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Background Several skin diseases and atopic disorders including Netherton syndrome and atopic dermatitis have been associated with mutations and deviations of expression of SPINK5, the gene encoding the human 15-domain serine proteinase inhibitor LEKTI. The biochemical mechanisms underlying this phenomenon have not yet been fully clarified. Objectives To identify target proteinases of LEKTI important for processes of desquamation and inflammation of the skin which will enable the development of specific drugs. Methods The inhibitory activities of LEKTI domains 6 and 15 were tested on a number of commercially available serine proteinases and also on the purified kallikreins hK5 and hK7. In addition, recombinant hK5 was used. Results LEKTI domain 6 is a potent inhibitor of hK5 and hK7, whereas LEKTI domain 15 exhibits inhibitory activity on plasmin. hK5 and hK7 in particular are relevant to skin disorders. Conclusions The inhibition of hK5 and hK7 by LEKTI domain 6 indicates an important regulatory role of LEKTI in processes of skin desquamation and inflammation, which may explain the severe pathological symptoms associated with abnormalities of SPINK5 and/or its expression. Thus, LEKTI represents a potential drug for the treatment of these disorders. [ABSTRACT FROM AUTHOR]

Epidermal Langerhans cells (LC) may occur in subsets with different phenotypic and functional characteristics. In this work we give further evidence that the CD1a-positive LC population in the normal human epidermis may be heterogeneous. We found that one of our monoclonal antibodies (TE4B) to stratum corneum chymotryptic enzyme (SCCE) stained a population of dendritic cells in the normal epidermis, in addition to high suprabasal keratinocytes. The staining of the dendritic cells was seen only when the biopsies had been fixed with formaldehyde and when the sections had been pretreated, either with proteolytic enzymes or with Triton X-100. The binding of the antibody was mediated through its antigen binding site, as it could be inhibited by adsorption with recombinant pro-SCCE. Experiments with double labelling showed that the TE4B-positive dendritic cells were also CD1a-positive. On the other hand, not all CD1a-positive cells were TE4B-positive. By means of confocal microscopy of double-labelled cells, the TE4B binding site could be localized intracellularly. SCCE-mRNA could be detected by in situ hybridization in high suprabasal keratinocytes only. A possible explanation may be that there is a subset of LC which have taken up SCCE secreted by high suprabasal keratinocytes. Alternatively. TE4B may bind to an epitope present in a subgroup of epidermal LC which cross-reacts immunologically with SCCE, It is suggested that the demonstrated heterogeneity of the population of LC in the normal epidermis should betaken into account in studies on the possible role of epidermal autoantigens in the development of immune-mediated skin diseases. [ABSTRACT FROM AUTHOR]

A mouse model for assessment of the anti-inflammatory effect of topical glucocorticoids is described. Mice, sensitized to picryl chloride, had both ears painted with the sensitizer followed 2 hours later by the application of the topical steroid to one ear and the corresponding vehicle to the other. The contact sensitivity reaction, measured by swelling of the ear, was recorded 24 hours later. Dilutions of the steroid formulations inhibited the ear swelling in a manner related to dose-response. Suppression of the contact sensitivity reaction of the vehicle-treated ear as well was regarded as a systemic effect of the glucocorticoid. There seems to be a good correlation between the efficacy of the topical steroids assessed in this mouse model and the vasoconstrictor test on intact human skin. [ABSTRACT FROM AUTHOR]