Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain. Among characteristics of MS pathology are cortical grey matter abnormalities, which have been linked to clinical signs such as cognitive impairment. To understand MS cortical grey matter pathogenesis, we performed differential gene expression analysis of MS normal appearing grey matter (NAGM) and control grey matter. HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of grey matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. Our data indicate that increased HLA-DRB1 expression in the brain of MS patients may be an important factor in how the HLA-DR15 haplotype contributes to MS risk in the target organ.
Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain. Among characteristics of MS pathology are cortical grey matter abnormalities, which have been linked to clinical signs such as cognitive impairment. To understand MS cortical grey matter lesion pathogenesis, we performed differential gene expression analysis of MS cortical normal-appearing grey matter (NAGM) and grey matter lesions. HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of grey matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. Our data indicate that increased HLA-DRB1 expression in the brain of MS patients may be an important factor in how the HLA-DR15 haplotype contributes to MS risk in the target organ.
Project description:Multiple sclerosis (MS) is chronic disease of the central nervous system characterized by demyelinated lesions in both grey and white matter. While white matter lesions are typically associated with inflammatory demyelination, grey matter lesions (GML) often indicate ongoing neurodegenerative processes. GML are linked to clinical disability, though non-demyelinated areas in grey matter also exhibit underlying neuropathology. In grey matter, the extracellular matrix (ECM) plays a vital role in maintaining neuronal health, with perineuronal nets (PNNs) functioning as barriers, regulating synaptic stability and limiting postsynaptic receptor mobility. Microglia impact ECM composition by secreting ECM-degrading matrix metalloproteinases (MMPs), while the ECM, in turn, affects microglia behaviour. In this study, we examined differences in non-cell-associated ECM composition between human control and MS tissue and investigate how this ECM influences microglia. Label-free quantitative mass spectrometry of decellularized control grey matter (dCGM) and normal appearing grey matter (dNAGM) tissue slices revealed differentially abundant ECM proteins, and several ECM proteins uniquely present in either dNAGM or dCGM. The altered ECM composition of dNAGM involved changes in PNN, synaptic and basement membrane components, potentially impacting synaptic and blood-brain barrier function. The ECM composition of decellularized GML (dGML) and surrounding perilesional grey matter (dPLGM) appeared relatively similar. When decellularized human grey matter brain tissue was recellularized with primary microglia, half of the microglia population lost IBA1 expression on dNAGM and dGML, while a portion of the remaining IBA1+ microglia expressed the proinflammatory marker iNOS . These findings suggest changes in non-cell-associated ECM composition in the absence of demyelination, potentially influencing microglial behaviour and contributing to MS pathology.