Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb?

TLDR

Alopecia areata is an autoimmune disease of sudden hair loss, yet the origin of its selective inflammatory infiltrate targeting anagen follicles remains unclear. This study tests a novel hypothesis that loss of MHC I negativity in the anagen hair bulb exposes melanogenesis‑related autoantigens, triggering cytotoxic T‑cell attacks, and explores strategies to suppress MHC I expression and induce tolerance to these antigens. Microtrauma, neurogenic inflammation, or microbial antigens locally disrupt MHC I negativity, exposing melanogenesis‑related proteins that activate CD8⁺ T cells and subsequently CD4⁺ T cells against additional autoantigens presented by damaged melanocytes and keratinocytes. The hypothesis accounts for AA’s clinical heterogeneity, follicular and extrafollicular damage, and shows that disease severity depends on immunogenetic background, indicating that AA arises only from a rare concurrence of multiple predisposing events.

Abstract

The etiology of alopecia areata (AA), a putative autoimmune disease characterized by sudden hair loss, has remained obscure. It is not understood, how the characteristic inflammatory infiltrate that selectively attacks anagen hair follicles in AA is generated. We hypothesize that this reflects an unexplored form of autoimmunity, a cytotoxic T cell attack on rhythmically synthesized autoantigens normally sequestered by a lack or very low level of MHC class I (MHC I)-expression, and suggest the following mechanism of AA pathogenesis: Microtrauma, neurogenic inflammation, or microbial antigens cause a localized breakdown of MHC I-"negativity" in the proximal anagen hair bulb via proinflammatory cytokines. This exposes autoantigens derived from melanogenesis-related proteins (MRP-DP), which are only generated during anagen, and triggers two successive waves of autoimmune responses: CD8+ cytotoxic T cells initiate AA after recognizing MRP-DP abnormally presented by MHC I molecules on hair matrix melanocytes and/or keratinocytes; a secondary attack, carried by CD4+ T cells and antigen presenting cells, is then mounted against MHC class II--presented additional autoantigens exposed by damaged melanocytes and keratinocytes. The latter causes most of the follicular damage, and extrafollicular disease, and depends greatly on the immunogenetic background of affected individuals. This unifying hypothesis explains the clinical heterogeneity and all salient features of AA, and argues that only the unlikely coincidence of multiple predisposing events triggers AA. The suppression of MHC I--expression and synthesis of MRP in the hair bulb, and the "tolerization" of MRP-DP autoreactive CD8+ T cells may be promising strategies for treating AA.