Journal Article

Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis

Ho, Hsin-Chun, Wei, Chun-Yu, Yang, Chih-Hsun, Liao, You-Di, Chung, Wen-Hung, Chen, Yuan-Tsong, Su, Shih-Chi, Hung, Shuen-Iu, Yang, Jui-Yung, Lu, Chi-Fang, Chin, See-Wen, Chu, Sung-Chao, Wu, Jer-Yuarn, Huang, Shien-Ping, Chiou, Chien-Chun

2008

Overview

Drug hypersensitivity reactions can result in life-threatening epidermal necrosis caused by cytotoxic T lymphocytes and natural killer cells. Chung et al . show that an unusual form of granulysin secreted from these cells is largely responsible for the cell death ( pages 1311–1313 ). 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animals / Antigens, Differentiation, T-Lymphocyte - genetics / Antigens, Differentiation, T-Lymphocyte - metabolism / Apoptosis / Biomedical and Life Sciences / Biomedicine / Biopsy / Blister - genetics / Blister - metabolism / Blister - pathology / Cancer Research / Care and treatment / Causes of / CD8 lymphocytes / Cell death / Cytotoxicity / Development and progression / Drug therapy / Epidermis - cytology / Epidermis - metabolism / Gangrene / Gene Expression Profiling / Gene Expression Regulation / Genetic aspects / Health aspects / Humans / Hypersensitivity / Immunity / Infectious Diseases / Keratinocytes - cytology / Keratinocytes - metabolism / Killer Cells, Natural - metabolism / letter / Lymphocytes / Metabolic Diseases / Mice / Mice, Nude / Molecular Medicine / Molecular Weight / Mortality / Necrosis / Neurosciences / Physiological aspects / Proteins / Side effects / Stevens-Johnson syndrome / Stevens-Johnson Syndrome - genetics / Stevens-Johnson Syndrome - metabolism / Stevens-Johnson Syndrome - pathology / Stevens-Johnson Syndrome - surgery / T-Lymphocytes, Cytotoxic - metabolism