Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.
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.
Chung
Wen-Hung
WH
Hung
Shuen-Iu
SI
Yang
Jui-Yung
JY
Su
Shih-Chi
SC
Huang
Shien-Ping
SP
Wei
Chun-Yu
CY
Chin
See-Wen
SW
Chiou
Chien-Chun
CC
Chu
Sung-Chao
SC
Ho
Hsin-Chun
HC
Yang
Chih-Hsun
CH
Lu
Chi-Fang
CF
Wu
Jer-Yuarn
JY
Liao
You-Di
YD
Chen
Yuan-Tsong
YT
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D001768:Blister / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009336:Necrosis; D013262:Stevens-Johnson Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human