细胞毒性T细胞介导角质形成细胞焦亡加重重症大疱性药疹SJS/TEN皮肤损害

重症大疱性药疹是一组主要由药物过敏引起的严重皮肤黏膜疾病，包括Stevens-Johnson综合征（SJS）和中毒性表皮坏死松解症（TEN）。以往认为角质形成细胞（KC）凋亡是其皮肤损害的病理基础。近年来发现细胞焦亡在炎症反应中发挥重要作用，细胞毒性T细胞（CTL）可以分泌细胞毒蛋白启动靶细胞焦亡。申请人前期发现SJS/TEN患者不仅存在CTL水平升高，而且焦亡执行蛋白GSDMD、GSDME及上游分子Caspase-8、3在皮损部位表达增加。据此，我们提出“CTL通过分泌细胞毒蛋白介导KC焦亡，加重SJS/TEN皮肤损害”假说，拟通过建立人源化的SJS/TEN小鼠模型，研究CTL介导KC焦亡在SJS/TEN中的作用；利用基因编辑和特异性抑制剂，在细胞水平探讨分子机制；最后用人群研究加以验证。本研究结果将进一步揭示SJS/TEN皮肤损害新的发病机制，为临床治疗SJS/TEN提供候选药物靶点。

Severe cutaneous adverse reactions to drugs are serious cutaneous and mucous membrane diseases due to drug hypersensitivity, including Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN). Keratinocytes (KC) apoptosis is known to play a role in the pathological mechanism of the skin damage of SJS/TEN. Recent studies showed that pyroptosis plays a vital role in inflammatory response, and Cytotoxic T lymphocyte (CTL) is a trigger of pyroptosis via secreting granules. Consistently, our previous work has demonstrated both an increased expression of CTL in peripheral blood and pyroptosis-related molecules, such as GSDMD, GSDME, Caspase-8 and Caspase-3 in SJS/TEN skin lesions. Therefore, we hypothesize that CTL might activate KC pyroptosis via secreting granules to aggravate skin damage in SJS/TEN. Humanized mouse model will be established to explore the role of CTL in KC pyroptosis, the underlying mechanisms are studied at molecular level by in vitro experiments, and finally clinical SJS/TEN studies will be carried out to verify the hypothesis. Our results will uncover a novel mechanism of the skin damage in SJS/TEN, and thereby may provide a promising therapeutic target for future management of SJS/TEN.