title: 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 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.
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Akiko
authors.initials: A
authors.lastname: Arakawa
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilian-University, D-82152 Planegg-Martinsried, Germany.
authors.forename: Katherina
authors.initials: K
authors.lastname: Siewert
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stöhr
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Besgen
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilian-University, D-82152 Planegg-Martinsried, Germany.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rühl
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Nickel
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Vollmer
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Gene Center Munich, Ludwig-Maximilian-University, D-81377 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pinkert
authors.affiliation: Laboratory of Immunogenetics and Molecular Diagnostics, Ludwig-Maximilian-University, D-81377 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilian-University, D-82152 Planegg-Martinsried, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Held
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kammerbauer
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilian-University, D-82152 Planegg-Martinsried, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dornmair
authors.affiliation: Department of Dermatology, Ludwig-Maximilian-University, D-80337 Munich, Germany joerg.prinz@med.uni-muenchen.de.
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Prinz
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071096:ADAMTS Proteins; D000328:Adult; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D015236:HLA-C Antigens / Q000276:immunology; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011565:Psoriasis / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism
chemical_list: D001324:Autoantigens; D000939:Epitopes; D015236:HLA-C Antigens; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C581035:ADAMTSL5 protein, human