title: Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.
abstract: 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.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.forename: Jui-Yung
authors.initials: JY
authors.lastname: Yang
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Su
authors.forename: Shien-Ping
authors.initials: SP
authors.lastname: Huang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Wei
authors.forename: See-Wen
authors.initials: SW
authors.lastname: Chin
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Chiou
authors.forename: Sung-Chao
authors.initials: SC
authors.lastname: Chu
authors.forename: Hsin-Chun
authors.initials: HC
authors.lastname: Ho
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.forename: Chi-Fang
authors.initials: CF
authors.lastname: Lu
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.forename: You-Di
authors.initials: YD
authors.lastname: Liao
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: 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
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human