Cardiovascular disease is a major global burden and atherosclerosis is the main underlying pathological process. Despite better management of cholesterol levels, there remains a significant... Show moreCardiovascular disease is a major global burden and atherosclerosis is the main underlying pathological process. Despite better management of cholesterol levels, there remains a significant residual risk of developing atherosclerosis and cardiovascular events. Hence, novel pathways and targets should be identified to optimize atherosclerosis therapy. Despite dyslipidemia, the immune system is also heavily involved in the pathophysiology of atherosclerosis. Protective immune responses in the acute setting of increased cholesterol levels eventually turn into debilitating responses when the immune system is chronically stimulated. Hence, we aimed to identify new therapeutic targets to dampen the immune response in atherosclerosis. More specifically, we focused our efforts on modulating the B lymphocyte response, for which there was a scarcity of data. In this thesis we describe novel ways to modulate the B cell response in atherosclerosis. We have found that there are specific B cell subsets that have different effects on the progress of atherosclerosis. For instance, removal of TIM-1+ B cells resulted in increased atherosclerosis, while removal of BTLA+ follicular B cells reduced atherosclerosis. In conclusion, this thesis provides promising immunological targets for the treatment of atherosclerosis. Show less
Human fitness is critically reliant on the immune system to provide protection against pathogens. We argue that a pro-inflammatory response is crucial for defense against pathogens and that it is... Show moreHuman fitness is critically reliant on the immune system to provide protection against pathogens. We argue that a pro-inflammatory response is crucial for defense against pathogens and that it is very likely that infectious pressure has resulted in selective survival for genetic variants encoding for higher pro-inflammatory responsiveness. In industrialized populations many chronic diseases have been associated with an imbalance in pro- and anti-inflammatory responsiveness. We argue that from an evolutionary perspective, these chronic diseases in later life could be explained by genetic adaptations to survive a harsh environment. In order to study the role of the innate immune response in life-history regulation in a pathogen-rich environment, we set out a study in Northern Ghana. In a population living under adverse conditions we studied the role of the inflammatory response in survival and fertility. In Chapter 1 a general introduction was given on the research hypotheses and an overview of aims and description of the study population and methods. The general frame-work of the study was explained in depth in Chapter 2. Here we hypothesized that human life-history regulation in our evolutionary past, or under adverse conditions can largely be explained by selections that operated in the innate immune response. We proposed that fertility is associated with an anti-inflammatory response, whereas survival in a pathogen-rich environment is dependent on a strong pro-inflammatory response. We hypothesize that populations living under adverse conditions have been selected for a pro-inflammatory innate immune response. Also we argue that fitness in itself is a conflict between pro- and anti-inflammatory responsiveness where concessions have to be made to allow reproduction as well as defense. Furthermore we argue that evolutionary programming of the inflammatory response might underlie age-related diseases as observed in populations living under affluent conditions. It is arbitrary how to measure an innate immune response ex vivo, that reflects a general response mode irrespective the type of pathogen involved. In Chapter 3 a method is described to test innate tendency of immune activation. The assay is also validated. Given the fact that bacteria and other pathogens normally use several TLRs together to induce an immune response, we argue that mixed stimulation of both TLR2 and TLR4 receptors gives a broader view of an immune response than with the usual assay on a single TLR-agonist. Compared to variability of cytokine production in the Netherlands, we show that ex vivo IL10 production is comparable. Therefore we suggest that in Ghana IL10 is highly genetically regulated. TNF_, on the other hand, is more prone to variation in general, but especially in Ghana and might be more dependent on environmental modulation. In Chapter 4 we compared age-related cytokine production in adverse and affluent conditions. When measured cross-sectionally, IL10 production decreases with age in the Netherlands and in Ghana. TNF_ production decreases with age in the Netherlands, but remained equal over all age-categories in Ghana or, dependent on the stimulation, increased with age. We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival may drive pro-inflammatory responses under adverse living conditions. As TLR2 and TLR4 are important recognition receptors for a large set of pathogens, it might be that variation in these receptors results in different induction of innate immune responses and selective survival. In Chapter 5 we report that at the end of the TLR4 gene there was variation that associated with higher ex vivo LPS-induced IL10 production. None of the variants in TLR2 or TLR4 however were associated with P. falciparum infection or survival. As the prevalence of malaria was high in this area, we conclude that it is likely that in contrast to other studies, these genetic variants do not play a role in disease state and outcome of infection. Another pathogen receptor is PTX3. It is not only involved in recognition of pathogens, but also in the formation of the extracellular matrix of the oocyte. Therefore it might be crucial for female fertility. In Chapter 6 we assess whether genetic variation in PTX3 production is associated with life-time reproductive success. We found genetic variants in PTX3 that associated with higher PTX3 production capacity ex vivo and increased fertility and vice versa. We found no evidence for selective survival of genetic variants. We conclude that PTX3 is important for human fertility, whereas no concessions were made with regard to survival. In Chapter 7 we asses the role of IL10 in survival. We report on genetic variation in the IL10 gene that associated with lower IL10 and higher TNF_ production. Carriers of these genetic variants had a higher survival chance when living under adverse conditions. However, survival chances of these variants decreased when people had access to clean drinking water. We conclude to have found evidence that adverse environmental conditions favor selection for a pro-inflammatory response pattern. Show less
Rheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50-60% has been described. The most prominent genetic association in RA is confined to the human leukocyte antigen (HLA) locus which has been known for ~30 years. The identification of RA-associated genes outside of the HLA region, however, had been a challenge. A few years ago, one such gene, protein tyrosine phosphatase, non-receptor type 22 (lymphoid), was identified in a large genetic-association study utilizing putative functional SNPs. The aim of this thesis was to take a candidate gene approach to identify risk factors involved in rheumatoid arthritis. It is divided into three parts in which part one is dedicated towards the identification of a novel risk factor for RA and autoimmunity. This region of the genome encompasses genes highly involved in the immune system, namely Tumour Necrosis Factor Receptor associated factor 1/Complement component 5 on chromosome 9q33. In the second part, we have investigated the role of an immunoregulatory cytokine interleukin 10 located on chromosome 1q32 and in part three we have investigated the role of additional genetic risk factors in RA. Show less
