Attenuation of Wnt/β-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

“…Blocking circulating retinoids could mitigate the symptoms of SJS/TEN ( Mawson et al, 2015 ). A study showed Wnt signaling was downregulated in drug-induced SJS/TEN, and enhancement of Wnt signaling attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients ( Chen et al, 2020 ). Plus, using metabonomics to study the metabolites might be helpful to identify the common etiology to cause SJS/TEN.…”