Alopecia areata exhibits cutaneous and systemic <scp>OX</scp>40 activation across atopic backgrounds
Madeline Kim, Ester Del Duca, Dante Dahabreh, Daniel Lozano‐Ojalvo, Britta Carroll, Meredith Manson, Swaroop Bose, Digpal Singh Gour, Monali NandyMazumdar, Ying Liu, Mitchelle L. Yu Ekey, Amira Chowdhury, Michael Angelov, Benjamin Ungar, Yeriel Estrada, Emma Guttman‐Yassky
Abstract
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.