Pathogenic T cells in discoid lupus erythematosus

项目摘要 盘状红斑狼疮（DLE）是一种毁容的自身免疫性皮肤病， 导致永久性疤痕、色素减退和脱发的头部和颈部。DLE不成比例 影响了非裔美国妇女，严重影响了生活质量。DLE可以单独发生，也可以在 系统性红斑狼疮（SLE）和DLE的治疗目前不能令人满意。述DLE 炎性浸润物主要由T细胞组成，其似乎促进组织炎症， 它们可以促进皮肤损伤，但它们如何适应皮肤环境并随后促进组织损伤尚不清楚。我们 最近发现了由转录因子缺氧诱导因子诱导的炎症基因程序 (HIF)这是狼疮易感小鼠中致病性T细胞的存活和效应能力所必需的， 类似程序在人类SLE中上调。然而，HIF 1如何促进损伤以及其他组织适应 DLE中皮肤浸润性T细胞中效应子途径的激活尚不清楚。根据我初步的 研究中，我假设HIF 1调节DLE皮肤中的致病性T细胞存活和效应子功能， 炎症和损伤可能部分由增强的细胞毒性介导。这种HIF-1调节的效应物 该计划还提出了一种组织浸润性T细胞的致病适应模式， 导致组织损伤为了验证我的假设，我将确定HIF 1受体阻滞剂在缓解 小鼠狼疮模型中的皮肤病。我还将研究人类DLE皮肤和血液样本使用单细胞 RNA测序用于探测人类T细胞的发育轨迹、表型和功能谱 DLE。最后，我将使用成像技术来研究细胞毒性在人类DLE组织损伤中的作用， 在小鼠组织中进行平行研究。我的研究不仅将阐明HIF 1和细胞毒性在DLE中的作用， 而且还将首次详细描述人类DLE中浸润和循环T细胞的特征， 未来的研究开发和评估这种毁灭性疾病的新疗法的方式。我的提议 我还将支持一段职业发展期，在此期间，我将接受基础和 约瑟夫·克拉夫特博士是狼疮研究和T 细胞生物学Craft博士在耶鲁大学免疫生物学系的实验室提供了一个高度协作和 支持性研究环境。为了进一步支持我的培训，我组建了一个咨询委员会， 转录组学分析、转化皮肤病学、皮肤T细胞生物学和自身免疫皮肤方面的专家 疾病我的研究和指导额外的职业发展活动集中在计算 方法，人类转化研究和临床研究中的生物统计学将使我能够 作为一名医生科学家，成功实现研究独立，并开设自己的实验室，以便我可以 使用基础和转化免疫学方法研究皮肤自身免疫性疾病，包括DLE。

PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with a predilection for affecting the head and neck that causes permanent scarring, hypopigmentation, and alopecia. DLE disproportionately affects African American women, and it severely impairs quality of life. DLE may occur alone or in the setting of systemic lupus erythematosus (SLE), and treatments for DLE are currently unsatisfactory. The DLE inflammatory infiltrate is predominantly composed of T cells, which appear to promote tissue inflammation and damage, but how they adapt to the skin environment and subsequently promote tissue injury is unknown. We recently identified an inflammatory gene program induced by the transcription factor hypoxia inducible factor (HIF) that is necessary for the survival and effector ability of pathogenic T cells in lupus-prone mice, with a similar program upregulated in human SLE. Yet, how HIF1 promotes damage and what other tissue adaptation and effector pathways are activated in skin-infiltrating T cells in DLE are not known. Based on my preliminary studies, I hypothesize that HIF1 regulates pathogenic T cell survival and effector function in DLE skin, causing inflammation and damage that may be mediated in part by enhanced cytotoxicity. This HIF1-regulated effector program also suggests a paradigm of pathogenic adaptation in tissue-infiltrating T cells with the potential to drive tissue damage. To test my hypothesis, I will determine the mechanism of HIF1 blockade in alleviating skin disease in a murine lupus model. I will also study human DLE skin and blood samples using single cell RNA sequencing to probe the developmental trajectory, phenotypic, and functional profile of T cells in human DLE. Finally, I will use imaging techniques to examine the role of cytotoxicity in tissue damage in human DLE, with parallel studies in mouse tissue. My studies will not only elucidate the role of HIF1 and cytotoxicity in DLE, but will also yield the first detailed characterization of infiltrating and circulating T cells in human DLE, paving the way for future studies to develop and evaluate novel therapeutics for this devastating disease. My proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Joseph Craft, a leader in the fields of lupus research and T cell biology. Dr. Craft's laboratory in the Yale Department of Immunobiology provides a highly collaborative and supportive research environment. To further support my training, I have assembled an advisory committee with experts in transcriptomic analyses, translational dermatology, cutaneous T cell biology, and autoimmune skin disease. My research studies and directed additional career development activities focused on computational approaches, human translational research, and biostatistics in clinical investigation will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study cutaneous autoimmune diseases including DLE.