Every day Tuberculosis (TB) kills approximately three thousand people, a number that is on the rise due to the impact of the current COVID-19 pandemic on essential TB services. The causative agent... Show moreEvery day Tuberculosis (TB) kills approximately three thousand people, a number that is on the rise due to the impact of the current COVID-19 pandemic on essential TB services. The causative agent of TB, Mycobacterium tuberculosis (Mtb), is an ancient pathogen that through its evolution developed complex mechanisms to evade immune surveillance and acquired the ability to establish persistent infection in its hosts. To achieve TB eradication, the discovery of Mtb antigens that effectively correlate with the human response to infection, with the curative host response following TB treatment, and with natural as well as vaccine induced protection is critical. This thesis contributes to this ambitious aim through several findings. First, it uncovers multiple new in vivo expressed Mtb (IVE-TB) antigens by combining Mtb-transcriptomic data with advanced bioinformatics tools and medium throughput cytokine screening. Second, it deepens our understanding of the cellular and humoral immunity to Mtb antigens in latently Mtb infected donors (LTBIs) and TB patients as well as in animal models. Lastly, it demonstrates the feasibility of combining and integrating pre-clinical research of multiple mycobacterial diseases, which are endemic in the same areas and against which vaccines could induce cross-disease protection (i.e., TB and leprosy). Show less
T cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T... Show moreT cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T cell responses. Using LCMV Clone-13 as a model of persistent viral infection, this thesis investigates the roles of IL-27 and IFN-I in regulating T cells during infection. In addition, the thesis explores the potential of JAK inhibitor in rescuing T cell exhaustion during persistent viral infection and cancer. Show less
For many years, cancer has been described as the accumulation of germinal and somatic mutations of the genome, impairing the function of tumor suppressor genes and stimulating oncogenes. Nowadays,... Show moreFor many years, cancer has been described as the accumulation of germinal and somatic mutations of the genome, impairing the function of tumor suppressor genes and stimulating oncogenes. Nowadays, it is commonly accepted that the tumor is not only a mass of malignant cells, rather than the result of a delicate network of interactions between tumor and stromal cells. Indeed, bidirectional communications between cancer cells and the surrounding microenvironment can strongly influence tumor development and progression. Stromal cells might support tumorigenesis, either via direct cell-cell contact mechanisms with tumor cells, or by releasing specific factors, including cytokines and growth factors in the surrounding extracellular matrix (ECM), with remodeling of the tumor microenvironment (TME) as a result.The aim of this thesis is to elucidate the delicate network of interactions between different TME components and tumor cells in prostate cancer (PCa) and oropharyngeal squamous cell carcinoma (OPSCC). Show less
The aim of this thesis was to get a better understanding of the incidence and course of neuropsychiatric symptoms in HD, particularly irritability that is a core behavioral symptoms. Also, we aimed... Show moreThe aim of this thesis was to get a better understanding of the incidence and course of neuropsychiatric symptoms in HD, particularly irritability that is a core behavioral symptoms. Also, we aimed to investigate the realtionship between activity of the immune system and presence of neuropsychiatric symptoms. In this thesis, the psychometric properties of the Irritability Scale, and cross sectional and longitudinal analyses of irritability are described. The role of the innate immune system was investigated using both plasma acute-phase proteins and cytokines. Show less
The aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low... Show moreThe aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low muscle strength, while high acute pro-inflammatory response is associated with high muscle strength. Show less
The work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It... Show moreThe work presented in this thesis aimed at increasing our understanding of the effect of helminths on Plasmodium spp. immune response in co-infected individuals living in endemic countries. It presents data from studies conducted in rural and semi urban areas of Lambaréné (Gabon) where the burden of malaria and helminths is particularly important. Although scarce previous studies have indicated an effect of helminths on malaria outcomes and immune response to Plasmodium spp. parasite in co-infected subjects. However it is still debated how consistent is this effect across study sites and teams and what its immunological basis is. Show less
Dit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden... Show moreDit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden voor. Omdat NTM sommige mensen ernstig en ook bij herhaling ziek maken, hebben wetenschappers zich lang afgevraagd of genetische afwijkingen daarbij een rol spelen. In de laatste vijftien jaar is dit vermoeden bevestigd. Wereldwijd zijn ruim 360 pati_nten met Mendelian Susceptibility to Mycobacterial Disease (MSMD) bekend. In dit proefschrift wordt NEMO defici_ntie voor het eerst aangemerkt als MSMD. Vervolgens legden wij het verband tussen het v__rkomen van mycobacteri_le infecties in jonge kinderen en variaties in IFNG en IL10. Ook onderzochten wij Cryopyrin Associated Periodic Syndrome (CAPS) waarbij een te hoge cytokine productie tot ontsteking leidt. Deze pati_nten bleken hun cytokine productie onvoldoende te kunnen verhogen na activatie van hun cellen. Dit bleek onafhankelijk van de IL-1_ antagonist Anakinra, een zeer effectief medicijn tegen deze ziekte, en daarom van IL-1_. Een zich steeds verder ontwikkelende medische wetenschap en toenemende hygi_ne zorgen ervoor dat immuundefici_nties slechts in gematigde vorm tot uiting komen. Tegelijkertijd blijven de meest ernstig zieke pati_nten nu veelal wel in leven. Deze pati_nten zijn een belangrijke bron van informatie over de werking van ons immuunsysteem. Show less
The work presented in this thesis is an investigation of the immune responses induced by chronic schistosomiasis in Gabonese schoolchildren. By investigating concurrently various aspects of the... Show moreThe work presented in this thesis is an investigation of the immune responses induced by chronic schistosomiasis in Gabonese schoolchildren. By investigating concurrently various aspects of the immune response, including innate, adaptive and regulatory responses, we are able to gain a more in-depth understanding of the dynamic changes brought about by infection. Through a number of cross-sectional and longitudinal studies we show that S. haematobium infection induces increased frequencies of regulatory B (Breg) and T (Treg) cell subsets which are associated with increased levels of IL-10 and adaptive immune hypo-responsiveness. Anti-schistosome treatment results in the reduction of regulatory subsets, an increase in effector T cells and alleviation of suppressed antigen immune responses. By showing that Treg cells are linked to effector responses and that schistosomes can induce Breg cells, the scene is set for future studies to determine antigen specificity of these cells as well as ways to control their activity. As regulatory responses have been shown to be not only important in chronic infectious disease, but also in chronic inflammatory diseases the knowledge gained here may be of substantial value to the health of those living in both low- to middle-income countries as well as high-income countries. Show less
Recent studies indicate that there is a global rise in the prevalence of asthma and other allergic disorders. Several epidemiological studies conducted in countries endemic for parasitic worms ... Show moreRecent studies indicate that there is a global rise in the prevalence of asthma and other allergic disorders. Several epidemiological studies conducted in countries endemic for parasitic worms (helminths) have reported an inverse association between the presence of helminth infections and allergic disease. The main objectives of the study described in this thesis were to: i. To determine urban-rural differences in allergy outcomes in Ghana, West Africa ii. To examine the association between helminth infections and allergies iii. To characterize IgE responses associated with helminth infections and allergies The thesis describes cross-sectional studies among schoolchildren aged 5-16 years living in urban and rural areas of Southern Ghana. Study findings showed marked urban-rural differences in the prevalence of allergy outcomes with current infection with the waterborne helminth schistosoma being inversely associated with mite skin prick test allergic sensitization. In the study population, elevated levels of allergen specific IgE were observed that did not translate into skin reactivity or reported symptoms. Differences in gene expression profiles were also observed between urban and rural children. Overall, study findings indicate that factors associated with urbanization such as reduced exposure to parasitic worms are associated with the increased prevalence of allergy outcomes in Ghanaian children 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
Growth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as... Show moreGrowth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as metastasizing, the extracellular matrix needs to be rearranged creating space for tumor cells to expand and angiogenesis to secure supply of nutrients and oxygen and removal of waste products. The net result of all contributing factors will lead to either progression or degradation of cervical cancer. In this thesis the role of contributing factors is investigated, e.g. cytokines, chemokines, inflammatory cells, the role of extracellular matrix and angiogenesis 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
Early childhood is a critical period where the maturation of the immune system occurs while it receives various challenges from the environment shared with the mother. Children growing in an... Show moreEarly childhood is a critical period where the maturation of the immune system occurs while it receives various challenges from the environment shared with the mother. Children growing in an environment rich in micro-organisms and parasites are thought to have a different pattern of immune response compared to those children growing in a more hygienic environment. This difference might contribute to the lower prevalence of allergic and autoimmune disorders in developing countries compared to affluent countries. Within this context, a number of cohort studies mostly performed in developed countries have focused on finding the link between the pattern of immune responses in early life and health outcomes in later life. In this thesis, we studied child__s innate and adaptive responses during the first 4 years of life in a helminth-endemic area in Indonesia Show less
Helminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the... Show moreHelminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the host, by preventing tissue damage due to excessive inflammation. There are indications that in countries where parasites have been eliminated the immune regulatory network is impaired, leading to inflammatory diseases such as allergies and asthma. An important player in immune regulation is the regulatory T cell (Treg). We have shown that the number and/or function of Tregs were indeed enhanced in several helminth and also malaria infections in humans. Tregs were not only involved in suppression of anti-parasite responses, but also of responses to other infections or vaccines. We further investigated the effect of helminth elimination in a randomized placebo-controlled trial. Treatment of helminths led to a strong increase in __mainly pro-inflammatory__ immune responses, which confirms the importance of immune regulation during infection. Furthermore, the prevalence of malaria was transiently increased and allergy was slightly on the rise in treated school children. These results further endorse the possible beneficial effects of helminthic therapy, which is currently being tested in a number of clinical trials. Show less
In the Netherlands 1 of 1.000 inhibitants undergo cardiac surgery annually. To compensate blood loss these patients receive often blood transfusions, which can cause unexpected adverse reactions.... Show moreIn the Netherlands 1 of 1.000 inhibitants undergo cardiac surgery annually. To compensate blood loss these patients receive often blood transfusions, which can cause unexpected adverse reactions. Allogeneic leukocytes may play a prominent role in the development of these adverse reactions. We found in a randomized trial in cardiac valve surgery that patients receiving buffy-coat depleted (which contain 20-30% donor leukocytes) red blood cell (RBC) transfusions had dose-dependently higher hospital-mortality and postoperative infections than patients receiving leukocyte-depleted RBCs. Cost-effectiveness analysis revealed that leukodepletion of RBCs reduces the costs after cardiac valve surgery. Additional analyses revealed that plasma transfusions were associated with mortality and platelet transfusions with postoperative infections and longer ICU-stay. Patients who received more than 3 red blood cell units had significantly higher cytokine IL-6 concentrations after leukocyte-containing, buffy-coat depleted red blood cells (RBC) as compared to patients who had received similar numbers of leukocyte-depleted RBC units. Patients who developed postoperative infections and multiple-organ-dysfunction-syndrome showed, respectively, increased concentrations of cytokines IL-6 and IL-12 in the group that received leukocyte-containing RBCs. This laboratory analysis suggests that buffy-coat depleted erythrocytes may affect the development of postoperative complications by modulation of the postoperative proinflammatory response after cardiac surgery. Show less
Osteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their... Show moreOsteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their regulation and the disease status of OA. We investigated the role of genetic variation at the interleukin(IL)-1 gene cluster in the innate bio-availability of IL-1beta. A haplotype that associated to low innate bio-availability also associated to higher hand OA scores. Although this is counterintuitive with respect to the generally accepted hypothesis that a pro-inflammatory status is detrimental to the cartilage it underlines a complex relationship between inflammation and OA. For the C-reactive protein we identified a haplotype associated to high CRP levels as well as to severe hand OA, which is more in line with expected directions of associations. Analysis of baseline cytokine and chemokine levels indicated that chemokine levels associated to hand OA scores, again with low levels associated to high OA scores. In a follow up functional genomic analysis of a previously identified OA susceptibility gene (DIO2) in our studies we show that the risk allele of this gene is transcribed at higher levels as compared to the non-risk allele. Furthermore, we showed increased DIO2 protein presence in OA affected cartilage. Show less
The studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular... Show moreThe studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular proteases, both activated by mechanical and vascular injury caused by these interventions, are thought to contribute largely to the development of post-angioplasty restenosis and vein graft disease. Therefore, viral and non-viral gene therapy techniques were used in these studies to deliver genes encoding protective as well as inhibiting proteins in order to modulate the inflammatory cascade (i.e. IL-10 and the MCP-1/CCR-2 pathway) in the first part of this thesis and the plasminogen activator and MMP-system in the second part. Finally, the expression of several involving genes was blocked locally by RNA interference techniques in the last part of this thesis. The possibilities and effects of these gene therapy applications were studied in cell cultures, in a human saphenous vein organ culture model and in two mouse models of restenosis and vein graft disease. Altogether, these studies provided more insight into the pathophysiology of post-interventional remodeling and several potential therapeutic strategies were assessed. Show less
Immune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be... Show moreImmune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be involved in stimulating the anti-tumor immune response or in tumor growth and progression. The studies in this thesis concern molecular analyses of immune escape mechanisms besides HLA class I loss, such as loss of TNF_ expression and TGF-_ insensitivity in cervical cancer. We identified SerpinA1 and SerpinA3 as candidate genes involved in immune suppression and/or carcinogenesis in HLA positive tumors. With regard to TGF-_ insensitivity, we showed in an in vitro model that TGF-_ insensitivity in cervical cancer cells is associated with activation of pathways involved in proliferation like MAPK. Furthermore, we provide evidence that the TGF-_-Smad signaling pathway is functional in most cervical carcinomas and that inactivation of Smad2 or Smad4 genes as a cause for TGF-_ insensitivity is unlikely. Overall, the studies in this thesis show that loss of HLA class I, lack of TNF_ expression, resistance to TGF-_ growth inhibition, production of TGF-_ and SerpinA1 and/or SerpinA3 expression occur in cervical cancer cells and represent possible strategies to evade eradication by immune cells. Show less
The aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of... Show moreThe aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of restenosis, vein graft failure and potential therapeutic preventive strategies. Therefore, we firstly focused on inflammation in general, using the anti-inflammatory agent Dexamethasone, assessing the effects of such a broad approach on restenosis and vein graft remodeling. Then, we further focused on some specific parts of the immune system, namely Interleukin 10 (IL10), chemokines and the complement cascade. Il10 was chosen because it is one of the most studied anti-inflammatory cytokines and this property makes it a potential candidate for ant-restenosis therapy. Furthermore, it was hypothesized that chemokines are involved in vascular remodeling, since they are generally known for their regulatory properties regarding influx of inflammatory cells to tissues and this is one of the first phenomena seen in vascular remodeling. The complement cascade was studied in this context since it contains pro-inflammatory activity and some end-products of the cascade, like chemokines, are potent chemotactic agents. Show less
Polymorphic light eruption (PLE) is a common sun-induced dermatosis presenting with itchy papules, plaques or vesicles on sun-exposed skin sites. In this thesis, epidemiological as well as... Show morePolymorphic light eruption (PLE) is a common sun-induced dermatosis presenting with itchy papules, plaques or vesicles on sun-exposed skin sites. In this thesis, epidemiological as well as pathogenetic mechanisms are desribed. By interviewing almost 7000 indoor working Europeans we found a lifetime prevalence of PLE of 18%. There is no evidence of increasing prevalence toward higher latitudes, as was formerly suggested. PLE is regarded an immunological disorder caused by a delayed type hypersensitivity reaction to a de novo photo-induced antigen in the skin. Upon UVB irradiation of the skin, more epidermal Langerhans cells persist in the epidermis of PLE patients and less neutrophilic granulocytes migrate into the epidermis, in contrast to healthy individuals. We show that UV-hardening therapy restores the epidermal cell migration to a normal situation. The reason for the aberrant cell responses in PLE skin remain for as yet unexplained. The presence of higher IL-1a en Il-1b levels in the skin of PLE patients was indicative of a pro-inflammatory situation after UVB irradiation when compared to healthy controls, but does not explain the aberrant cell responses. Our study further shows that the results of artificial UVA nor UVB provocation have any predictive value for the clinical severity of PLE Show less
