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J Exp Med. 2015 Dec 14;212(13):2203-12. doi: 10.1084/jem.20151093. Epub 2015 Nov 30.

Melanocyte antigen triggers autoimmunity in human psoriasis.

Author information

1
Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
2
Institute of Clinical Neuroimmunology, Ludwig-Maximilian-University, D-82152 Planegg-Martinsried, Germany.
3
Gene Center Munich, Ludwig-Maximilian-University, D-81377 Munich, Germany.
4
German Cancer Research Center, D-69120 Heidelberg, Germany.
5
Laboratory of Immunogenetics and Molecular Diagnostics, Ludwig-Maximilian-University, D-81377 Munich, Germany.
6
Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany joerg.prinz@med.uni-muenchen.de.

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 Vα3S1/Vβ13S1 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 Vα3S1/Vβ13S1 TCR. Consistent with the Vα3S1/Vβ13S1-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.

PMID:
26621454
PMCID:
PMC4689169
DOI:
10.1084/jem.20151093
[Indexed for MEDLINE]
Free PMC Article

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