Karolinska Institutet
Clinical Neuroscience

Author Of 1 Presentation

Genetics and Epigenetics Poster Presentation

P0525 - Investigating a role of B cells and their depletion in relapsing-remitting Multiple Sclerosis using DNA methylation patterns (ID 892)

Speakers
Presentation Number
P0525
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by autoimmune attack and destruction of myelin and neuroaxonal degeneration in the central nervous system (CNS). Previous reports have indicated that widespread differences in DNA methylation between MS cases and healthy controls in B cells. Importantly, B cells have come under renewed interest due to the effectiveness of treatments that deplete B cells, such as rituximab.

Objectives

To characterize epigenetic changes and their functional consequences in CD19+ B cells from MS patients, and to investigate changes in CD4+ T cells and CD14+ monocytes following B cell depletion with rituximab.

Methods

We measured DNA methylation in CD19+ B cells sorted from peripheral blood from relapsing-remitting (RRMS) (n= 26) and healthy controls (HC) (n = 15), which we compared and integrated with previously analyzed cohort (RRMS n = 12, HC n = 10). We also quantified DNA methylation in CD4+ T cells (n = 17) and CD14+ monocytes (n = 17) sorted from peripheral blood at baseline and 6 months of rituximab treatment. DNA methylation was measured using Infinium HumanMethylationEPIC arrays. Rituximab results were compared with results from a dimethyl fumarate treated cohort.

Results

Meta-analysis of the two B cell cohorts revealed 3 003 differentially methylated CpGs between RRMS and HC (with adjusted p-value < 0.05). Pathway analyses of the cohorts implicated dysregulation of genes involved in cell-to-cell communication, cell migration and activation. Rituximab treatment did not yield genome-wide significant changes in DNA methylation in CD4+ and CD14+ cells likely due to the indirect action of the drugs. Nevertheless pathway analysis of candidate differentially methylated CpGs associated with changes in activation immune activation, subset differentiation and motility being affected by B cell depletion.

Conclusions

Our data establish that B cells from MS patients acquire a distinct epigenetic profile connected to changes in pathways of importance for B cell functions. Furthermore, we demonstrate changes in other cell types following B cell depletion as a therapeutic modality.

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