IL)-4, IL-5 and IL-13. Further, changes in the composition of beneficial commensal bacterial communities have been associated with increased susceptibility to TH2 cytokine-associated inflammation, suggesting that microbial signals could have a significant influence on diseases like AD. Despite our increased understanding of the factors that promote allergic inflammation, the cellular and molecular mechanisms that regulate the development of AD remain poorly defined. In recent studies, I identified a previously unrecognized population of group 2 innate lymphoid cells (ILC2s) that are present in healthy human skin and are enriched in the lesional skin of AD patients. ILC2s lack markers for a variety of well-described cell types such as T cells, B cells, dendritic cells, macrophages, natural killer cells and granulocytes, and therefore are referred to as lineage-negative (Lin-). However, they do express markers such as CD25 and IL-33R and can produce TH2 cell-associated cytokines following stimulation with the epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25 or IL-33. Employing a murine model of AD, I identified that TSLP is required for the elicitation of ILC2s in the skin and that these TSLP-elicited ILC2s are essential for the development of AD-like disease in mice lacking T and B cells. In addition, when TSLP-elicited ILC2s were transferred into na¿ve wild-type mice, AD-like disease and adaptive TH2 cell responses ensued. These studies provoked the hypothesis that TSLP-elicited skin-associated ILC2s are necessary for the progression of AD-like disease and that they may directly influence TH2 cell responses in lymphocyte-sufficient hosts. This hypothesis forms the basis of Aim 1, which will address how skin-associated ILC2s influence AD-like disease and TH2 cell responses in mice and how skin-resident ILC2s in humans may influence AD in patients. In new preliminary studies, I also found that depletion or deliberate alteration of commensal bacteria by treatment with broad- spectrum antibiotics (ABX) resulted in increased TSLP expression and elevated numbers of ILC2s in the skin- draining lymph nodes, provoking the hypothesis that commensal bacteria may influence TSLP-elicited ILC2 responses and susceptibility to AD. This hypothesis forms the basis of Aim 2, which will address how alterations in commensal bacteria may regulate ILC2 responses and murine AD-like inflammation. These aims will be addressed employing the intellectual and scientific resources available to me in the Artis lab, novel TSLP-related reagents and the University of Pennsylvania Gnotobiotic Mouse Facility. As a board-certified dermatologist and a student in the Masters in Translational Research program at UPenn, I will directly accomplish the translational aspects of this project employing my clinical and translational skill sets.