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Available from: Steven G Shimada, Mar 28, 2014
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    • "Cathepsin S is a potent elastase and is critical to antigen presentation as it cleaves the Ii chain[17]–[19]. Cathepsin S causes pain via a PAR2-dependent mechanism in a mouse model of inflammatory bowel disease and evokes itch when applied to human skin, potentially as a result of PAR2 activation[5], [20]. These observations support the possibility that cathepsin S cleaves PAR2 but the cleavage site(s) involved in activation of this receptor have not been identified. "
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    ABSTRACT: Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Levels of cathepsin S, an activator of proteinase-activated receptor-2 (PAR2) [27], were recently shown to be increased, along with PAR2 and histamine, in subjects with SD, and to be correlated with clinical parameters linked to the severity of SD and itching, suggesting that cathepsin S could be used as a biomarker of pruritus. Biomarkers of pruritus [28], inflammation, hyperproliferation and skin barrier function were recently shown to be modified in SD and restored by therapeutic intervention [for review, see 4]. "
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    ABSTRACT: Few studies have investigated the long-term effects of a maintenance regimen in the prevention of relapses in scalp seborrheic dermatitis (SD), in particular following biomarker changes. A new shampoo containing beta-glycyrrhetinic acid (18βGA) in addition to cyclopiroxolamine (CPO) and zinc pyrithione (ZP) was tested in 67 subjects suffering from SD with moderate to severe erythema and itching in a biphasic study. After a first common intensive treatment phase (investigational product thrice a week × 2 weeks), subjects randomly received the investigational product once a week × 8 weeks (maintenance) or a neutral shampoo (discontinuation) in a comparative, parallel group maintenance phase. Efficacy was assessed clinically (overall clinical dandruff score, erythema, overall efficacy, self-evaluation), biochemically and microbiologically by quantitative polymerase chain reaction (qPCR), high performance liquid chromatography (HPLC) or enzyme-linked immunoabsorbent assay (ELISA) analysis of scale samples (Malassezia species (restricta and globosa), cohesion proteins (plakoglobins), inflammation (Interleukin (IL)-8, IL-1RA/IL-1α) and pruritus (histamine, cathepsin S) markers). During the intensive treatment phase, SD improved significantly (p < 0.0001) with a decrease in clinical signs as well as Malassezia species, cohesion proteins, inflammation and pruritus markers. During the maintenance phase, the improvement persisted in the 'maintenance' group only, with a significant intergroup difference. A consistently positive relationship was found between dandruff, itching, erythema and Malassezia populations, histamine levels and IL-1RA/IL-1α ratio. The effectiveness of this maintenance regimen was objectively demonstrated at the clinical, biochemical and microbiological level. Correlations between clinical signs and biomarkers could provide clues to explain the resolution of SD and confirm the interest of biomarkers for SD treatment assessment.
    Preview · Article · Mar 2014
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    • "Moreover, overexpression of cathepsin B in the thyroid has also been reported in autoimmune thyroid diseases (34). Similar extracellular matrix remodeling occurs in other autoimmune diseases, such as RA, where Cat S, K, B, and L are secreted to synovial fluid and tissue (35, 36). Thus, the differential processing by APCs may be relevant when comparing thymus and autoimmune peripheral tissue. "
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    ABSTRACT: T-cell tolerance to self-antigens is established in the thymus through the recognition by developing thymocytes of self-peptide-MHC complexes and induced and maintained in the periphery. Efficient negative selection of auto-reactive T cells in the thymus is dependent on the in situ expression of both ubiquitous and tissue-restricted self-antigens and on the presentation of derived peptides. Weak or inadequate intrathymic expression of self-antigens increases the risk to generate an autoimmune-prone T-cell repertoire. Indeed, even small changes of self-antigen expression in the thymus affect negative selection and increase the predisposition to autoimmunity. Together with other mechanisms, tolerance is maintained in the peripheral lymphoid organs via the recognition by mature T cells of a similar set of self-peptides in homeostatic conditions. However, non-lymphoid peripheral tissue, where organ-specific autoimmunity takes place, often have differential functional processes that may lead to the generation of epitopes that are absent or non-presented in the thymus. These putative differences between peptides presented by MHC molecules in the thymus and in peripheral tissues might be a major key to the initiation and maintenance of autoimmune conditions.
    Full-text · Article · Dec 2013 · Frontiers in Immunology
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