LAUSR

fludarabine, one of the cytotoxic substances used to induce apoptosis in haematopoietic cells. It is known that during inflammation, dermal fibroblasts respond to signals such as interleukin-1b and tumour necrosis factor-a by increasing COL7A1 gene expression. This is mediated through downstream transcription factors of the transforming growth factor-b pathway, specifically SMAD3 and SMAD4. Furthermore, dermal fibroblasts have been shown to upregulate COL7A1 gene expression on exposure to ultraviolet light. This upregulation is mediated via activation of the activator protein 1 (AP-1) transcription factor, which binds to an AP-1 response element in the COL7A1 promoter. In their work, Vanden Oever et al. show that dermal fibroblasts exposed to fludarabine also upregulate existing type VII collagen (C7) protein in normal and recessive dystrophic EB fibroblasts. This effect is mediated, in part, through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/protein kinase B and transforming growth factor-b pathways. Activation of these pathways leads to activation of downstream transcription factors, including AP-1 and SMAD. Subsequently, both AP-1 and SMAD bind the COL7A1 promoter and increase COL7A1 expression. Thus, molecular pathways leading to increased expression of C7 seem to be relatively conserved over chemical, physical and inflammatory pathways. This knowledge gives us a better handle on the expression of C7, a molecule that is on the crossroads of mechanical stability, autoimmune inflammation, wound healing and tumour development in the skin. Importantly, it might be possible to specifically downregulate the expression of nonfunctional patient-derived C7 during or after allo-HCT in patients with EB to facilitate the therapeutic effect of newly produced donor-derived functional C7 protein.