Alopecia areata (AA) is a complex autoimmune disease shaped by genetic susceptibility plus environmental factors, and clarifying its pathophysiology can reveal new therapeutic targets—especially for pediatric AA, which can have a worse course. Genetic evidence includes higher rates in children with a family history and monozygotic twin concordance up to around 55%. Risk loci cluster in immune-regulating pathways, with strong signals in the human leukocyte antigen (HLA) region (especially HLA-DR) and additional associations involving T-cell signaling and immune checkpoints (e.g., IL2RA, CTLA4, PTPN22), supporting AA as a polygenic condition. Potentially AA-specific immune markers include NKG2D ligands such as ULBP3/ULBP6, which may help drive cytotoxic T-cell activation in affected follicles.

Mechanistically, AA centers on collapse of hair follicle immune privilege (particularly in anagen), exposing follicular antigens and triggering an immune attack led by NKG2D+ CD8 T cells (with CD4 T cells and NK cells). Proposed triggers include infection, oxidative stress, vaccinations/hypersensitivity, stress, and immunotherapies—potentially via plasmacytoid dendritic cells and type I interferons. IFN-γ–driven JAK–STAT signaling is a key amplifier, increasing MHC expression, inducing CXCL9/10/11 to recruit CXCR3+ lymphocytes, and sustaining positive feedback loops through IL-2 and IL-15 that reinforce IFN-γ and cytotoxic activity. Th17/Treg imbalance (IL-17/IL-22) may also contribute. Pediatric poor-prognosis features include early onset (prepuberty), nail involvement, atopy, ophiasis pattern, recurrent/longstanding disease, and family history. Yet, researchers note, pediatric-specific pathophysiologic differences remain unclear and warrant focused study.

Reference: Fitzhugh MH, Hansen JG, Jabbari A, Berrebi KG. Pathophysiology of Alopecia Areata in the Pediatric Patient. Pediatr Dermatol. 2025 Mar;42 Suppl 1(Suppl 1):24-30. doi: 10.1111/pde.15842. PMID: 40044623; PMCID: PMC11882487.

Link: Pathophysiology of Alopecia Areata in the Pediatric Patient – PMC