Alopecia areata exhibits cutaneous and systemic OX40 activation across atopic backgrounds

Abstract Background Alopecia areata (AA) is a chronic, nonscarring hair‐loss disorder associated with significant quality‐of‐life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1‐ and Th2‐driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking. Methods Lesional and nonlesional scalp biopsies obtained from AA patients with ( n = 16) or without ( n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA‐seq, RT‐PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold‐change| > 1.5 and false‐discovery rate <0.05. Results AA scalp exhibited robust upregulation of Th1‐ ( IFNG , CXCL9 , CXCL10 , CXCL11 ) and Th2‐related products ( CCL26 , CCR4 , IL10 , IL13 , TSLP , TNFRSF4 /OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2‐skewing ( IL10 , IL13 , IL33 , CCR4 , CCL26 ). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40 + and OX40L + leukocytes, regardless of atopic background. Conclusion Our results suggest some atopy‐associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.