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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.

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Figure 1: Cytotoxicity of blister fluids and blister cells of subjects with SJS-TEN.
Figure 2: Gene expression analyses of blister cells (BCs) and PBMCs of subjects with SJS-TEN.
Figure 3: Immunohistochemistry staining of cytotoxic proteins in skin biopsies.
Figure 4: Analyses of cytotoxic proteins in the blister fluids.
Figure 5: In vitro cytotoxicity of granulysin, perforin, granzyme B and sFasL against keratinocytes (KERTr cells).
Figure 6: Intradermal injection of 15-kDa granulysin in mice.

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DH4 monoclonal antibody was a gift from A.M. Krensky (Stanford University). We thank H.-J. Lin, S.-J. Li, K.-H. Chen, L.-H. Lu of the Institute of Biomedical Sciences, Academia Sinica and members of the National Microarray & Gene Expression Analysis Core Facility, National Yang-Ming University, Taiwan, for excellent technical assistance. This work was supported by grants from the National Science Council, Taiwan (NSC95-2314-B-182A-048, 95-2314-B-010-096, 96-2320-B-010-021-MY2 and 96-2628-B-182A-065-MY2), Chang-Gung Memorial Hospital, Taiwan Ministry of Education (Aim for the Top University Plan, National Yang-Ming University), National Research Program for Genomic Medicine, Taiwan (National Clinical Core, NSC-95-3112-B-001-010 and National Genotyping Core, NSC-95-3112-B-001-011) and the Genomics and Proteomics Program, Academia Sinica.

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Authors and Affiliations



W.-H.C. and S.-I.H. designed and conducted the experiments and data analysis and wrote the manuscript. J.-Y.Y., C.-C.C., S.-C.C., H.-C.H., C.-H.Y. and C.-F.L. cared for the involved human subjects and provided clinical samples. S.-C.S., S.-P.H., C.-Y.W. and S.-W.C. performed experiments. J.-Y.W. and Y.-D.L. helped design the expression of protein. Y.-T.C. supervised the entire project and wrote the manuscript.

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Correspondence to Yuan-Tsong Chen.

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W.-H.C., S.-I.H. amd Y.-T.C. have filed a patent application to the Taiwan and US patent offices on granulysin and uses thereof.

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Supplementary Figs. 1 and 2, Supplementary Methods, Supplementary References and Supplementary Tables 1–3 (PDF 635 kb)

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Chung, WH., Hung, SI., Yang, JY. et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 14, 1343–1350 (2008).

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