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Melanocyte antigen triggers autoimmunity in human psoriasis.

ABSTRACT: Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic T cell response. We found that a V?3S1/V?13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA-C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the V?3S1/V?13S1 TCR. Consistent with the V?3S1/V?13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.

SUBMITTER: Arakawa A

PROVIDER: S-EPMC4689169 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Melanocyte antigen triggers autoimmunity in human psoriasis.

Arakawa Akiko A Siewert Katherina K Stöhr Julia J Besgen Petra P Kim Song-Min SM Rühl Geraldine G Nickel Jens J Vollmer Sigrid S Thomas Peter P Krebs Stefan S Pinkert Stefan S Spannagl Michael M Held Kathrin K Kammerbauer Claudia C Besch Robert R Dornmair Klaus K Prinz Jörg C JC

The Journal of experimental medicine 20151130 13

Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic ...[more]

PMID: 26621454

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Project description:The pigment cells form the largest population of neural crest cells to migrate into the epidermis and hair follicle along each dermatomic area from the neural folds. The melanopsin system responsible for photoentrainment, was isolated from the photosensitive dermal melanophores of frogs Xenopus laevis responding to light. Melanocytes form a photoresponsive network which reads the environmental seasonal variations in the light cycles in the same manner. The present work was undertaken to study the organization of this system by: I. Experimental assessment of photoresponse and II. Evidence of an organized system of photoreception in the skin. Melanocytes, in whole skin organ cultures and epidermal strips, from margin of vitiligo in G2 phase show prominent dendricity, and express pigment, biogenic amines and hormones on UV exposure. The photoresponse depends on the photosensitive enzymes NAT/HIOMT and dopaoxidase. Melanocytes interact with adjacent keratinocytes, dermal capillaries, and nerve endings. The melanocyte network reads the diurnal and seasonal photophase by the melatonin/serotonin switch like the pineal. Sleep disorders and winter depression are corrected by phototherapy utilising this mechanism. Melanocytes showing photoactivity, aplasia, hypoplasia and hyperplasia, and interactive keratinocytes occupy the trigeminal, brachial and lumbosacral dermatomes, zones of high embryonic induction, forming an ectodermal placodal system. Melanin units and hair follicles serve as photoreceptors. Migration of active melanocytes to defined areas is evident in pigment patterns in guinea pigs. This study identifies defined photoreceptor melanocyte/epidermal domains which read the seasonal photophase and control the sleep waking cycle in response to the environmental light. I. Whole skin organ cultures, and epidermal strips from margin of vitiligo in G2 phase are exposed to UV and IR to study sequential and dose response of marginal melanocytes, using histochemistry, immunohistochemistry to assess pigment, biogenic amines and hormones on UV exposure. II. Dermatomic Distributions: Detailed maps of melanocyte photoresponse in 356 biopsies, lesions in 297 vitiligo, 100 melanosis, 165 melanomas 142 leprosy and 442 basal cell/keratinocytes lesions were assessed for patterns of dermatomic distribution. Embryonal melanocyte migration along dermatomes was assessed in 285 guinea pigs from an inbred colony having black, brown and white patches.

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Melanocyte antigen triggers autoimmunity in human psoriasis.

Publications

Melanocyte antigen triggers autoimmunity in human psoriasis.

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