This review aims to address the mechanisms of compromised immune tolerance contributing to the development and maintenance of Alopecia Areata (AA). Our goal is to also highlight future treatment opportunities and therapeutics that will safely and efficiently restore hair growth and maintain patients in remission.
AA is a presumptive autoimmune disorder that coincides and genetically clusters to several other autoimmune diseases. In this review, we pay attention to the learnings from the mechanistic research and drug development in these other autoimmune conditions. Interestingly, most of these diseases have been linked to compromised central and peripheral tolerance, and increased intestinal inflammation with enhanced gut permeability. Break of tolerance and priming of the autoreactive T-cells to attack antigenic epitopes in the hair follicle most likely requires several steps which include escape from negative selection and compromised peripheral tolerance. Local skin-related changes are also of importance due to the patchy manifestation of the skin areas with loss of hair, particularly in the early disease. Here, we discuss the defective mechanisms of tolerance, both central and peripheral, and hypothesize that the disease is driven by areas of tolerance break, and that these could be targeted for successful therapeutic interventions.