No abstract

Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3D skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del mediated psoriasis risk.

Please be advised that this information was generated on 2018-05-11 and may be subject to change. JOURNAL OFD e r m a to lo g ic a AbstractEndoglin is a glycoprotein with TGF-jS binding capacity and is predominantly expressed on endothelial cells. In psoriasis, TGF-/3 has appeared to play a role in the extravasation of peripheral blood mononuclear cells via the endothelium. In order to find out more about the role of endoglin in psoriasis, immunohistochemical staining with PN-E2, a novel anti-endoglin, and of PAL-E, recognizing vascular endothelium, was carried out in psoriatic involved, psoriatic uninvolved and normal skin. The expression of the antigens was assessed semi-quantitatively using a fivepoint scale. In psoriatic involved skin, a high endoglin expression was found. In psoriatic uninvolved skin, however, we found that endoglin expression was significantly decreased compared with normal skin. The relevance of these findings to the pathogenesis of psoriasis is discussed.

Topical application of leukotriene-B4 (LTB4) on normal skin has been used as an in-vivo model to investigate cutaneous inflammation and epidermal proliferation, which are important phenomena in the pathogenesis of psoriasis. The aim of the present investigation is to further elucidate the interrelation between inflammation and epidermal proliferation, using specific monoclonal antibodies as markers for the different cell types involved. Aliquots of LTB4 were applied on the upperarms of eight healthy volunteers. After LTB4-application, biopsies were taken at consecutive time intervals. On frozen sections, epidermal proliferation was assessed by Ks8.12-(keratin 16) and Ki-67-binding (cycling cells), inflammation was characterized using anti-elastase (PMN), T11 (T-lymphocytes), pan-B (B-lymphocytes), WT 14 (CD14-positive cells) and OKT 6 (Langerhans cells). New observations were that the density of CD14-positive cells was increased even at 8 h and decreased slightly at 72 h. A striking rearrangement of Langerhans cells was seen in close vicinity to intra-epidermal accumulations of PMN. Remarkably an increased density of these cells in the dermis at 72 h was seen and a decrease in the epidermis. In line with previous studies, the accumulation of PMN reached a maximum 24 h after LTB4-challenge. The identity of the mononuclear infiltrate cells which have been reported 48-72 h after LTB4 proved to be T-lymphocytes. No B-lymphocytes were observed. Ki-67-positive nuclei were maximally increased 72 h after LTB4-application, which implies that recruitment of cycling cells is of relevance for the LTB4-induced proliferation in vivo. The hyperproliferation-related keratin 16 was expressed inconsistently in the suprabasal compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution of three (recently discovered) extracellular matrix components (tenascin, biglycan and decorin) was studied in normal adult human skin and in a number of monogenic disorders of keratinization, using immunohistology. The expression of tenascin, which is sparsely distributed in normal human dermis, was found to be grossly increased in epidermolytic hyperkeratoses and in Darier's disease. Tenascin expression in three types of ichthyosis (X-linked recessive ichthyosis, autosomal dominant ichthyosis vulgaris, non-erythrodermic lamellar ichthyosis) was similar to that of normal skin. The presence of biglycan and decorin did not show a marked variation between the different disorders studied, suggesting that their expression is subject to regulatory mechanisms distinct from those of tenascin. The increased expression of tenascin in two disorders of keratinization with a hyperproliferative phenotype, lends further support to the hypothesis that dermal tenascin expression is increased as a result of epidermal hyperproliferation.