Frontiers in alopecia areata pathobiology research

Abstract

This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential ''new'' players in AA pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8 1 T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called ''unconventional'' T cells (invariant NK T cells, gd T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-g, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8 1 T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, gd regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.

Hair follicle immune privilege and its collapse in alopecia areata

“…This supports the concept that pathological mast cell‐T cell interactions may contribute to the pathogenesis of human AA, perhaps particularly so in atopic individuals 6,44,179 . Recent experiments have demonstrated that the AA phenotype can also be triggered by non–antigen‐specific innate lymphocytes such as type 1 innate lymphoid cells 44,284 . Therefore, besides mast cells, several innate and adaptive immune cell lineages may be functionally important in AA pathogenesis.…”

“…Mast cells strikingly switch from an immunoinhibitory phenotype and infrequent interactions with CD8 + T cells to a profoundly pro‐inflammatory phenotype and greatly enhanced interactions with CD8 + lymphocytes, and—highly unusual for mast cells—even proliferate around lesional HFs in situ 179 . This supports the concept that pathological mast cell‐T cell interactions may contribute to the pathogenesis of human AA, perhaps particularly so in atopic individuals 6,44,179 . Recent experiments have demonstrated that the AA phenotype can also be triggered by non–antigen‐specific innate lymphocytes such as type 1 innate lymphoid cells 44,284 .…”

“…The literature reveals that there are different NK and NKT subsets including regulatory ones 324,325 . Collectively, these studies indicate that multiple cell types may have roles in AA aetiology by breaking the delicate balance between scalp skin‐resident memory T cells versus immune cells with regulatory effects 44 …”

“…Compelling functional evidence for the existence of HF IP has not only been provided long ago by Billingham 21,22 but also in mutant mice overexpressing non‐HF antigens (e.g. 39 ) as well as by the observation that AA does not occur without HF IP collapse 4,6,33,43,44 …”

“…Using a humanized mouse model of AA, Gilhar and colleagues have provided further functional evidence for this concept: The injection of large numbers of autologous IL‐2‐stimulated (activated) CD56 + and NKG2D + cells (T cells, NK and NKT cells) from healthy donors into healthy human scalp skin transplanted onto SCID/beige mice suffices to induce a clinical phenocopy of AA in the skin transplants 278 . Hence, AA should be viewed as a HF response pattern, for whose initiation a genuine autoimmune response pattern is only one of several distinct options (Figure 3; Table 3, 1a‐c) 4,6,33,44 …”