中毒性表皮坏死松解症(TEN)和Stevens-Johson综合征(SJS) 以广泛表皮/上皮细胞死亡为主要表现。很多药物引起的SJS-TEN与HLA-Ⅰ类基因强相关，通过活化CD8+细胞毒性 T细胞(CTL)介导病理损伤。然而，CTL活化及杀伤表皮/上皮的机制仍不清楚。最新研究显示药物与HLA-Ⅰ类分子的肽结合沟槽非共价结合，选择提呈新的内源性肽段，诱导特异性CTL活化。我们推测这种自身肽的选择提呈发生于皮肤，并在介导CTL活化和杀伤表皮细胞中发挥关键作用。我们拟利用液相色谱-串联质谱技术，找到卡马西平处理树突状细胞后HLA-B*15:02提呈表皮抗原的新自身肽，用亲合力分析、晶体结构法验证其结合，并明确新自身肽、药物与HLA-B*15:02结合诱导特异性CTL的作用。本项目将从自身肽异常提呈角度揭示CTL活化及杀伤表皮/上皮机制，为探索SJS-TEN新的治疗策略奠定基础。

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe cutaneous adverse drug reactions involving widespread epidermal and epithelial keratinocyte death. Many such reactions are strongly associated with specific HLA-Ⅰ alleles and driven by drug-specific activation of CD8+ cytotoxic T cells(CTL). However, the mechanism by which CTL is activated and attack epidermis/epithelia remains unclear. It was recently shown that drugs binds non-covalently within peptide-binding grooves of the genetic linked HLA-Ⅰmolecules. In this way, the drug guides the selection of new endogenous peptides, which as neoantigen drive CD8+ CTL activation. We speculate that altered HLA-peptide display also occur in epidermis and epithelia, which account for attacking epidermal cells by driving CD8+ T cells activation against epidermis and epithelia. We will search for epidermal self-peptides newly presented by HLA-B*15:02 expressed by dendritic cells under carbamazepine treatment using LC-MS/MS. Moreover, we will confirm its binding with HLA-*B15:02 by analyzing the affinity and the X-ray crystal strucutre of HLA-B*15:02+peptide+carbamzepine complex.Moreover, we will characterize its pathogenic role in stimulating specific CTL activation. Our project will reveal the mechanism by which CTL is activated and attack epidermis and epithelia, and will lay a solid foundation for development of novel therapeutic strategies for SJS-TEN.