Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis
Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis
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DOI：
10.1038/nm.1884
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发表时间：
2008-12-01
期刊：
影响因子：
82.9
通讯作者：
Chen, Yuan-Tsong
中科院分区：
文献类型：
--
作者：
Chung, Wen-Hung;Hung, Shuen-Iu;Chen, Yuan-Tsong
Stevens-Johnson综合征（SJS）和中毒性表皮坏死松解症（TEN）是以大面积表皮坏死为特征的危及生命的药物不良反应，其中涉及的具体危险信号尚不清楚。在这里，我们表明SJS-TEN皮肤病变中的水泡细胞主要由细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞组成，水泡液和细胞都具有细胞毒性。基因表达谱确定颗粒溶素作为最高表达的细胞毒性分子，通过定量PCR和免疫组化证实。水疱液中的颗粒溶素浓度比穿孔素、颗粒酶B或可溶性Fas配体浓度高两到四个数量级，并且耗尽颗粒溶素降低了细胞毒性。水疱液中的颗粒溶素是一种15 kDa的分泌形式，将其注射到小鼠皮肤中会产生模仿SJS-TEN的特征。我们的研究结果表明，分泌性颗粒溶素是一个关键的分子，负责播散角质形成细胞死亡的SJS-TEN和突出的CTL或NK细胞介导的细胞毒性，不需要直接的细胞接触的机制。
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell-mediated cytotoxicity that does not require direct cellular contact.