A methylome-wide study of immune cells in relapsing-remitting multiple sclerosis

• Applicant: Jordi Tomàs Roig, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Bioinformatics and Theoretical Biology ; Human Genetics
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329218662

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, neurodegeneration and progressive axonal injury. All these pathophysiological features lead to weakness, loss of sensory function, visual abnormalities and create a significant socioeconomic burden. B and T cells are two pivotal components over-activated in MS and are closely supporting each other in an inflammatory but also in a regulatory manner. B cells are antibody-secreting plasma cells implicated in processing of intact myelin antigen and subsequent activation and pro-inflammatory differentiation of T cells. Reciprocally, differentiated T cells activate T cell polarizing B cell properties by a positive feedback mechanism of joint pro- or anti-inflammatory B and T cell rearrangements. In the pathophysiology of the disease, B-cells participate in the initiation and perpetuation of CNS-targeting inflammation while T cells regulate autoreactive and inflammatory responses and act as inducers of immune tolerance. The etiology of the disease is unknown, but requires a complex interaction between genetic and environmental factors. DNA methylation moderates gene-environment interactions and provides a stable and heritable component of epigenetic regulation. DNA methylation is important for many key biological processes including gene regulation, normal brain development, psychiatric disorders and distinct autoimmune diseases. In contrast to previous studies of the DNA methylation performed in MS, the present investigation aims to study a homogenous cohort of B and regulatory T cells separately instead of a pool of cells. Furthermore, all plausible modifications of the DNA methylation will be supported by transcriptomics, neuroimaging, clinical history of the patient and biochemical characterization techniques.We hypothesize that changes in the DNA methylation of regulatory T cells (CD4+/CD25+) and B cells (CD19+) collected from whole peripheral blood (WB) in RRMS patients may modulate disease onset and progression as well as the treatment response to drug. Therefore, our main objective is to analyze and compare the methylome profiles and mRNA expression of immune cells subsets in two different scenarios: 1) at the time of diagnosis for the disease and 2) during the first two years after starting to use disease-modifying drugs. To test our hypothesis, we propose the following objectives:1. To assess the DNA methylation profile in purified CD4+/CD25+ and CD19+ cells. 2. To quantify transcriptional alterations caused by differentially DNA methylated regions in both lymphocyte subsets. 3. To measure 25-hydroxyvitamin D concentrations.4. To determine IgG and lipid specific IgM oligoclonal bands.5. To quantify brain tissue volume with automated lesion segmentation and filling

• DFG Programme: Research Fellowships
• International Connection: Spain
• Host: Professor Lluís Ramió-Torrentà, Ph.D.