Melanocyte antigen triggers autoimmunity in human psoriasis

Area of Science:

• Immunology
• Dermatology
• Genetics

Background:

• Psoriasis vulgaris is a T cell-mediated inflammatory skin disease with suspected autoimmune origins.
• The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is a major genetic risk factor for psoriasis.
• The precise mechanisms of T cell activation and the role of HLA-C*06:02 in psoriasis pathogenesis have been unclear.

Purpose of the Study:

• To elucidate the functional role of HLA-C*06:02 in psoriatic T cell responses.
• To identify the specific target cells and autoantigens involved in HLA-C*06:02-restricted autoimmune reactions in psoriasis.
• To understand the mechanisms underlying T cell activation in psoriasis lesions.

Main Methods:

• Reconstitution of a T cell receptor (TCR) from an epidermal CD8(+) T cell clone of a psoriasis patient.
• Peptide library screening to identify autoantigens presented by HLA-C*06:02.
• Analysis of T cell reactivity and cytokine production (IL-17A) upon stimulation with identified autoantigens.
• Immunohistochemical analysis of psoriasis lesions to identify T cells targeting specific epidermal cells.

Main Results:

• Melanocytes were identified as specific target cells of an HLA-C*06:02-restricted T cell response in psoriasis.
• ADAMTS-like protein 5 (ADAMTSL5) was identified as a melanocytic autoantigen presented by HLA-C*06:02.
• CD8(+) T cells in psoriasis lesions were observed attacking melanocytes expressing ADAMTSL5.
• ADAMTSL5 stimulation induced IL-17A production in CD8(+) T cells from psoriasis patients, but not controls.

Conclusions:

• The study reveals that HLA-C*06:02 directs an autoimmune response against melanocytes in psoriasis through the presentation of the autoantigen ADAMTSL5.
• This identifies a novel autoimmune pathway in psoriasis pathogenesis, implicating melanocytes as key targets.
• The findings suggest that HLA-C*06:02 may predispose individuals to psoriasis via this newly discovered autoimmune mechanism.