Atopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier... Show moreAtopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier function and various other epidermal changes, as well as immunological changes. A decreased skin barrier function allows environmental factors such as allergens and pathogens to penetrate through the skin and evoke an immunological response, which in turn may negatively affect the skin barrier function. The skin barrier is composed of cornified keratinocytes, extracellular lipids and multiple proteins, including filaggrin. The discovery of mutations in the filaggrin gene as a major risk factor for development of AD has intensified research on this protein and its role in AD development, but its exact role in AD is still not clarified. This thesis describes the development of several reconstructed human skin equivalents (HSEs) which recapitulate various characteristics of AD. They display for example reduced filaggrin expression or alterations in epidermal characteristics due to the presence of AD-related inflammatory cytokines. These HSEs are a powerful tool that in the future might be used for screening purposes and/or development of new therapies for this life disabling skin disease. Show less
This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less
Atherosclerosis, restenosis and cardiac remodeling after myocardial infarction can cause serious clinical problems that greatly contribute to both high morbidity and mortality. In all these... Show moreAtherosclerosis, restenosis and cardiac remodeling after myocardial infarction can cause serious clinical problems that greatly contribute to both high morbidity and mortality. In all these processes, the inflammatory responses caused by activation of the immune system play a very prominent role. This thesis elaborates on the role of specific components of the immune system and the therapeutic possibilities that lay hidden therein. This was done by focussing on the pathophysiological process in which Damage Associated Molecular Patterns (DAMPs) are released upon cell stress and cell death or other tissue damage, and may play an important role via different mechanisms. The data in this thesis illustrates specific involvement of DAMPs recognizing factors such as Toll-like Receptors in vascular remodeling and the therapeutic potential that lies within these findings. We show that endogenous activation of the immune s ystem plays an important role in the post-interventional vascular remodeling process. Multiple DAMPs such as HMGB1 are absent before intervention however they were found highly up regulated locally in the vessel wall after intervention indicating a specific relation with the intervention procedure. The presence and involvement of a variety of Toll Like Receptors in different models of vascular remodeling is interesting since these receptors are considered to be important recognizers of the DAMPs locally found in the vessel wall. Different intracellular signalling pathways and TLR accessory molecules seem to mediate the outcome of the specific DAMP-TLR interactions on vascular remodeling majorly. Protective effects of TLR3 and different outcomes of RP105 deficiency on vascular remodeling processes indicate the complexity of the underlying pathophysiological processes. These results can be partly explained by downstream TLR signalling and involvement of specific cell subtypes. The exploration of these underlying mechanisms offers new opportunities for biomarker selection and therapy development. Show less
Vein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein... Show moreVein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein grafting is that within 10 years after vein graft surgery 50-60 % of the vein grafts suffer from patency loss due to thrombosis, intimal hyperplasia formation, accelerated atherosclerosis and rupture. Endogenous factors orchestrate the development and failure of vein grafts. Investigating the role of endogenous constituents on vein graft remodeling can enhance our basic knowledge of the involvement of these factors in vein graft remodeling. By interfering in the function of endogenous factors, as we showed in this thesis, vein graft remodeling can be negatively or positively influenced depending on the factor and strategy used. New therapeutic strategies can be developed based on this knowledge. In this thesis we investigate the role of innate immune components, complement system factors, toll like receptors, mast cells and NK cells and the role of Annexin A5 in vein graft remodeling. Furthermore we explored the role of plaque stability, plaque neovascularization and extracellular matrix remodeling in a hypercholersterolemic mouse vein graft model. Show less
