An autoimmune "attack" on melanocytes triggers psoriasis and cellular hyperplasia.

A new study by Jörg Prinz’s group has identified a melanocyte-derived autoantigen that triggers T cell activation in psoriasis vulgaris.

Insight from James Krueger

For two decades, psoriasis has been classified as a probable autoimmune disease based on a strong disease association with HLA-C*06:02, the ability of T cell–directed therapies to produce disease resolution, and the absence of a known infectious agent or exogenous antigen that triggers the disease. Only recently, there has been the suggestion that cathelicidin (LL37), a keratinocyte-derived antimicrobial peptide might serve as an autoantigen in psoriasis, but not all patients have T cell reactivity to this target.

In this study, a second plausible antigen, ADAMTS-like protein 5 (ADAMTSL5) that is produced by melanocytes is identified as an activating antigen for IL-17–producing T cells that are restricted by HLA-C*06:02. The activation of IL-17–producing T cells is important, as increasing evidence places Th17 and Tc17 cells as the central pathogenic immune cells in psoriasis. Although T cells are found juxtaposed to melanocytes in psoriasis lesions, the type of response that is triggered is not cytotoxic to melanocytes, and in fact, melanocytes are increased in psoriasis lesions, paralleling epidermal hyperplasia that is a key feature of this disease.

In psoriasis, CD8+ T cells recognize ADAMTSL5 as an autoantigen presented by melanocytes in HLA-C*06:02 molecules. ADAMTSL5 stimulation triggers the psoriasis signature cytokine, IL-17A.

From the standpoint of autoimmune responses that damage cells and tissues in many other organs, the response in psoriasis is distinctly different, as the immune reaction triggers a wound-healing response pathway in the skin that can resolve with restoration of normal skin structure and function. In part, this may be related to the functions of Th17 and Tc17 cells that, rather than serving as cytotoxic effectors, stimulate and amplify innate immune pathways in target cells. By targeting keratinocytes, IL-17 increases transcription of many antimicrobial proteins, including the autoantigen LL37, and induces the production of chemokines CXCL1, 2, 3, and 8, attracting neutrophils to the site of inflammation. Moreover, CXCL1 may also amplify the autoimmune response because it was first identified as a melanocyte growth factor and might also drive melanocyte and ADAMTSL5 expansion in psoriasis lesions.

This work has some other interesting pathogenic implications. First, the selective growth of melanocytes in skin epithelium may help to explain why psoriasis is largely a skin-restricted disease. Second, the absence of melanocytes from the interfollicular epidermis in most nonhuman species may help to explain why a spontaneous psoriasis-like disease does not occur in lower species.