Expression of the Inhibitory CD200 Receptor Is Associated with Alternative Macrophage Activation

Classical macrophage activation is inhibited by the CD200 receptor (CD200R). Here, we show that CD200R expression was specifically induced on human in vitro polarized macrophages of the alternatively activated M2a subtype, generated by incubation with IL-4 or IL-13. In mice, peritoneal M2 macrophages, elicited during infection with the parasites Taenia crassiceps or Tryponosoma brucei brucei, expressed increased CD200R levels compared to those derived from uninfected mice. However, in vitro stimulation of mouse peritoneal macrophages and T crassiceps infection in IL-4-/- and IL-4R-/- mice showed that, in contrast to humans, induction of CD200R in mice was not IL-4 or IL-13 dependent. Our data identify CD200R as a suitable marker for alternatively activated macrophages in humans and corroborate observations of distinct species- and/or site-specific mechanisms regulating macrophage polarization in mouse and man. Copyright (C) 2009 S. Karger AG, Base

Identification of neuropathology-based subgroups in multiple sclerosis using a data-driven approach

Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pathophysiology. Stratification into biologically distinct subgroups could enhance prognostication and efficacious allocation to disease-modifying therapies. In this study, we identified MS subgroups by performing a clustering analysis on neuropathology data collected for MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The input dataset contained detailed information on white matter lesion load, the proportion of active, mixed active/inactive, inactive and remyelinating lesions, microglia morphology in these lesions, and the presence of microglial nodules, perivascular cuffs and cortical lesions for 228 donors. A factor analysis was performed to reduce noise and redundancy prior to hierarchical clustering with K-means consolidation. Four subgroups with distinct patterns of white matter lesions were identified. These were subsequently validated with additional clinical, neuropathological and genetic data. The subgroups differed with regards to disease progression and duration, the timing of motor, sensory and other relevant signs and symptoms, patterns of cortical lesions and the presence of B cells. Age at MS onset and sex, previously associated with milder forms of MS, did not differ between the subgroups; the subgroups could also not be distinguished based on the manifestation of clinical signs and symptoms. The available genetic data was used to calculate MS polygenic risk scores (PRSs) for donors included in the NBB cohort. The MS PRS did not differ between the subgroups, but was significantly correlated with the first and second dimension of the factor analysis, the latter lending genetic support to our subdivision. Taken together, these findings suggest a complex relationship between neuropathological subgroups and clinical characteristics, indicating that post-mortem cohort studies are critical to better stratify patients and understand underlying neuropathophysiological mechanisms, in order to ultimately achieve personalised medicine in MS

Exploring reported genes of microglia RNA-sequencing data:Uses and considerations

The advent of RNA-sequencing techniques has made it possible to generate large, unbiased gene expression datasets of tissues and cell types. Several studies describing gene expression data of microglia from Alzheimer's disease or multiple sclerosis have been published, aiming to generate more insight into the role of microglia in these neurological diseases. Though the raw sequencing data are often deposited in open access databases, the most accessible source of data for scientists is what is reported in published manuscripts. We observed a relatively limited overlap in reported differentially expressed genes between various microglia RNA-sequencing studies from multiple sclerosis or Alzheimer's diseases. It was clear that differences in experimental set up influenced the number of overlapping reported genes. However, even when the experimental set up was very similar, we observed that overlap in reported genes could be low. We identified that papers reporting large numbers of differentially expressed microglial genes generally showed higher overlap with other papers. In addition, though the pathology present within the tissue used for sequencing can greatly influence microglia gene expression, often the pathology present in samples used for sequencing was underreported, leaving it difficult to assess the data. Whereas reanalyzing every raw dataset could reduce the variation that contributes to the observed limited overlap in reported genes, this is not feasible for labs without (access to) bioinformatic expertise. In this study, we thus provide an overview of data present in manuscripts and their supplementary files and how these data can be interpreted

Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.</p

Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.</p

Експортно­імпортні операції в Чернігівській губернії на початку ХХ ст.

У статті на основі маловідомих фактів досліджується організація зовнішньої торгівлі в Чернігівській губернії Російської імперії на початку ХХ ст. Показані основні екпортно-імпортні операції, особливості економічного розвитку регіону.В научной статье на основании использования неизвестных ранее фактов исследуется организация внешней торговли в Черниговской губернии Российской империи в начале ХХ века. Показаны основные экспортно-импортные операции и особенности экономического развития региона.In scientific article author research the special organization of foreign trade in Chernigov’s region of Russian empire in the beginning of 20 century. Export-import operations and economic development had illustration in this work

Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis

Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using postmortem FFPE tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 patients with progressive MS, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions, and greater immune cell accumulation was associated with larger subpial lesion areas. Patients with a higher extent of meningeal inflammation harbored a greater proportion of active and mixed active/inactive WM lesions and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury and point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical WM

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

Microglia nodules (HLA-DR+ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation

Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-ap