Rheumatoid arthritis is a chronic auto-immune disorder, of which persistent synovitis, bone erosions and auto-antibody formation are characteristic features. Although the etiology of the disease... Show moreRheumatoid arthritis is a chronic auto-immune disorder, of which persistent synovitis, bone erosions and auto-antibody formation are characteristic features. Although the etiology of the disease remains largely unknown, it is established that genetic risk factors play a pivotal role in disease pathology. Both family and twin studies have shown that the genetic contribution to the disease can be estimated around 50%. In the current thesis the genetic contribution of non-HLA genes to RA susceptibility was further investigated and the functional relevance of these loci was explored. The studies described were able to establish several previously identified risk factors in a statistical robust manner. Also novel genetic risk factors that are associated with RA susceptibility could be identified, as well as risk factors that are conferred to specific subgroups of the disease. Show less
Dendritic cells (DCs) are antigen-presenting cells (APCs) which play a key role in the regulation of immune responses. DCs are often referred to as __professional__ APCs, since their primary... Show moreDendritic cells (DCs) are antigen-presenting cells (APCs) which play a key role in the regulation of immune responses. DCs are often referred to as __professional__ APCs, since their primary function is to present antigens from pathogens or malignant cells. Consequently, there is a great deal of interest in how DCs might be exploited as a form of immunotherapy e.g. to induce immunity to cancers. However, DCs are also thought to play an important role in directing regulatory immune responses to innocuous antigens, which are targeted in autoimmune disease or during transplantation. Soluble factors secreted by DCs are crucial mediators in determining this balance between the immunogenic and regulatory arms of the immune system. One such group of factors is cytokines and one family which is gaining increasing attention is the IL-12 family. It is composed of four members; two are immunogenic and their expression has been very well characterised in DCs. The other two are regulatory, but relatively little is known about their regulation and expression in DC populations. In this thesis we aim to give a comprehensive overview of the expression and regulation of IL-12 family members in human DCs, with a particularly emphasis on IL-12, IL-27 and IL-35. Show less
The complement system has been shown to have a role in various systemic autoimmune (AI) diseases which have a renal component. This includes systemic lupus erythematosus (SLE), goodpastures... Show moreThe complement system has been shown to have a role in various systemic autoimmune (AI) diseases which have a renal component. This includes systemic lupus erythematosus (SLE), goodpastures syndrome and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides. In particular the classical pathway (CP) of complement is involved in SLE, with the exact mechanism of how these SLE autoantigens along with their autoantibodies interact with complement in the glomerulus remaining ambiguous. Furthermore, recent studies have demonstrated the expanding role of the alternative pathway (AP) of complement activation in steady state or in aspects of ANCA associated vasculitides or anti-GBM disease. The precise means of activation of the AP in these immune complex mediated disease settings remains unclear. Regulation is imperative in the AP due to its inherent ability to autoactivate. Factor H and properdin are both key opposing regulators in the AP with novel emerging roles in initiation and control of the AP. Deciphering the specific modes of AP activation and involvement is an ever expanding field requiring further elucidation, with previously unexpected roles for AP components revealing the diversity and complexity of this ancient pathway. Show less
The studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury... Show moreThe studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury based on animal studies could not be confirmed in our clinical study in humans. However, we found new evidence of complement activation and endothelial cell activation in human renal I/R injury. Moreover, there were large differences between deceased and living donor kidneys; brain dead donor kidneys have a unique proinflammatory cytokine release after reperfusion. Finally it appears that both brain dead and cardiac dead donor kidneys are not able to upregulate their metabolism-related genes upon reperfusion as living donor kidneys do, indicating that failure to restart metabolism may be a factor expanding I/R injury. All of these findings contribute to the understanding of renal I/R injury in humans and instigate the further search for therapeutical modalities to limit renal I/R injury. Show less
Preeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia... Show morePreeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia have been identified, including a (family) history of preeclampsia, autoimmune disease and conditions associated with endothelial damage, including hypertension, diabetes mellitus and preexistent renal disease. This thesis aims to further investigate through which mechanisms these risk factors increase the risk for preeclampsia. It deals with both the genetic background of preeclampsia, as well as the role of complement activation in its pathogenesis. Finally, it touches upon the role of angiogenic factors in the development of preeclampsia. Show less
