The work presented in this thesis has provided new insights into the mechanisms involved in the regulation of innate immune responses in zebrafish embryos. Furthermore, cell-specific transcriptome... Show moreThe work presented in this thesis has provided new insights into the mechanisms involved in the regulation of innate immune responses in zebrafish embryos. Furthermore, cell-specific transcriptome profiling studies identified novel marker genes for distinguishing immune cell types, which is highly useful information to fulfill the demand for new fluorescent reporter lines and lineage-specific antibodies in the zebrafish model. We have shown that Ptpn6, a protein tyrosine phosphatase homolog of human SHP1, functions as a critical negative regulator, required for a properly balanced innate immune response and for controlling infections with bacterial pathogens. In Salmonella typhimurium infection, ptpn6 deficiency caused a general hyperinduction of pro-inflammatory genes, which was contraproductive as it impaired the infection control. In Mycobacterium marinum infection, a more specific effect of ptpn6 deficiency on matrix metalloproteinase gene expression was found as a major underlying cause of increased bacterial burden. We further concluded that Ptpn6 functions as a much stronger negative regulator than infection-inducible miRNAs of the miR-146 family, which may be involved in more subtle fine-tuning of the innate immune response. Knowledge about the distinct roles of Ptpn6 and miR-146 miRNAs has practical applicability in regard to their potential as therapeutic targets for inflammatory diseases and cancer. Show less
The studies presented in this thesis focused on cutaneous CD30-positive lymphoproliferations, particularly on primary cutaneous anaplastic large cell lymphoma (C-ALCL), a distinct type of cutaneous... Show moreThe studies presented in this thesis focused on cutaneous CD30-positive lymphoproliferations, particularly on primary cutaneous anaplastic large cell lymphoma (C-ALCL), a distinct type of cutaneous T-cell lymphoma (CTCL). In the initial staging of patients with an anaplastic large cell lymphoma first presenting in the skin, bone marrow examination has limited value (chapter 4). C-ALCL patients usually have an excellent prognosis, although some patients follow an unfavorable course. These patients often have extensive disease with leg involvement (chapter 2). Several phenotypical markers have been reported to aid in the differentiation between different types of cutaneous CD30-positive lymphoproliferations, however, TRAF1, MUM1 and BCL2 are not useful for this purpose (chapter 3). The miRNA expression profile of C-ALCL does show differences with that of tumor stage mycosis fungoides (MF), another type of CTCL, suggesting a different contribution to the pathogenesis of these lymphomas (chapter 5). In patients with transformed MF, several parameters can be used as prognostic factors, including CD30 expression, folliculotropic MF, extent of skin lesions and extracutaneous transformations (chapter 6). Show less
This thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in... Show moreThis thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in vascular homeostasis is reviewed. Chapter 3 focuses on the role of miRNA-126 in ischemia induced angiogenesis, followed by Chapter 4 which describes the potential role of miRNA-126 the mobilization of vasculogenic progenitor cells upon ischemia. Both chapters utilize antagomir-technology to specifically silence miRNA-126 in vivo. This approach to silence miRNA-126 was also used in Chapter 5 to elucidate the regulatory role of miRNA-126 in vascular cell adhesion molecule-1 expression in the kidney vasculature. Chapter 6 details our findings that circulating miRNA-126 in the periphery is not exclusively derived from endothelial cells but can also originate from platelets. Consequently, the use of aspirin has to be taken into account when relating circulating miRNA-126 levels to the progression of cardiovascular disease. Chapter 7 demonstrates that the angiogenic potential of miRNA-126 as described in Chapter 3 might reach beyond the presence of this pro-angiogenic miRNA in endothelium, but that neovascularization can also be supported by miRNA-126 expressed in circulating cells. Finally, Chapter 8 provides a summary of research presented in this thesis, presents the major conclusions that could be drawn and further discusses the role of miRNA-126 in vascular homeostasis. Show less
