角质形成细胞重编程在白癜风发病中的作用机制研究

白癜风黑素细胞（MC）损伤系氧化应激下CD8+T细胞介导的自身免疫所致。占表皮绝大多数的角质形成细胞（KC）在这一过程发挥的作用仍不清楚。我们最近发现，氧化应激诱导白癜风KC中调控CD8+T细胞向皮肤迁移、效应功能及免疫记忆的关键基因发生DNA甲基化/组蛋白乙酰化介导的重编程，提示KC重编程激活细胞免疫应答导致白癜风MC损伤。然而，氧化应激下KC发生重编程及调控免疫应答的具体机制仍不清楚。因此，我们拟结合DNA甲基化谱、组蛋白乙酰化谱及基因/蛋白表达谱，系统鉴定白癜风患者角质形成细胞中氧化应激诱导的表观遗传修饰介导的重编程，进一步构建KC特定基因敲除的小鼠模型，阐明KC重编程促进CD8+T细胞趋化迁移、抗原识别、增殖/活化、靶向杀伤以及免疫记忆，导致MC损伤的具体分子机制，并研究靶向治疗策略。预期将阐明KC重编程调控细胞免疫导致白癜风发生发展的具体机制，完善对KC功能特性和调控机制的认识。

In vitiligo, melanocytes (MC) loss is caused by CD8+ T cell-mediated autoimmune response under oxidative stress. Keratinocytes (KC), the main cell type of skin epidermis, play a role in oxidative stress-initiated autoimmunity in vitiligo, although the underlying mechanisms remain unknown. Recently, in vitiligo-specific oxidative stressed-KCs, we found several DNA methylation and/or histone acetylation changes in key genes that regulate the skin infiltration, the effect function, and the immune memory of CD8+ T cells, suggesting KC reprogramming could activate autoimmune response that targeting MC in vitiligo. However, the exact mechanisms of reprogramming-induced autoimmune response under oxidative stress in vitiligo remains unclear. Therefore, it is critically important to identify oxidative stress-induced reprogramming in KC of vitiligo patients by performing DNA methylation profiles, histone acetylation profiles and gene/protein expression profiles. We also plan to construct vitiligo mice with KC-specific candidate genes knockout, and clarify the detailed mechanisms of how oxidative stress-induced KC reprogramming regulate CD8+T cells effect function, with promoting skin trafficking, melanocyte-specific antigens recognition, proliferation and activation as well as the immunologic memory of CD8+T cells, and consequently lead to MC destruction by the autoimmune system. And further we will investigate the potential targeted therapy. Our study can elucidate the pathogenesis of KC reprogramming caused by cellular immunity in vitiligo and better understand the biological function and regulatory mechanisms of KC.