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      Cutaneous Expression of A Disintegrin-like and Metalloprotease domain containing Thrombospondin Type 1 motif-like 5 (ADAMTSL5) in Psoriasis goes beyond Melanocytes

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          Abstract

          A Disintegrin-like and Metalloprotease domain containing Thrombospondin type 1 motif-like 5 (ADAMTSL5) is a melanocyte-derived protein that has recently been implicated as an activating antigen for IL-17-producing T cells in psoriasis. There is a potential disconnect between the basal location of the melanocytes in the epidermis and the fact that T-cell infiltrates are seen mostly scattered in the epidermis with very large infiltrates in the dermis. Thus, we hypothesized that ADAMTSL5 may be expressed in other cells aside from melanocytes in skin. To further investigate the cutaneous expression of ADAMTSL5, we performed immunohistochemistry staining on lesional and nonlesional skin biopsies from psoriasis patients using three different commercially available antibodies. We confirmed that all ADAMTSL5 antibodies reacted with epidermal melanocytes. However, we also observed a strong expression of this protein in keratinocytes throughout the epidermis, and scattered expression in some dermal blood vessels and other perivascular dermal cells. Overall, the pattern of ADAMTSL5 expression is very similar to the infiltrating pattern of T-cells and dendritic cells in psoriasis lesions.

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          The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.

          Psoriasis is a common T-cell-mediated skin disease with 2-3% prevalence worldwide. Psoriasis is considered to be an autoimmune disease, but the precise nature of the autoantigens triggering T-cell activation remains poorly understood. Here we find that two-thirds of patients with moderate-to-severe plaque psoriasis harbour CD4(+) and/or CD8(+) T cells specific for LL37, an antimicrobial peptide (AMP) overexpressed in psoriatic skin and reported to trigger activation of innate immune cells. LL37-specific T cells produce IFN-γ, and CD4(+) T cells also produce Th17 cytokines. LL37-specific T cells can infiltrate lesional skin and may be tracked in patients blood by tetramers staining. Presence of circulating LL37-specific T cells correlates significantly with disease activity, suggesting a contribution to disease pathogenesis. Thus, we uncover a role of LL37 as a T-cell autoantigen in psoriasis and provide evidence for a role of AMPs in both innate and adaptive immune cell activation.
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            Melanocyte antigen triggers autoimmunity in human psoriasis

            Arakawa et al. discovered that the autoimmune response in psoriasis is directed against melanocytes. They show that the main psoriasis risk allele HLA-C*06:02 mediates melanocyte-specific autoimmunity and identify ADAMTSL5 as a melanocyte autoantigen, which stimulates IL-17 and IFN-γ production in CD8+ T cells.
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              A subpopulation of CD163-positive macrophages is classically activated in psoriasis.

              Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163(+) macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, CD205/DEC205, or CD83. Microarray analysis of in vitro-derived macrophages treated with IFN-γ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR. CD163(+) macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products.
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                Author and article information

                Journal
                101694972
                45826
                J Pigment Disord
                J Pigment Disord
                Journal of pigmentary disorders
                2376-0427
                5 November 2016
                19 September 2016
                October 2016
                15 November 2016
                : 3
                : 3
                : 244
                Affiliations
                Laboratory for Investigative Dermatology, The Rockefeller University, New York, USA
                Author notes
                [* ]Corresponding author: Judilyn Fuentes-Duculan, Laboratory for Investigative Dermatology, The Rockefeller University 1230 York Avenue, Box 178, New York, USA, Tel: 212-327-7730; jfuentes@ 123456rockefeller.edu
                Article
                NIHMS824679
                10.4172/2376-0427.1000244
                5110039
                27857980
                649a7748-77d1-4ea3-9017-d61b6f7cf7f4

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                psoriasis,adamtsl5,melanocytes,keratinocytes,t-cells,dendritic cells

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