Letter abstract
Nature Medicine 14, 1343 - 1350 (2008)
Published online: 23 November 2008 | doi:10.1038/nm.1884
Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis
Wen-Hung Chung1,2,3,9, Shuen-Iu Hung2,4,9, Jui-Yung Yang5, Shih-Chi Su2, Shien-Ping Huang2, Chun-Yu Wei2, See-Wen Chin4, Chien-Chun Chiou1, Sung-Chao Chu6, Hsin-Chun Ho1, Chih-Hsun Yang1, Chi-Fang Lu7, Jer-Yuarn Wu2, You-Di Liao2 & Yuan-Tsong Chen2,8
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.
- Department of Dermatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 199 Tunghwa North Road, Taipei 105, Taiwan.
- Taiwan International Graduate Program, Molecular Medicine Program, Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
- Institute of Biochemistry and Molecular Biology, School of Life Sciences, 155 Section 2, Linong Street, Taipei 112, Taiwan.
- Institute of Pharmacology, School of Medicine, National Yang-Ming University, 155 Section 2, Linong Street, Taipei 112, Taiwan.
- Linkou Burn Center & Department of Plastic Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 199 Tunghwa North Road, Taipei 105, Taiwan.
- Division of Oncology and Hematology, Buddhist Tzu Chi General Hospital, 707 Section 3, Chungyang Road, Hualien 971, Taiwan.
- Department of Dermatology, Chung Shan Hospital, 11, Lane 112, Section 4, Jenai Road, Taipei 105, Taiwan.
- Department of Pediatrics, Duke University Medical Center, Box 103856, 595 LaSalle Street, Durham, North Carolina 27710, USA.
- These authors contributed equally to this work.
Correspondence to: Yuan-Tsong Chen2,8 e-mail: chen0010@ibms.sinica.edu.tw
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