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2015 ; 212
(13
): 2203-12
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Melanocyte antigen triggers autoimmunity in human psoriasis
#MMPMID26621454
Arakawa A
; Siewert K
; Stöhr J
; Besgen P
; Kim SM
; Rühl G
; Nickel J
; Vollmer S
; Thomas P
; Krebs S
; Pinkert S
; Spannagl M
; Held K
; Kammerbauer C
; Besch R
; Dornmair K
; Prinz JC
J Exp Med
2015[Dec]; 212
(13
): 2203-12
PMID26621454
show ga
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.
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