Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb?
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.
Paus
R
R
Department of Dermatology, University Hospital Rudolf Virchow Freie Universität Berlin, Germany.
Slominski
A
A
Czarnetzki
B M
BM
D000506:Alopecia Areata / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006197:Hair / Q000254:growth & development / Q000276:immunology / Q000473:pathology; D015395:Histocompatibility Antigens Class I; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D008954:Models, Biological; D011506:Proteins / Q000276:immunology
D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D008543:Melanins; D011506:Proteins