Innate Immune Regulation of Skin Inflammation

皮肤炎症的先天免疫调节

• 批准号: 8915923
• 负责人: Brian Kim
• 金额: $ 12.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915923
• 关键词: Address; Adoptive Transfer; Adult; Affect; Allergic; Allergic Disease; Allergic inflammation; Antibiotics; Antigen-Presenting Cells; Asthma; Atopic Dermatitis; B-Lymphocytes; Biological Assay; Blood; Cells; Child; Chimera organism; Chronic; Clinical; Coculture Techniques; Communities; Data; Dendritic Cells; Dermatologist; Development; Disease; Economic Burden; Epithelial Cells; Flare; Food Hypersensitivity; Genetic; Germ-Free; Gnotobiotic; Human; IL2RA gene; IgE; Immune; Immune response; In Vitro; Incidence; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Interleukins; Lesion; Lymphocyte; Lymphoid Cell; Mediating; Medical; Modeling; Molecular; Monoclonal Antibodies; Mus; Natural Killer Cells; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Population; Population Group; Predisposition; Probiotics; Public Health; Rag1 Mouse; Reagent; Regulation; Relapse; Resources; Severities; Signal Transduction; Skin; Source; Students; T-Lymphocyte; Testing; Th2 Cells; Translational Research; Universities; Wild Type Mouse; base; cell type; commensal microbes; cost; cytokine; granulocyte; high risk; human TSLP protein; in vivo; loss of function; lymph nodes; macrophage; microbial; novel; prevent; programs; public health relevance; response; skills; skin disorder

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.

项目总结/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%的成人 据估计，仅在美国，每年的直接医疗费用就超过30亿美元。AD与 发展以细胞因子表达增加为特征的辅助性T细胞2型（TH 2）细胞应答 白细胞介素（IL）-4、IL-5和IL-13。此外，有益肠道细菌组成的变化 社区与增加的对TH 2烟碱相关炎症的易感性有关， 这表明微生物信号可能对AD等疾病有重大影响。尽管我们 增加对促进过敏性炎症的因素的理解，细胞和分子 调节AD发展的机制仍然不清楚。在最近的研究中，我发现 以前未识别的存在于健康人中的第2组先天性淋巴样细胞（ILC 2）群体 皮肤，并在AD患者的病变皮肤中富集。ILC 2缺乏多种描述良好的细胞的标记物 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，因此 被称为谱系阴性（Lin-）。然而，它们确实表达标记物如CD 25和IL-33 R， 在用上皮细胞衍生的细胞因子胸腺刺激后可以产生TH 2细胞相关的细胞因子 基质淋巴细胞生成素（TSLP）、IL-25或IL-33。采用AD的小鼠模型，我确定TSLP是 这些TSLP诱导的ILC 2对于皮肤中ILC 2的诱导是必需的，并且这些TSLP诱导的ILC 2对于皮肤中ILC 2的诱导是必需的。 在缺乏T和B细胞的小鼠中发生AD样疾病。此外，当TSLP诱导的ILC 2被 转移到幼稚野生型小鼠，AD样疾病和适应性TH 2细胞反应随之而来。这些研究 激发了这样的假设，即TSLP引起的皮肤相关ILC 2是AD样疾病进展所必需的。 疾病，它们可能直接影响淋巴细胞充足的宿主中的TH 2细胞应答。这一假设 形成了目标1的基础，目标1将解决皮肤相关ILC 2如何影响AD样疾病和TH 2细胞 小鼠的反应以及人类皮肤中的ILC 2如何影响患者的AD。在新的初步 研究中，我还发现，通过广泛的治疗来消耗或故意改变肠道细菌， 广谱抗生素（ABX）导致皮肤中TSLP表达增加和ILC 2数量增加， 引流淋巴结，激发了肠道细菌可能影响TSLP引起的ILC 2的假设 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 肠道细菌的改变可以调节ILC 2反应和鼠AD样炎症。这些目标 我将利用Artis实验室的知识和科学资源来解决这个问题，小说 TSLP相关试剂和宾夕法尼亚大学Gnotobiotic小鼠设施。作为董事会认证的 我是一名皮肤科医生，也是宾夕法尼亚大学转化研究硕士项目的学生，我将直接 完成这个项目的翻译方面运用我的临床和翻译技能集。