Is Epstein-Barr virus present in the CNS of patients with MS?
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
C J De Groot
Publications and source records attributed to C J De Groot.
Upregulation of transcription factors controlling MHC expression in multiple sclerosis lesions.
The expression of major histocompatibility complex (MHC) class I and class II in the CNS has received considerable interest because of its importance in neurodegenerative or inflammatory diseases, such as multiple sclerosis (MS). However, at the moment nothing is known about the expression patterns of transcription factors controlling MHC expression in MS lesions. Here, we performed an extensive immunohistochemical analysis on MS affected postmortem brain tissue to determine the cellular localization and distribution of different MHC-controlling transcription factors. We show that phagocytic macrophages in active demyelinating MS lesions displayed a moderate to strong immunostaining of the MHC-specific transcription factors RFX and CIITA, as well as the general transcription factors NF-kappaB, IRF1, STAT1, USF, and CREB, which was congruent with a strongly enhanced expression of HLA-DR, HLA-DQ, HLA-DP, and HLA class I. In the normal-appearing white matter (NAWM), clusters of activated microglial cells forming preactive lesions displayed an overall stronger expression level of these transcription factors, combined with a strong to intense level of MHC class I and class II immunostaining. In general, astrocytes and oligodendrocytes either did not express, or weakly expressed, these transcription factors, correlating with a lack of MHC class II and weak MHC class I expression. Together, the elevated expression level of transcription factors governing expression of MHC class I and class II molecules in activated microglial cells and phagocytic macrophages strongly suggests a general state of microglial cell activation in MS lesions.
Adult↗
Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain.
Epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) lower the risk of developing Alzheimer's disease (AD). Most NSAIDs act upon local inflammatory events by inhibiting the expression or activation of cylooxygenase (COX). In the present study the expression of COX-1 and COX-2 in AD and non-demented control temporal and frontal cortex was investigated using immunohistochemistry. COX-1 expression was detected in microglial cells, while COX-2 expression was found in neuronal cells. In AD brains, COX-1-positive microglial cells were primarily associated with amyloid beta plaques, while the number of COX-2-positive neurons was increased compared to that in control brains. No COX expression was detected in astrocytes. In vitro, primary human microglial and astrocyte cultures, and human neuroblastoma cells (SK-N-SH) were found to secrete prostaglandin E2 (PGE2), especially when stimulated. PGE2 synthesis by astrocytes and SK-N-SH cells was stimulated by interleukin-1beta. Microglial cell PGE2 synthesis was stimulated by lipopolysaccharide only. Although astrocytes are used in studies in vitro to investigate the role of COX in AD, there are no indications that these cells express COX-1 or COX-2 in vivo. The different distribution patterns of COX-1 and COX-2 in AD could implicate that these enzymes are involved in different cellular processes in the pathogenesis of AD.
Aged↗
The role of chemokines and chemokine receptors in CNS inflammation.
Explore the source record for details and available documents.
Animals↗
In vitro biocompatibility of biodegradable dextran-based hydrogels tested with human fibroblasts.
The cytotoxicity of dextran T40, methacrylated dextran (dex-MA) and hydroxyethyl-methacrylated dextran (dex-HEMA), dextran-based hydrogel discs and microspheres, and their degradation products, was studied by measuring the cell proliferation inhibition index (CPII) on human fibroblasts in vitro. In addition, during the 72 h incubation period light-microscopic observations were performed daily. After 24 h of incubation with dextran and dex-HEMA polymers, the cells showed elongated or spider-like forms, some lipid droplets and intracellular granula, indicative of pinocytosis and internalization of the polymers. During the next two days, the fibroblasts' appearance did not change. Methacrylic acid (MAA), formed by hydrolysis of dex-HEMA, did not influence the cell morphology. Dex-HEMA polymer solutions with a low and high degree of substitution (DS) at 100 mg/ml caused a CPII of 30-40% after 72 h. This is less than 10% growth inhibition per cell cycle and statistically not different from the CPII induced by 100 mg/ml dextran T40. Growth inhibition induced by MAA was also low. The various dex-MA hydrogel discs caused similar low growth inhibition. Interestingly, hydrogel microspheres of dex-MA and dex-(lactate-)HEMA caused a CPII of only 0-20% after 72 h. The results presented in this study demonstrate that methacrylate-derivatized dextran hydrogels show good biocompatibility in vitro making these degradable biomaterials promising systems for drug delivery purposes.
Biocompatible Materials↗
Infants exposed to alcohol prenatally: outcome at 3 and 7 months of age.
To investigate early recognition of the consequences of alcohol exposure in utero, we studied 79 infants at the ages of 3 and 7 months. Twenty-nine of them were exposed to varying levels of maternal alcohol intake and 50 had no exposure and formed a control group. Special attention was paid to fetal alcohol syndrome-related facial features, neurological development and behavioural performance of the infants. To monitor facial features, pictures were taken at 3 and 7 months of age. Significant differences in facial features were found between the alcohol-exposed and non-exposed children at 3 months only. An age-adequate neurological examination showed no significant difference at 3 months but a significant difference at 7 months of age between the alcohol-exposed infants and the controls. Mothers reported more misbehaviour in the exposed than in the non-exposed group. These results indicate that it is possible to recognise alcohol-related defects within the 1st year of life thus allowing early intervention.
Alcohol Drinking↗
Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions.
Macroscopic sampling of multiple sclerosis lesions in the brain tends to find chronic lesions. For a better understanding of the dynamics of the multiple sclerosis disease process, research into new and developing lesions is of great interest. As MRI in vivo effectively demonstrates lesions in multiple sclerosis patients, we have applied it to unfixed post-mortem brain slices to identify abnormalities, in order to obtain a higher yield of active lesions. The Netherlands Brain Bank organized the rapid autopsy of 29 multiple sclerosis patients. The brain was cut in 1 cm coronal slices. One or two slices were subjected to T(1)- and T(2)-weighted MRI, and then cut at the plane of the MRI scan into 5 mm thick opposing sections. Areas of interest were identified based on the MRI findings and excised. One half was fixed in 10% formalin and paraffin-embedded, and the corresponding area in the adjacent half was snap-frozen in liquid nitrogen. In total, 136 out of 174 brain tissue samples could be matched with the abnormalities seen on T(2)-weighted MRIs. The stage of lesional development was determined (immuno) histochemically. For 54 MRI-detectable samples, it was recorded whether they were macroscopically detectable, i.e. visible and/or palpable. Histopathological analysis revealed that 48% of the hyperintense areas seen on T(2)-weighted images represented active lesions, including lesions localized in the normal appearing white matter, without apparent loss of myelin but nevertheless showing a variable degree of oedema, small clusters of microglial cells with enhanced major histocompatibility complex class II antigen, CD45 and CD68 antigen expression and a variable number of perivascular lymphocytes around small blood vessels [designated as (p)reactive lesions]. From the macroscopically not-visible/not-palpable MRI-detected abnormalities, 58% were (p)reactive lesions and 21% contained active demyelinating lesions. In contrast, visible and/or palpable brain tissue samples mainly contained chronic inactive lesions. We conclude that MRI-guided sampling of brain tissue increases the yield of active multiple sclerosis lesions, including active demyelinating and (p)reactive lesions.
Adult↗
The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis.
In multiple sclerosis, matrix metalloproteinases (MMPs) are effectors of crucial pathogenetic steps, such as blood-brain barrier breakdown, invasion of brain parenchyma by immune cells and demyelination. However, only limited data are available on the types of MMPs induced in the course of multiple sclerosis, and on the role of their endogenous antagonists, the tissue inhibitors of metalloproteinases (TIMPs). We quantified the transcriptional expression of six MMPs and the four TIMPs in lesions and in normal appearing white matter (NAWM) from post-mortem multiple sclerosis brain tissue by real-time polymerase chain reaction, and compared levels with those in brain tissue from six control patients without neurological disease. The mRNA expression of MMP-7 and -9, but not of other metalloproteinases [MMP-2 and -3, and tumour necrosis factor (TNF)-alpha-converting-enzyme] was equally upregulated throughout all stages of lesion formation with active inflammation, and in most of matched NAWM tissue. The transcription of cytokines TNF-alpha/beta and IL (interleukin)-2, known modulators of MMPs, was upregulated only in distinct stages of lesion formation, while their receptors were not induced at all, which suggests that additional signalling molecules participate in the sustained upregulation of MMP-7 and -9 in multiple sclerosis. None of the TIMPs showed a significant induction over baseline expression of controls. We hypothesize that an imbalance between MMP and TIMP expression may cause a persistent proteolytic overactivity in multiple sclerosis, that may be a factor for continuous tissue destruction, and hence for secondary disease progression.
ADAM Proteins↗
Hypothalamic lesions in multiple sclerosis.
Demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e. the fornix. anterior commissure, internal capsule, and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients. Therefore we investigated the presence and immunological activity of lesions in hypothalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed demyelinated lesions. The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the internal capsule (p = 0.005). In 4 of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients grey matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score (r = -0.72, p = 0.001). Since comparison of hypothalamic lesions with MS lesions in other areas of the brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02). In the median eminence region that lacks a blood-brain barrier, all controls showed a strong HLA expression around the blood vessels. We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.
Adult↗
Evidence of endothelium involvement in the pathophysiology of hydrops fetalis?
A fetus with signs of hydrops is at high risk of intrauterine death. The pathophysiology of hydrops fetalis is still unclear. We found decreased concentrations of cyclic guanosine monophosphate in fetal plasma of alloimmunized pregnancies complicated by hydrops fetalis, which might suggest reduced nitric oxide production due to injury of fetal vascular endothelial cells.
Adult↗
Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue.
The present study provides a detailed description of the simultaneous establishment and immunocytochemical characterization of highly enriched human adult microglial cell cultures as well as of oligodendrocyte cultures. For this study, brain tissue specimens were collected at autopsy with relatively short postmortem times (3-9 h) from various regions of the CNS of Alzheimer's disease, Pick's disease and non-demented control cases. Although methods to isolate viable glial cells from human adult brain tissue have been described, these human brain specimens were often derived from surgical resections, i.e., in order to treat intractable epilepsy, brain tumors or cardiovascular diseases involving the brain. However, for the study of many neurological disorders, surgical material is not available. Furthermore, for obvious reasons, there is a limit to the number of central nervous system (CNS) regions from which (enough) tissue can be obtained at surgery. The adherent primary microglial cells, isolated according to the here described procedures consisted of proliferating, phagocytotic cells that expressed various microglia/macrophage-specific markers as judged by immunocytochemical analysis. Non-adherent cells isolated from the same brain tissue samples expressed oligodendrocyte-specific markers. The current described culture system may provide a valuable tool in studying human CNS biology and disease.
Aged↗
Macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and RANTES mRNA semiquantification and protein expression in active demyelinating multiple sclerosis (MS) lesions.
MS is a demyelinating disease characterized by infiltration of monocytes and lymphocytes into the brain parenchyma, destruction of oligodendrocytes and loss of myelin. Since chemokines play a major role in the migration of monocytes and T cells, we here investigated the expression of the CC chemokines MIP-1alpha, MIP-1beta, and RANTES in brain tissue from MS patients using reverse transcriptase-polymerase chain reaction techniques. Both MIP-1beta as well as RANTES were found to be significantly elevated in brain tissue of MS patients. In addition, MIP-1alpha was also increased, although not significantly. Immunohistochemistry revealed that, whereas RANTES was mainly localized in reactive astrocytes, MIP-1alpha and MIP-1beta immunoreactivity was predominantly found in perivascular and parenchymal macrophages, containing myelin degradation products. Thus, chemokines appear to be associated with MS and an increased chemokine expression may further enhance disease progression by attracting more leucocytes into the brain parenchyma and by activation of effector functions of astrocytes and microglial cells.
Adult↗
Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS.
Several processes take place during an attack of demyelination in multiple sclerosis (MS). The timing of these various processes, and thus of the attack in its entirety, is important if therapeutic stratagies are to be planned. Attempts have been made to introduce and investigate variables relevant to timing the disease processes, leading to staging systems for MS. Here, the terminology and the various parameters used are reviewed, including inflammatory cells, glial cells, axonal loss and myelin staining; then the different systems are compared, including the system put forward by Bö and Trapp, our own modification of that, the Brück and Lassmann system and the recent consensus reached at a Vienna meeting. It is concluded that an ideal staging system does not yet exist, and that, more than anything else, the material dictates the choice for a staging system. The terminology of the Vienna consensus could be used as a reference to facilitate international comparison.
Disease Progression↗
Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia.
In human immunodeficiency virus (HIV)-1-associated dementia (HAD), consequences of interactions between infiltrating monocytes and brain endothelial cells are not yet fully understood. This study investigated whether the blood-brain barrier is affected in brain tissue of patients suffering from HAD and whether it was possible to find a correlation with the presence or absence of monocytic cells, which have been suggested to play a major role in HAD. Immunohistochemical analysis for zonula occludens 1, a tight junction protein, and CD68, a macrophage marker, revealed that loss of tight junction immunoreactivity was highly correlated with monocyte infiltration and with HAD. This suggests that the presence of perivascular macrophages cells is associated with breakdown of the blood-brain barrier thereby facilitating infiltration of more monocytic cells hence enhancing disease progression.
AIDS Dementia Complex↗
Is Chlamydia pneumoniae present in the central nervous system of multiple sclerosis patients?
Explore the source record for details and available documents.
Central Nervous System Bacterial Infections↗
Nitric oxide synthase expression and apoptotic cell death in brains of AIDS and AIDS dementia patients.
OBJECTIVES: To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients. DESIGN AND METHODS: Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight control subjects was processed for iNOS immunocytochemistry, NADPH-diaphorase activity staining as an index of NOS activity, and in situ end-labelling to detect cell death. RESULTS: iNOS-positive cells were present in the white matter of 14 out of 16 AIDS and ADC patients, whereas two out of eight control subjects showed iNOS-positive cells. iNOS immunoreactivity was exclusively localized in activated macrophages and microglial cells that both showed NADPH-diaphorase activity. In addition, NADPH-diaphorase activity, not related to iNOS immunoreactivity, was observed in astrocytes in both white and grey matter of AIDS and ADC patients. All AIDS and ADC patients, and only one control subject showed characteristic features of apoptotic cell death. CONCLUSIONS: Different forms of NOS are present in microglial cells and astrocytes of AIDS and ADC patients but are largely absent in control subjects. Although more NOS-expressing cells occur in ADC than in AIDS patients, apoptotic cell death was found in both patient groups to the same extent. We postulate that NO production in brains of AIDS patients results in cumulative cortical cell loss, which becomes neurologically evident at later stages of disease and is expressed as ADC.
AIDS Dementia Complex↗
Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability.
Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.
Adult↗
Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.
Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.
Aged↗