DNA羟甲基化对组织原位记忆T细胞活化的调控及其在白癜风发病中的作用和机制研究

Vitiligo is a life and health threatening autoimmune disease. The pathogenesis and mechanism remains unclear. Recently, tissue resident memory T（TRM） cells, a newly discovered subset of memory T cells, was reported to be displayed abnormal expression and function in vitiligo. Our previous study showed that CD8+ CD69+ TRM cells were significantly increased in skin from patients with vitiligo. The expression of perforin, granzyme B and 5-hydroxymethylcytosine (5-hmC), which was associated with the activation gene transcription, was significantly up-regulated in the CD8+ CD69+ TRM cells. Therefore, we hypothesize: DNA hydroxymethylation contributes to the abnormalities in TRM cell by regulating activation related genes, and this process may ultimately induce or exacerbate vitiligo. To address the hypothesis, this project aims to identify certain DNA hydroxymethylated genes which play a key role in vitiligo TRM cells’ activation, and then evaluate the effect of overexpressing or interfering the expression of these genes in in vitro condition and in mouse model. This study will further reveal the pathogenesis and mechanism of development of vitiligo, and provide potential therapeutic targets and new approaches for treatment of vitiligo.

白癜风是一种影响患者生活和健康的自身免疫性疾病。其发病机制尚不明确。最新研究发现组织原位记忆T（Tissue resident memory T，TRM）细胞在白癜风患者皮损中比例和功能异常，然而机制不明。我们前期研究发现在白癜风患者皮损中CD8+ CD69+ TRM细胞明显增多，细胞中perforin、granzyme B和基因转录活化相关的5-羟甲基化胞嘧啶（5-hmC）的表达明显升高。为此我们提出：DNA羟甲基化修饰通过调控某关键靶基因导致TRM细胞异常活化，在白癜风发生发展中起重要作用的全新假说。本项目拟通过筛选与鉴定白癜风TRM细胞活化中DNA羟甲基化修饰的关键基因，体外实验和小鼠模型抑制DNA羟甲基化修饰的关键基因对TRM细胞活化及自身免疫反应的影响来证实这一假说。该研究将有助于深入揭示白癜风发生发展的机制，并为寻找白癜风治疗新靶点提供新思路和实验依据。

白癜风是一种影响患者生活和健康的自身免疫性疾病。其具体发病机制尚不明确。能量代谢与免疫系统之间相互影响、相互联系, 其在机体内与自身免疫性疾病的发生有密切关系，有研究报道白癜风患者体内存在脂肪和糖代谢异常，然而在白癜风的发生机制的作用仍然不清。因此，本研究项目对白癜风患者皮损和正常人皮肤进行转录组测序及分析，筛选出可能与能量代谢和在白癜风发病中起作用的CD8+ T细胞相关的关键基因并验证，通过体外和体内实验探索该差异基因在CD8+ T细胞激活中的作用和可能的调节机制。结果发现白癜风患者皮损和正常对照皮肤中CD36、Leptin和LEPR表达有显著差异，进而通过体外实验证实了Leptin能够抑制CD8+ TRM细胞的增加，可能是通过TET3的羟甲基化表观调节起作用。然而，在动物体内实验中，Leptin未能抑制或诱导出白癜风样皮损的发生，说明体内机制复杂，单一因素的刺激不足以起到关键性的作用。本研究结果将有助于深入揭示白癜风发生发展的机制，并为寻找白癜风治疗新靶点提供新思路和实验依据。