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
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
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
Osteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age... Show moreOsteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age. The main objective is to identify risk factors that play a role in the development of OA in order to gain further insight in the aetiology of OA. The secondary objective is to investigate factors that determine the outcome in OA. This thesis provides evidence that familial clustering of symptomatic OA is most prominent for hand and hip OA. In search for genetic risk factors, we present data suggesting that a proportion of the genetic susceptibility for OA at multiple sites is encoded by variation in innate cytokine activity. Further, we find HLA-DR antigens to be associated with radiological hand OA. In addition to genetic risk factors, this thesis demonstrates that other systemic risk factors such as hormonal status and local factors, to be important in the susceptibility of familial OA at multiple sites, underscoring the multicausal etioliology of this phenotype. Finally, this thesis addresses the resulting disability from OA. Using the International Classification of Functioning, Disability and Health as framework, we show illness perceptions and mental health to be important modifying factors in OA in the hands and lower extremities. Show less
