Acute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is... Show moreAcute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is atherosclerosis, which is caused by the accumulation of lipids and inflammatory cells in the vessel wall, in so-called atherosclerotic plaques. Current therapies mainly target the disturbed lipid homeostasis, but recent clinical trials have shown a clear benefit in treating patients with anti-inflammatory drugs. However, more specific targeting is required to avoid unwanted side effects. In this thesis, we have generated a detailed atlas of all the cells present in human atherosclerotic plaques using a novel state-of-the-art technique called single-cell RNA sequencing. This data set can be applied as a powerful tool to select potential drug targets with a functional relevance for atherosclerosis. We showed that the majority of the immune cells in the human atherosclerotic plaque consisted of T cells. Subsequently, we identified a pro-inflammatory population of T cells that likely responds to a plaque-derived antigen, suggesting that atherosclerosis has an autoimmune-like component. Finally, we have applied our single-cell atlas to define and validate targets to intervene with the recruitment and activation of mast cells and other immune cells in atherosclerosis. Show less
This thesis contains a variety of information about the natural and vaccine induced immunity against the human papillomavirus. The spontaneously induced HPV-specific humoral response after... Show moreThis thesis contains a variety of information about the natural and vaccine induced immunity against the human papillomavirus. The spontaneously induced HPV-specific humoral response after infection was assessed in population-based studies. The vaccine-induced changes in HPV-seroprevalence among the HPV unvaccinated Dutch population aged 0-89 years, where we compared the HPV-seroprevalence before the introduction of the HPV vaccine with data of approximately six years post-implementation of the national HPV vaccination program. Also, the HPV immune status of the Dutch Caribbean population just after introduction of HPV vaccination was determined. Moreover, the longitudinal relation between the hr-HPV antibody levels and the prevalence of HPV infections in three-dose vaccinated girls were studied. And more insight was gained into humoral and cellular immune responses after just a one-dose of the HPV vaccine. At last, the kinetics of innate and adaptive immune responses directly after vaccination different HPV vaccines were investigated. In the coming years some important changes are expected regarding HPV screening and vaccination. The effectiveness of the one-dose schedule will become clear as clinical trials end. In the Netherlands, a sex-neutral vaccination will be implemented soon. These changes will need to be monitored to provide scientific answers about the effectiveness and immunogenicity. Show less
Uveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of... Show moreUveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of infiltrating macrophages and T cells is associated with a poor prognosis rather than a good one. The clear link between inflammation and this malignancy provides a paradigm for macrophage plasticity and function. Macrophages in uveal melanoma have an M2-like phenotype and are associated with the loss of one specific chromosome - monosomy 3. The central players involved in this process and discussed include macrophages, T lymphocytes, chemokines and cytokines, including the macrophage-attraction molecules. When a tumor acquires the ability to release significant amounts of macrophage-attraction molecules it causes the expansion of a population of myeloid immature cells that may not only help the tumor to suppress immune reactions but also aid in the construction of new blood vessels for tumor growth. A better understanding of the molecular basis of a local myelomonocytic cell population will bring a better understanding of the immunopathology of this disease and will lead to therapeutic interventions in uveal melanoma. This thesis focuses on the roles of the local inflammatory microenvironment in the development and progression of uveal melanoma. Show less
Atherosclerose wordt veroorzaakt door een combinatie van verhoogde cholesterolniveaus en een chronische ontstekingsreactie. Deze ontstekingsreactie is het gevolg van een verstoorde balans tussen... Show moreAtherosclerose wordt veroorzaakt door een combinatie van verhoogde cholesterolniveaus en een chronische ontstekingsreactie. Deze ontstekingsreactie is het gevolg van een verstoorde balans tussen slechte, agressieve en goede, beschermende ontstekingscellen. In dit proefschrift wordt onderzocht hoe deze verstoorde balans in atherosclerose hersteld kan worden. Het onderzoek richt zich hierbij enerzijds op het remmen van de slechte ontstekingscellen en anderzijds op het stimuleren van de goede ontstekingscellen. Dit kan bereikt worden door de werking van costimulatoire en coinhibitoire eiwitten te be_nvloeden. Deze eiwitten zijn aanwezig op het celoppervlak van heel veel verschillende ontstekingscellen en bepalen of een ontstekingscel agressief of beschermend is. Costimulatoire eiwitten zorgen voor de activatie van een ontstekingscel, terwijl coinhibitoire eiwitten ontstekingscellen remmen. Blokkade van de costimulatoire eiwitten OX40L en CD30L remt atherosclerose, terwijl blokkade van het coinhibitoire eiwit Tim-3 atherosclerose verergert. Stimulatie van het coinhibitoire eiwit TIGIT vermindert de functie van T cellen. Een andere manier om de balans tussen goede en slechte ontstekingscellen te herstellen is door het aantal goede ontstekingscellen, zoals regulatoire T cellen en myeloid derived suppressor cellen, te laten toenemen. Eliminatie van regulatoire T cellen tot meer atherosclerose, terwijl een enorme expansie van regulatoire T cellen en myeloid derived suppressor cellen beschermend is. Show less
