Melanocyte antigen triggers autoimmunity in human psoriasis

A Arakawa, K Siewert, J Stöhr, P Besgen… - Journal of Experimental …, 2015 - rupress.org
A Arakawa, K Siewert, J Stöhr, P Besgen, SM Kim, G Rühl, J Nickel, S Vollmer, P Thomas…
Journal of Experimental Medicine, 2015rupress.org
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 …
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.
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