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
Chauhan, P.; Hansson, B.; Kraaijeveld, K.; Knijff, P. de; Svensson, E.I.; Wellenreuther, M. 2014
In this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis... Show moreIn this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis as a core stress system underlying psychopathophysiology in stress-related disorders. Homeostatic systems, including the HPA axis, are by nature nonlinear in their function, with suboptimal states of function at both sides of the curve, e.g. hyper- versus hypofunction. By taken the HPA axis as starting point, we were able redefine the clinical phenotype in relation to both dysfunctional states, i.e., hyper- and hypocortisolism. Furthermore, starting with the stress system enabled us to investigate the effects of HPA axis dysfunction on the metabolic and immune system. Based on the studies presented in this thesis, we hypothesize that the nonlinear aspect of HPA axis function reflects different time points during the stress process, from a hyperactive HPA axis when the stress begins to, eventually, a hypoactive HPA axis when stress holds on. Secondly, we hypothesize that both dysfunctional states of the HPA axis, i.e., hyper- and hypocortisolism, differ in their effects on the metabolic and immune system. Show less
May, Linda; Bodegom, David van; Frolich, Marijke; Lieshout, Lisette van; Slagboom, P Eline; Westendorp, Rudi GJ and Kuningas, Maris 2010
Toll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and... Show moreToll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and lead to variability in cytokine production and survival. We tested this hypothesis in 4292 participants who were followed up for all-cause mortality for 6 years and live under adverse environmental conditions in the Upper-East region of Ghana, where malaria is endemic. In 605 participants, tumor necrosis factor-a and interleukin-10 (IL10) production, after stimulation with lipopolysaccharide and zymosan, was measured. In addition, 34 single-nucleotide polymorphisms (SNPs) in TLR4 and 12 SNPs in TLR2 were genotyped and tested for association with cytokine production, malaria infection and mortality. In this comprehensive gene-wide approach, we identified novel SNPs in the TLR4 gene that influence cytokine production. From the analyzed SNPs, rs7860896 associated the strongest with IL10 production (P¼0.0005). None of the SNPs in this study associated with malaria or overall mortality risks. In conclusion, we demonstrate that genetic variation within the TLR4 gene influences cytokine production capacity, but in an endemic area does not influence the susceptibility to malaria infection or mortality. Show less
May, Linda; Kuningas, Maris; Bodegom, David van; Meij, Hans J.; Frolich, Marijke; Slagboom, P. Eline; ... ; and Westendorp, Rudi G.J. 2009
Pentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we... Show morePentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n ¼ 4346). We studied the association between the number of children given birth by women during their lifetime and ex vivo, lipopolysaccharide (LPS)-induced PTX3 production (n ¼ 362). In addition, we studied the association of genetic variation in the PTX3 gene with PTX3 production (n ¼ 617) and with female fertility (n ¼ 1999). We found that ex vivo LPS-induced PTX3 production was associated with fertility (P ¼ 0.040). Furthermore, we identified genetic variants in the PTX3 gene that influence PTX3 production, and also fertility. The strongest associations were observed for the rs6788044 single-nucleotide polymorphism (SNP). We found that carriers of this SNP had higher PTX3 production capacity (P ¼ 0.003) and higher fertility (P ¼ 0.043). The results reported here provide the first evidence, based on protein production and analysis of polymorphisms, that the long pentraxin PTX3 plays a role in female fertility in humans. Show less
In general, biological and chemical causes for harmful effects were studied through bioinformatics and cheminformatics efforts. A database of human genetic variants in G protein-coupled receptors... Show moreIn general, biological and chemical causes for harmful effects were studied through bioinformatics and cheminformatics efforts. A database of human genetic variants in G protein-coupled receptors was constructed, and differences between neutral and harmful variants were studied. A database of compounds with their mutagenicity data was constructed, and substructures were extracted that distinguish between Ames positive and Ames negative compounds. 6. Keywords (At most 10, in English), preferably from the thesaurus in use within your discipline. Do not use very general terms. cheminformatics, chemoinformatics, bioinformatics, databases, data mining, drug discovery, SNPs, polymorphisms, substructures. Show less
Tuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis. MTB infection does not necessarily progress to TB. Only 5-10% of exposed individuals develop clinical signs and... Show moreTuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis. MTB infection does not necessarily progress to TB. Only 5-10% of exposed individuals develop clinical signs and symptoms of TB. Given the impact of mycobacterial exposure and the immunoregulatory consequences for host immunity, it is important to study the integrity and the regulation of immune responses and their downstream signaling pathways in TB endemic areas. Indonesia is a highly TB-burdened country and ranks third globally in TB cases. This thesis, consisting of six studies, explored variation in host immune responses to TB and their genetic background, and variation in clinical presentation. (1) MTB-specific stimulation of IFN-_ production as well as IFN-_ receptor signaling was significantly down-regulated during active TB, correlated with disease severity and __activity. (2) Concentrations of plasma granulysin of active TB patients were found to be low during acute disease. (3) Several genetic markers have been identified to affect susceptibility to TB (IL12B, IL12RB1, IFNG and IFNGR1) and (4) TLR8, DC-SIGN, complement component and scavenger receptor. (5) NRAMP polymorphisms were, however, not associated with susceptibility to TB. (6) TB with concomitant type2 DM presented more symptoms; screening fasting blood glucose in TB patients is clinically important. Show less
