Autoimmune Disease Induction in a Healthy Human Organ: A Humanized Mouse Model of Alopecia Areata

A genome-wide association study conducted on 1,054 cases and 3,278 controls identified several susceptibility loci for alopecia areata, suggesting the involvement of both innate and adaptive immunity in the disease. The study highlighted significant associations with genes related to regulatory T cells, CTLA4, IL-2/IL-21, IL-2RA, and the HLA region, as well as genes expressed in the hair follicle like PRDX5 and STX17. Notably, the ULBP gene cluster on chromosome 6q25.1, encoding ligands for the natural killer cell receptor NKG2D, was implicated for the first time in autoimmune disease, with ULBP3 expression upregulated in the hair follicle during active disease. This research provided insights into the genetic basis of alopecia areata and suggested a novel mechanism involving ULBP ligand upregulation in autoimmunity.

The study explored how hair follicles (HFs) maintain immune privilege (IP) to avoid natural killer (NK) cell attacks, which typically target cells with low MHC class I expression. It was found that HFs actively suppress NK cells, with the HF epithelium expressing the NK cell inhibitor macrophage migration inhibitory factor. In healthy individuals, fewer NK function-activating receptors and more inhibitory receptors were present compared to those with alopecia areata (AA), an autoimmune disease linked to a breakdown of HF-IP. AA patients showed increased NK cell activity around hair follicles, suggesting a defect in NK cell inhibition that contributes to the disease's pathogenesis. This defect was previously unreported and highlighted the need for considering NK cell activity in AA management.