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Expression of CD1d by astrocytes corresponds with relative activity in multiple sclerosis lesions.

ABSTRACT: The CD1 protein family present lipid antigens to the immune system. CD1d has been observed in the CNS of MS patients, yet no studies have quantitatively characterized this expression and related it to inflammatory demyelinative activity in MS plaques. In this study, we set out to localize and quantify the presence of CD1d expression by astrocytes in MS brain tissue lesions. Formalin-fixed, paraffin-embedded MS and control brain tissues were examined. Lesions were classified as active, chronic active or chronic silent. Using immunofluorescence, the density of CD1d-positive cells was determined in active lesions, chronic active lesion edges and chronic active lesion centers. The percentage of CD1d-positive cells that were GFAP-positive was also determined in each of these regions. CD1d immunoreactivity was significantly increased in MS compared to control tissue, was significantly more prevalent in areas of active demyelination, and colocalized with GFAP-positive reactive astrocytes. Increases of CD1d immunoreactivity in the CNS of MS patients being greatest in areas of active demyelination and localized to GFAP-positive astrocytes lend support to the hypothesis of a lipid-targeted autoimmune process contributing to the pathogenesis of MS.

SUBMITTER: Muir FGW

PROVIDER: S-EPMC6916356 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Multiple Sclerosis: Destruction and Regeneration of Astrocytes in Acute Lesions.

Project description:There are reports that astrocyte perivascular endfeet are damaged in some cases of multiple sclerosis (MS). This study was designed to determine the origin and outcome of astrocyte damage in acute, resolving, and inactive plaques. Ten acute plaques from 10 early MS cases and 14 plaques of differing histological age from 9 subacute and chronic cases were examined immunohistochemically. Also examined were nonnecrotic early lesions in 3 patients with neuromyelitis optica (NMO). Plaques from 3 MS cases were examined electron microscopically. The edge zones in each of the 10 acute MS lesions revealed a complete loss of astrocyte cell bodies and their pericapillary, perineuronal, and perivascular foot processes. Dendrophagocytosis of degenerate astrocytes was observed. Astrocyte precursors, similar to those that replace destroyed astrocytes in nonnecrotic NMO lesions, were present in areas depleted of astrocytes. Resolving plaques were repopulated initially by stellate astrocytes that stained negatively for the water channel molecule aquaporin4 (AQP4). In older lesions, astrocytes were predominantly AQP4-positive. Loss and recovery of astrocytes in new MS lesions may be as important as myelin loss as a cause of conduction block responsible for symptoms in patients with relapsing and remitting and secondary progressive MS.

| S-EPMC6330170 | biostudies-literature

Cell type-specific Nrf2 expression in multiple sclerosis lesions.

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| S-EPMC4503875 | biostudies-literature

KIAA1199 expression and hyaluronan degradation colocalize in multiple sclerosis lesions.

Project description:Modification of hyaluronan (HA) accumulation has been shown to play a key role in regulating inflammatory processes linked to the progression of multiple sclerosis (MS). The aim of this study was to characterize the enzymatic activity involved in HA degradation observed within focal demyelinating lesions in the experimental autoimmune encephalomyelitis (EAE) animal model. EAE was induced in 3-month-old female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 33-35 (MOG33-35) peptide. The mice were monitored for 21 days. Formalin-fixed paraffin-embedded tissue from control and EAE mice were labeled with an immunoadhesin against HA, antibodies against KIAA1199 and glial fibrillary acidic protein, a marker for astrocytes. In situ hybridization was conducted using a KIAA1199 nucleic acid probe. In histologic sections of spinal cord from EAE mice, abnormal HA accumulation was observed in the close vicinity of the affected areas, whereas HA was totally degraded within the focal loci of damaged tissue. KIAA1199 immunoreactivity was exclusively associated with focal loci in damaged white columns of the spinal cord. KIAA1199 was mainly expressed by activated astrocytes that invaded damaged tissue. Similar findings were observed in tissue from an MS patient. Here, we show that KIAA1199, a protein that plays a role in a HA degradation pathway independent of the canonical hyaluronidases such as PH20, is specifically expressed in tissue lesions in which HA is degraded. KIAA1199 expression by activated astrocytes may explain the focal HA degradation observed during progression of MS and could represent a possible new therapeutic target.

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Multiple Sclerosis Pattern II Demyelinating Lesions

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-03 | E-GEOD-60943 | biostudies-arrayexpress

Multiple Sclerosis Pattern II Demyelinating Lesions

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-01-01 | GSE60943 | GEO

Increased HLA-E expression in white matter lesions in multiple sclerosis.

Project description:The molecular mechanisms underpinning central nervous system damage in multiple sclerosis (MS) are complex and it is widely accepted that there is an autoimmune component. Both adaptive and innate immune effector mechanisms are believed to contribute to tissue disease aetiology. HLA-E is a non-classical MHC class Ib molecule that acts as the ligand for the NKG2A inhibitory receptor present on natural killer (NK) and CD8+ cells. Peptide binding and stabilization of HLA-E is often considered to signal infection or cell stress. Here we examine the up-regulation of HLA-E in MS brain tissue. Expression is significantly increased in white matter lesions in the brain of MS patients compared with white matter of neurologically healthy controls. Furthermore, using quantitative immunohistochemistry and confocal microscopy, we show increased HLA-E protein expression in endothelial cells of active MS lesions. Non-inflammatory chronic lesions express significantly less HLA-E protein, comparable to levels found in white matter from controls. Increased HLA-E protein levels were associated with higher scores of inflammation. These results suggest the potential for an effect in central nervous system pathogenesis from HLA-E modulation in stressed tissue. Co-localization with infiltrating CD8+ cells implicates a possible role for HLA-E-restricted regulatory CD8+ cells, as has been proposed in other autoimmune diseases.

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The Role of Astrocytes in Multiple Sclerosis.

Project description:The role traditionally assigned to astrocytes in the pathogenesis of multiple sclerosis (MS) lesions has been the formation of the glial scar once inflammation has subsided. Astrocytes are now recognized to be early and highly active players during lesion formation and key for providing peripheral immune cells access to the central nervous system. Here, we review the role of astrocytes in the formation and evolution of MS lesions, including the recently described functional polarization of astrocytes, discuss prototypical pathways for astrocyte activation, and summarize mechanisms by which MS treatments affect astrocyte function.

| S-EPMC5826071 | biostudies-literature

Slowly eroding lesions in multiple sclerosis.

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| S-EPMC5182188 | biostudies-literature

Expression Pattern of Myelin-Related Apolipoprotein D in Human Multiple Sclerosis Lesions.

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| S-EPMC6110904 | biostudies-literature

Expression of antioxidant enzymes in lesions of multiple sclerosis and its models.

Project description:Oxidative stress promotes tissue injury in the central nervous system in neurological disorders such as multiple sclerosis (MS). To protect against this, antioxidant enzymes including superoxide dismutase-1 (SOD1), heme oxygenase-1 (HO-1), peroxiredoxin-5 (PRDX5) and glutathione peroxidase-4 (GPX4) may be upregulated. However, whether antioxidant enzyme elevation in mouse models of neurodegeneration corresponds to their expression in human diseases such as MS requires investigation. Here, we analyzed and compared the expression of SOD1, HO-1, PRDX5 and GPX4 in the murine spinal cord of three models of MS: focal lesions induced by (1) oxidized phosphatidylcholine or (2) lysophosphatidylcholine (lysolecithin), and (3) diffuse lesions of experimental autoimmune encephalomyelitis. Notably, CD68+ microglia/macrophages were the predominant cellular populations that expressed the highest levels of the detected antioxidant enzymes. Overall, the expression patterns of antioxidant enzymes across the models were similar. The increase of these antioxidant enzymes was corroborated in MS brain tissue using spatial RNA sequencing. Collectively, these results show that antioxidant capacity is relatively conserved between mouse models and MS lesions, and suggest a need to investigate whether the antioxidant elevation in microglia/macrophages is a protective response during oxidative injury, neurodegeneration, and MS.

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