Nikitorowicz-Buniak, J; (2014) Investigating the role of epidermal keratinocytes in the pathogenesis of systemic sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Systemic sclerosis (SSc) is an inflammatory connective tissue disorder of unknown aetiology, characterised by progressive fibrosis of skin and internal organs. The correct epithelial-mesenchymal interactions are essential for skin homeostasis and tissue repair, but little is known about these interactions in SSc. Moreover, epithelial cells were demonstrated to secrete cytokines and growth factors influencing phenotype and proliferation rate of fibroblasts. SSc epithelial cells have recently been shown to take on an activated phenotype similar to wound healing. Therefore, this thesis aims to further characterise SSc epidermis using immunohistochemistry, mRNA assays, and phosphoarrays. Furthermore evidence of SSc keratinocytes releasing factors capable of promoting fibrosis is explored, using immunoassays for proteins secretion and in vitro experiments on primary fibroblasts and HaCaT cells. Additionally, this thesis also addresses the question if SSc epidermis contributes to increased number of contractile fibroblasts via epithelial-to–mesenchymal transition. This thesis demonstrates that the SSc epidermis has expanded thickness, and hypertrophied cells, as well as altered expression pattern of terminal differentiation markers. It also is releasing profibrotic and proinflammatory mediators, CTGF and S100A9, which are considered targets for novel therapies in rheumatology. In addition, it illustrates that S100A9 signalling via TLR4 is capable of promoting fibroblast responses in addition to its known proinflammatory effects. Also the CTGF induction and active profibrotic signaling is shown to affect cells in the upper dermis adjacent to the abnormally differentiated epidermis, consistent with cross-talk activation of the local fibroblasts. These changes in the epithelial layer may have a role in the SSc pathogenesis and contribute to the inflammation and fibrosis seen in the disease. Despite active Smad signaling seen to affect the adjacent papillary dermis in active SSc consistent with cross-talk, no evidence of full EMT in the SSc epidermis was found. However, I report changes consistent with partial EMT process resembling those seen during wound re-epithelialisation.

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