Sensory neuroimmune signaling in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions often triggered by medications. While the involvement of CD8+ T cells causing keratinocyte death is well recognized, the contribution of neural elements to the persistent skin inflammation has been largely overlooked. Objective: We investigated the potential neuroimmune regulation in SJS/TEN. Methods: Unbiased single-cell RNA sequencing and flow cytometry were performed using circulating CD8+ T cells from healthy controls and patients with SJS/TEN. ELISA and LEGENDplex assays were respectively used to detect neuropeptides and inflammatory mediators. Skin tissues were examined by immunofluorescence staining for neuropeptideassociated nerves and cytokine receptors. Calcium imaging, Smart-seq, and a 3-D skin model were used for cultured human Results: Unbiased RNA sequencing revealed an upregulation of the receptor for neuropeptide calcitonin gene-related peptide (CGRP), known as RAMP), in effector CD8+ T cells in SJS/ TEN. Increased CGRP+ nerve fibers and CGRP levels, along with upregulated IL-15R and IL-18R on CD8+ T cells, were displayed in the affected skin of SJS/TEN. The CGRP-RAMP1 axis was necessary and sufficient to enhance receptors for IL-15 and IL-18 and cytotoxic activities in CD8+ T cells, ultimately resulting in keratinocyte apoptosis. Calcium influx was detected in CGRP-stimulated CD8+ T cells. HCN2, a hyperpolarizationactivated cation channel, was required for this process and the subsequent cytotoxic effects. Conclusions: Our study highlights the role of neural elements in regulating CD8+ T-cell-mediated inflammatory responses and provides new potential translational targets to improve the outcomes of severe cutaneous drug reactions. (J Allergy Clin Immunol 2025;155:533-46.)