Connecting Skin and Gut in Dermatitis Herpetiformis: Insights from Gluten Challenge Transcriptomics

Dermatitis herpetiformis (DH) is a dietary gluten -induced autoimmune blistering skin disease. It is hypothesized to be initiated by a small intestinal mucosal immune response. Gluten-free diet (GFD) is the primary treatment for DHdermatitis herpetiformis and effectively resolves skin lesions. Previous studies show that after gluten reintroduction, peripheral cell responses are detectable already in six6 days, and most patients relapse clinically within months. The relapse presentation may differ between patients, with some experiencing both rash and small intestinal mucosal damage and some only one of these. Here, RNA transcriptomics were utilized to characterize temporal systemic and small intestinal mucosal responses to gluten in DH,dermatitis herpetiformis and to identify transcriptomic profiles specific for rash or villous atrophy as relapse presentations. The cohort consisted of 19 DHdermatitis herpetiformis patients on GFDgluten-free diet who underwent a gluten challenge. Gluten challenge elicited pronounced gene expression changes related to inflammation in the small intestine. In patients relapsing with rash, DOCK8 expression was significantly upregulated, while IL10RB was downregulated at end of follow-up. These patients also had significantly increased frequency of intraepithelial lymphocytes. Our findings show that prolonged gluten exposure alters duodenal transcriptomic profiles considerably. Moreover, patterns related to rash could be detected and present interesting candidates for future studies.