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.
Toxic epidermal necrolysis (TEN) is a rare but life-threatening skin disease that is most commonly drug-induced. It has recently been suggested that Stevens-Johnson syndrome (SJS) belongs to the same group of skin disorders, although it has a lower mortality rate than TEN. We report the case of a 26-year-old male schizophrenic patient with a history of carbamazepine-induced SJS 5 years earlier. At the time of his current admission, he was admitted to our psychiatry department with acute agitation due to schizophrenia. However, the patient and his family denied history of drug allergy. After 3 days of carbamazepine treatment, the patient developed TEN (body surface area > 90%). He was transferred to the burn center, but despite appropriate treatment, including intravenous hydrocortisone 200 mg q6h and being covered with sterile biological material, he died. It is important to note that re-administration of a drug that previously caused SJS may lead to TEN, which has a very high mortality rate.
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