Reduced TLR3 and TLR9 Expression in Epidermodysplasia Verruciformis: Evidence From a Comparative Skin Study

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by lifelong β-human papillomavirus (β-HPV) persistence, extensive flat warts, and increased risk of cutaneous squamous cell carcinoma. While TMC6, TMC8, and CIB1 mutations are recognized as genetic drivers, innate immune mechanisms contributing to HPV persistence remain incompletely defined. This study quantified the expression of Toll-like receptors (TLRs) 3, 4, 5, and 9 in normal skin and flat warts from patients with EV and immunocompetent individuals without EV (NEV). We performed immunohistochemical analysis on 135 formalin-fixed, paraffin-embedded specimens using standardized digital morphometry of epidermal keratinocytes. EV patients exhibited significantly reduced TLR3 and TLR9 expression in both normal skin and flat warts relative to controls, whereas TLR4 and TLR5 levels were comparable. Notably, flat warts from NEV individuals showed marked TLR3 upregulation relative to matched normal skin, whereas this response was absent in EV patients. These findings are consistent with an EV-associated epithelial innate-sensing phenotype. Our data suggest innate immune deficiencies may interact with previously described keratinocyte abnormalities, amplifying local immune dysfunction. These findings provide a framework for investigating TLR-based therapeutic approaches in EV.