AIRE Deficiency Leads to the Development of Alopecia Areata‒Like Lesions in Mice

Alopecia areata (AA) is an autoimmune hair loss disorder with no cure. Patients with sequence variation in AIRE are 15 times more likely to develop AA than the general population, yet the roles of AIRE in AA pathogenesis are unknown. In this study, we report that 62% of C57BL/6J female Aire^‒/‒ mice spontaneously developed persistent AA-like lesions that displayed several hallmarks of human AA. Lesional Aire^‒/‒ skin exhibited hair follicle (HF) dystrophy as determined by a reduced number of anagen HFs, decreased anagen HF proliferation, hair pigmentary changes, and decreased hair width and length. Inflammatory infiltrate comprising CD8⁺ T cells, CD4⁺ T cells, CD68⁺ macrophages, and mast cells was prominent in lesional Aire^‒/‒ HFs. From gene expression analyses, we found lesional Aire^‒/‒ skin to have significantly increased expression of human AA signature genes, including H2-Ab1, Ifnγ, IFN-γ‒induced chemokines (Ccl5, Cxcl9‒11), γ_c family cytokine receptor Il2RA, and JAK‒signal transducer and activator of transcription (STAT) signaling components (Stat1, Stat2, Stat4). By immunostaining, lesional Aire^‒/‒ HFs also show upregulated major histocompatibility complex class I and downregulated α-melanocyte-stimulating hormone, signifying immune privilege collapse, and increased STAT1 activation in HF keratinocytes. Our study highlights a role for AIRE in HF biology and shows that Aire^‒/‒ mice may serve as a valuable model system to study AA pathogenesis.