title: Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand.
abstract: The pathogeneses of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), both severe blistering diseases usually associated with drug intake, are not fully elucidated. Histologically, both TEN and SJS are characterized by extensive keratinocyte apoptosis. Previous studies have shown that keratinocyte apoptosis in TEN and SJS was induced by a suicidal interaction between Fas and Fas ligand (FasL), which are both expressed by keratinocytes. However, our preliminary examinations demonstrated that FasL is hardly detected on keratinocytes. We hypothesized that soluble FasL (sFasL) is secreted by peripheral blood mononuclear cells (PBMCs), and this interacts with the Fas expressed on keratinocytes in TEN and SJS. To justify this hypothesis, we investigated whether sFasL secreted by PBMCs could induce the keratinocyte apoptosis in TEN and SJS. Enzyme-linked immunosorbent assay analysis demonstrated that there was no significant sFasL increase in any samples of healthy controls (<40 pg/ml, n = 14) and patients with an ordinary erythema multiforme-type drug eruption (41.5 +/- 3.1 pg/ml, n = 14), whereas high concentrations are detected in all samples of TEN and SJS patients (TEN: 131.5 +/- 57.4 pg/ml, n = 8; SJS: 119.1 +/- 41.0 pg/ml, n = 14) (P < 0.0001). In vitro analysis using cultured keratinocytes revealed that the sera of TEN and SJS patients induced abundant keratinocyte apoptosis compared to erythema multiforme-type drug eruption sera. Furthermore, on stimulation with the causal drug, PBMCs obtained from TEN and SJS patients secreted high levels of sFasL. Taken together, these results indicate that sFasL secreted by PBMCs, not keratinocytes, plays a crucial role in the apoptosis and pathomechanism of TEN and SJS, and that the serum sFasL level may be a good indicator for the early diagnosis of TEN and SJS.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. aberi@med.hokudai.ac.jp
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shibaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000328:Adult; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D012016:Reference Values; D012867:Skin / Q000276:immunology*; D013262:Stevens-Johnson Syndrome / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor