Alopecia areata (AA) is an immune-mediated hair loss disorder characterized by elevated levels of IFNγ and Th1-driven inflammatory responses toward the hair follicle (HF) bulb. This results in immune privilege (IP) collapse, premature catagen development, and HF dystrophy. Given the critical role of interleukin (IL)-12 in priming Th1 responses, we investigated whether IL-12 could be directly involved in inducing HF-IP collapse and whether the selective tyrosine kinase 2 (TYK2) inhibitor, BMS-986202, could prevent or reverse the process. By quantitative immunohistomorphometry, we showed that ex vivo treatment of microdissected HFs with IL-12 (3 ng/mL) + IL-18 (20 ng/mL) upregulated MHC-I and II as well as MICA/B expression in the hair bulb (cardinal features of IP collapse), increased the numbers of CD3+ or CD56+ cells in HF epithelium and mesenchyme, and selectively enriched IFNγ-inducible genes. In addition, more peribulbar IL-12RB2+ cells were found in acute lesional scalp skin samples of AA patients than healthy controls. We further confirmed the role of IL-12 in the HF-IP collapse by selectively blocking IL-12 receptor signaling. BMS-986202 (300 nM), when administered to microdissected HFs before or after IL-12 + IL-18 stimulation, prevented or attenuated the expression of MHC-I and II as well as secretion of IFNγ. Therefore, our data demonstrate that local IL-12 directly promotes perifollicular immune cell expansion, IFNγ secretion, and HF-IP collapse. These findings support a potential role of IL-12 signaling in AA pathogenesis and highlight IL-12 as a potential new target for pharmacologic AA therapy.

ESDR061 - Selective inhibition of tyrosine kinase 2 prevents and restores interleukin-12-induced hair follicle immune privilege collapse: a novel approach to alopecia areata therapy?

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING