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ePaper created 2014-09-15, 12:31:02 | version 1.32.01
Skin barrier function Our laboratory led by Joost Schalkwijk from 1993 onwards, was the first to describe the epithelial protease inhibitor and antimicrobial protein SKALP [1,2], which was shortly thereafter referred to in publications by others under the name ‘Elafin’. The cDNA and gene were cloned and the chromosomal localization determined. We established its biochemical and biological function, which included the protection of epidermis against elastase-mediated damage. The work of Patrick L. Zeeuwen led to the identification of a new biochemical pathway that controls epidermal cornification and desquamation, centred around the cysteine protease inhibitor cystatin M/E.[3] The research group of our department described the role of keratinocytes in the expression of the matrix protein tenascin-C. Subsequently we demonstrated that its family member tenascin-X regulates collagen and elastin stability as witnessed by the new form of Ehlers-Danlos syndrome (tenascin-X deficiency) that we discovered. This finding was published in the New England Journal of Medicine and is a landmark paper in Ehlers-Danlos research and joint hypermobility syndromes.[4,5] The biology of tenascin-X was investigated and revealed interactions with elastin and collagen, explaining the phenotype in deficient patients. We discovered LCE3B/C deletion as an important risk factor for psoriasis. This established psoriasis as a disease that is caused not only by immune mechanisms but also by skin barrier abnormalities. Among our Dutch research community, we were the first to find a genetic interaction between HLA-Cw6 and the LCE3B/C deletion. This finding was published in Nature Genetics, and details the first psoriasis risk gene that is associated with skin barrier function.[6,7] At the functional level, we described the expression and putative role of LCE proteins in normal human epidermis.[8] We have invested heavily in the development of submerged and 3-D skin models. Recently we succeeded in designing a skin model that completely mimics normal epidermis, as opposed to most existing models that have an activated phenotype. This was designed to generate both a 3-D psoriasis and atopic dermatitis model and a wound healing model.[9,10] Using these models we performed drug discovery studies and found the working mechanism of coal tar in atopic dermatitis. We established the arylhydrocarbon receptor as the receptor of coal tar components that transmits a signal to the nucleus and which induces the expression of skin barrier proteins. We also found that coal tar inhibits spongiosis induction by Th2 cytokines such as IL-4 and IL-13. This finding was published in the leading periodical the Journal of Clinical Investigation and received world-wide media attention. 104 Hyperextensibility of the skin in Ehlers-Danlos syndrome. BWEADVSMGFINCORR:Opmaak 1 21-07-2014 17:40 Pagina 104