In this thesis the aim was to study immune cell interactions at the maternal-fetal interface to understand the role for immune cells during healthy pregnancy development an pregnancy complications.... Show moreIn this thesis the aim was to study immune cell interactions at the maternal-fetal interface to understand the role for immune cells during healthy pregnancy development an pregnancy complications. Specifically in cases of recurrent pregnancy loss and chronic histiocytic intervillositis. Show less
This thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome... Show moreThis thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome scale metabolic reconstruction for zebrafish, that we used to study zebrafish metabolism upon infection with Mycobacterium marinum integrating gene expression data from control and infected zebrafish larvae. The chapters focusing on cell motility in response to the environment, revolve around the question of how the environmental inputs of cell-matrix interactions, cell-sized obstacles and cell-signalling upon wounding shape and guide cell motility. Show less
Purpose of Review Caregivers of children with a chronic illness are a neglected group in medical research and patient care, and are frequently confronted with chronic psychological distress. The... Show morePurpose of Review Caregivers of children with a chronic illness are a neglected group in medical research and patient care, and are frequently confronted with chronic psychological distress. The biological consequences of this chronic distress are unclear but highly relevant, as these caregivers have a lifelong task in caring for their child. In this review, the authors specifically describe caregiver distress related to autism spectrum disorder (ASD), but the review may be relevant to other chronic diseases, including cancer. Recent Findings Epidemiological evidence illustrates the increased mortality risk in caregivers of children with ASD although some individual factors appear to diminish these risks. Biological studies demonstrate that caregiver distress can lead to dysregulation of the hypothalamic-pituitary-adrenal-axis, a pro-inflammatory state of the immune and central nervous system, and gut microbiome imbalance. Caregivers of children with a chronic illness like ASD deserve more health-related attention with respect to their psychological and physical well-being. Such attention would benefit individual caregivers, as well as their children, as both are highly interconnected. Structural psychological and physical screening of caregivers can be considered. Show less
The immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B and T lymphocyte attenuator (BTLA) is a novel co-receptor that... Show moreThe immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B and T lymphocyte attenuator (BTLA) is a novel co-receptor that negatively regulates the activation of B and T cells, however, there have been no reports of BTLA and its function in atherosclerosis or cardiovascular disease (CVD). We aimed to assess the dominant BTLA expressing leukocyte in CVD patients and to investigate whether BTLA has a functional role in experimental atherosclerosis. Stimulation of the BTLA pathway in Ldlr-/-mice reduces initial lesion development and increases collagen content of established lesions, presumably by shifting the balance between atherogenic follicular B cells and atheroprotective B cells and directing CD4+ T cells towards regulatory T cells. We provide the first evidence that BTLA is a very promising target for the treatment of atherosclerosis.We show that BTLA is primarily expressed on B cells in CVD patients and follicular B2 cells in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. We treated Ldlr-/- mice that were fed a Western-type diet (WTD) with PBS, an isotype antibody or an agonistic BTLA antibody (3C10) for 6 weeks. We report here that the agonistic BTLA antibody significantly attenuated atherosclerosis. This was associated with a strong reduction in follicular B2 cells, while regulatory B and T cells were increased. The BTLA antibody showed similar immunomodulating effects in a progression study in which Ldlr-/- mice were fed a WTD for 10 weeks before receiving antibody treatment. Most importantly, BTLA stimulation enhanced collagen content, a feature of stable lesions, in preexisting lesions. Show less
The main aim of this thesis is to examine the effectiveness of innovative psychological interventions on health optimization by (1) evaluating the effectiveness of innovative psychological tools, i... Show moreThe main aim of this thesis is to examine the effectiveness of innovative psychological interventions on health optimization by (1) evaluating the effectiveness of innovative psychological tools, i.e., serious gaming, verbal suggestions, and internet-based interventions, to optimize various health behaviors and psychophysiological outcomes; (2) providing a concise overview of the currently existing evidence of psychological interventions in optimizing immune function in response to in vitro or in vivo immunological as well as psychophysiological challenges; and (3) incorporating various self-reporting, behavioral and psychophysiological outcome measures, but also physical and psychophysiological challenges, including psychophysiological, physical and/or cognitive stressors, to evaluate the effectiveness of psychological interventions on health outcomes. Show less
The immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B and T lymphocyte attenuator (BTLA) is a novel co-receptor that... Show moreThe immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B and T lymphocyte attenuator (BTLA) is a novel co-receptor that negatively regulates the activation of B and T cells, however, there have been no reports of BTLA and its function in atherosclerosis or cardiovascular disease (CVD). We aimed to assess the dominant BTLA expressing leukocyte in CVD patients and to investigate whether BTLA has a functional role in experimental atherosclerosis.\nStimulation of the BTLA pathway in Ldlr-/-mice reduces initial lesion development and increases collagen content of established lesions, presumably by shifting the balance between atherogenic follicular B cells and atheroprotective B cells and directing CD4+ T cells towards regulatory T cells. We provide the first evidence that BTLA is a very promising target for the treatment of atherosclerosis.\nWe show that BTLA is primarily expressed on B cells in CVD patients and follicular B2 cells in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. We treated Ldlr-/- mice that were fed a Western-type diet (WTD) with PBS, an isotype antibody or an agonistic BTLA antibody (3C10) for 6 weeks. We report here that the agonistic BTLA antibody significantly attenuated atherosclerosis. This was associated with a strong reduction in follicular B2 cells, while regulatory B and T cells were increased. The BTLA antibody showed similar immunomodulating effects in a progression study in which Ldlr-/- mice were fed a WTD for 10 weeks before receiving antibody treatment. Most importantly, BTLA stimulation enhanced collagen content, a feature of stable lesions, in preexisting lesions. Show less
Cardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis... Show moreCardiovascular syndromes are the major cause of death in Western societies. The main underlying pathology is atherosclerosis, a chronic disease affecting the arteries. During atherosclerosis progression, LDL, or “bad” cholesterol, accumulates in the arterial wall, resulting in the formation of a lipid-rich atherosclerotic plaque. This event activates the immune system, which increases plaque inflammation. Mast cells are components of the immune system known for their role in allergy. However, it has been established that mast cells are also important in atherosclerosis. In this PhD dissertation, we explored the interaction of mast cells with other immune cells. We examined the interrelation between mast cells and T-lymphocytes and discovered that mast cells can function as antigen presenting cells in atherosclerosis and, enhance the development of an atherosclerotic plaque via a direct interaction. Nonetheless, mast cells can also act on the Natural Killer T-cells, resulting in a protective function against atherosclerosis. Importantly, we used a relatively novel technical approach to explore the characteristics of mast cells inside human atherosclerotic plaques. We found that mast cells are highly activated and thus possibly promote disease progression. In conclusion, mast cells possess both protective and harmful effects, acting as regulators of the immune response in atherosclerosis. Show less
Previous research has provided evidence for the link between psychological processes and psychophysiological health outcomes. Psychological interventions, such as face-to-face or online cognitive... Show morePrevious research has provided evidence for the link between psychological processes and psychophysiological health outcomes. Psychological interventions, such as face-to-face or online cognitive behavioral therapy (CBT) and serious games aimed at improving health, have shown promising results in promoting health outcomes. Few studies so far, however, have examined whether Internet-based CBT combined with serious gaming elements is effective in modulating health outcomes. Moreover, studies often did not incorporate psychophysiological or immunological challenges in order to gain insight into physiological responses to real-life challenges after psychological interventions. The overall aim of this study is to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges. Show less
Metastatic cancer is aggressive and rapidly developing, making it difficult to treat, often leading to mortality. Cancer cells are not isolated, but rather survive and proliferate in complex tumor...Show moreMetastatic cancer is aggressive and rapidly developing, making it difficult to treat, often leading to mortality. Cancer cells are not isolated, but rather survive and proliferate in complex tumor microenvironments. Importantly, tumor cells “educate” immune cells to play a supportive role during cancer progression. Therefore, understanding how cancer cells and immune cells communicate is of pivotal importance to limit tumor progression. In this project, we identified the chemokine receptor CXCR4 and its correspondent ligand, CXCL12, as a key couple that regulate the interaction between tumor cells and immune cells. The research has been performed using the zebrafish xenograft model. This model offers the advantage of looking at tumor-immune cell interaction on a single cell level and in a living whole organism. The transparency of the embryo and the current genetic tools available, in combination with the ease in pharmacological approaches, make this model an excellent tool to determine and impair cancer-microenvironment inter-communication. We showed that inhibiting the CXCL12-CXCR4 axis either on the tumor side or on the immune cell side leads to impaired tumor progression, during the early phases of metastasis formation. We propose that blocking cancer-stroma communication represents a promising therapeutic strategy to fight cancer.Show less
Part I describes the prognostic effect and interactions of the immune system in breast cancer patients. Part II of the thesis describes the prognostic effect of these prognostic immune parameters... Show morePart I describes the prognostic effect and interactions of the immune system in breast cancer patients. Part II of the thesis describes the prognostic effect of these prognostic immune parameters and biomarkers molecular subtypes and stem cell marker ALDH-1, which are known to be strong breast cancer prognostic factors, in elderly breast cancer patients compared to their younger counterparts. 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
In peripheral arterial occlusive disease (PAOD), the formation of an atherosclerotic lesion eventually results in a significant stenosis of a major artery thereby disrupting blood flow in... Show moreIn peripheral arterial occlusive disease (PAOD), the formation of an atherosclerotic lesion eventually results in a significant stenosis of a major artery thereby disrupting blood flow in peripheral arteries towards lower limb tissue. Unfortunately, there is a substantial number of patients that suffer from severe critical limb ischemia, which is associated with a poor prognosis and high rates of amputation and mortality. Despite state-of-the-art revascularization treatment options and optimal control of co-morbidities these 'no option' patients remain at high risk for limb amputation. It is these patients that require new therapeutic applications to augment neovascularization and prevent them from limb amputation. Expansion of our current knowledge is required to gain insight in cellular and molecular mechanisms that are involved in neovascularization, to optimize revascularization therapies for patients with critical limb ischemia. This thesis provides a role for multiple leukocytes in blood flow recovery, in particular Natural Killer cells and CD4+ T lymphocytes, and shows that genetic differences in the Natural Killer gene complex induce differences in vascular remodeling. It was also shown how growth factor expression, signaling and regulation of gene expression modulate revascularization. Show less
Toll-like receptors (TLRs) are receptors that continuously scour their direct surroundings for pathogen associated molecular patterns (PAMPs) of bacterial, viral or fungal origin. TLRs can be found... Show moreToll-like receptors (TLRs) are receptors that continuously scour their direct surroundings for pathogen associated molecular patterns (PAMPs) of bacterial, viral or fungal origin. TLRs can be found at cells that play a role in the immune system. Binding of the TLR with its corresponding ligand results in a signaling cascade, which initially activates the innate immune system and can eventually result in activation of the adaptive immune system. When used as well-defined adjuvants, their combination with antigen may increase the immunogenicity of the antigen itself. This so-called vaccine principle may lead to a desired long-lasting adaptive immune response or humoral memory. Currently a total of 11 TLRs are known in humans and their specific PAMPs are directly related to the location where the receptor resides. TLRs 1, 2, 4, 5, 6, 10 and 11 are situated on the outside of the cell membrane, where they come into direct contact with membrane components of pathogens. TLRs 3, 7, 8 and 9 can be found intracellularly and their ligands mainly consist of viral components released after cellular uptake and degradation of the invader. A large diversity of natural and synthetic TLR ligands is available. The newest generation of vaccines is based on synthetic TLR ligands having a well-defined chemical structure. The research described in this thesis is a first step towards the development of well-defined vaccines, able to trigger a controlled immune response by means of using TLR 2, 7 or 9. Discussed in detail are the synthesis and the immunological evaluation of ligands and conjugates aimed at activation of Toll-like receptors 2, 7 and 9. Some examples are the synthesis of a CpG DNA-peptide conjugate (TLR 9), a Pam3Cys-peptide conjugate (TLR 2) and a 7-hydro-8-oxo-adenine-peptide conjugate (TLR 7). After synthesis of the peptide (containing the antigen), several methods were applied to conjugate it to TLR2, 7 and 9 ligands. Resulting from the research performed, is that when well chosen, covalent coupling of a TLR ligand with an antigenic peptide results in an increase of cytokine production as well as antigen presentation, two of the most desired characteristics of a synthetic vaccine of this class. It is not unlikely, that future synthetic vaccines will be sharing these properties. Show less
