Immunopathogenesis and Experimental Models of Alopecia Areata: From Mechanistic Insights to Translational Platforms.

Alopecia areata (AA) is a common autoimmune, non-scarring hair loss disorder with substantial clinical heterogeneity and psychosocial burden. Although recent therapeutic advances, particularly Janus kinase (JAK) inhibitors, have transformed management, the pathogenic mechanisms underlying disease initiation, progression, and relapse remain incompletely understood. Current evidence supports the collapse of hair follicle immune privilege as a central event in AA, followed by the activation of cytotoxic T-cell-dominant responses and amplification through IFN-γ/IL-15-driven inflammatory circuits. However, the contributions of innate immune populations, neuroimmune stress pathways, and hair follicle resident compartments to disease heterogeneity are still being clarified. In parallel, experimental models have proven essential for mechanistic investigation and therapeutic development. Classical C3H/HeJ mice, humanized models, and genetically engineered systems provide critical insights into immune-mediated follicular injury and serve as valuable platforms for drug screening. Furthermore, in vitro and ex vivo models, including hair follicle organ cultures, scalp explants, and novel bioengineered platforms, facilitate the detailed investigation of early pathological events and their underlying mechanisms. Yet, no single model fully captures the entire disease continuum. This review synthesizes the current understanding of AA immunopathology and systematically evaluates available experimental platforms with an emphasis on their biological fidelity, strengths, limitations, and translational applications. By integrating pathogenic mechanisms with model selection, this review aims to provide a practical framework for future AA research and therapeutic innovation.