A molecular characterization of meningeal inflammatory infiltrates in the progressive multiple sclerosis brain
ECTRIMS Online Library. Fuentes Font L. Oct 12, 2018; 232041
Laura Fuentes Font
Laura Fuentes Font
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Abstract: 288

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Pathology

Introduction: The presence of lymphoid-like immune cell aggregates in the leptomeninges is suggested to promote damage to the cerebral cortex and play a role in accumulating disability in multiple sclerosis (MS).
Aim: We aimed to analyse the transcriptome of the MS meninges to understand some of the molecular mechanisms that drive their formation.
Methods: Cryosections were cut from five cortical blocks per case from 55 SPMS and 14 control post-mortem brains. Meningeal tissue was dissected and RNA extracted. Affymetrix HTA 2.0 GeneChips were used to obtain the meningeal transcriptome and gene expression determined using R package Limma. Differentially expressed genes with FC>2 and FDR>0.05 were used to perform gene set enrichment analysis using WebGestalt and gene networks constructed using R package WGCNA.
Results: When comparing controls with highly inflamed MS cases, alterations were mainly found in expression of homing chemokines and receptors and cytokines that enhance B cell survival, proliferation and antibody and IFNγ production (IL10, IL18, PPBP, CXCR4, XBP1, CS1 and CD27). Modifications in genes involved in the development of lymphatic vessels (LYVE1) and cell motility, survival and antigen presentation (HLA-B) were prominent. Gene network analysis revealed networks associated with immune response, specially highlighting processes such as response to virus, chemokine signalling and antigen presentation. Functional pathway analysis for these network modules identified significant involvement in the MS meninges, of pathways associated with cell adhesion, TCR and BCR co-stimulation and activation, Th17, Th1/Th2 cell differentiation, haematopoietic and lymphoid organ development. The most highly altered genes were loaded into Ingenuity Pathway Analysis, yielding results that suggest a dysregulation of pathways critical for B-T cell interaction, disrupting antigen presentation and its subsequent outcomes. A panel of 55 inflammatory genes was chosen for validation of the microarray data using TaqMan OpenArrays. Highly significant, strong and moderately strong, correlations were found between the TaqMan and Affymetrix data for most individual genes, providing robustness to our meningeal transcriptomics data.
Conclusions: We have identified molecular cues that are likely to play a major role in mediating meningeal inflammation in MS, which suggest a dysregulation of pathways that are critical for B-cell trafficking and recruitment into the CNS.
Disclosure: Nothing to disclose.

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