The hair follicle and immune privilege

This essay reviews the available evidence that the proximal hair follicle epithelium generates and maintains an area of relative immune privilege during a defined segment of the hair cycle (i.e., during anagen). This immune privilege is chiefly characterized by a very low level of expression of MHC class Ia antigens and by the local production of potent immunosuppressive agents, such as alpha-MSH and TGF-beta1. We discuss the putative functions of immune privilige of the anagen hair bulb, favoring the view that immune privilege serves mainly to sequester anagen- and/or melanogenesis-associated autoantigens from immune recognition by autoreactive CD8+ T cells. On this basis, we develop how the "immune privilege collapse model" of alopecia areata pathogenesis was conceived. In our discussion of the clinical implications of immune privilege, we outline the currently available evidence in support of this still hypothetical scenario to explain the initiation, progression, and termination of alopecia areata lesions. We review the most recent evidence from our laboratory that alpha-MSH, IGF-1, and TGF-beta1 can downregulate IFN-gamma-induced ectopic MHC class I expression in human anagen hair bulbs in vitro. Finally, we suggest that hair follicle-derived alpha-MSH, IGF-gamma, and TGF-beta1 form part of a constitutively active "IP restoration machinery" of the anagen hair bulb, which we propose to be recruited whenever the hair follicle suffers immune injury. Finally, we sketch some particularly promising avenues for future investigation into the far too long ignored hair follicle immune privilege.