Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression

Abstract

Background Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. Methods We measured DNA methylation in CD4 + T cells ( n = 31), CD8 + T cells ( n = 28), CD14 + monocytes ( n = 35) and CD19 + B cells ( n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte ( n = 25) and whole blood ( n = 275) cohorts were used for validations. Findings B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. Interpretation We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. Fund This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.

Identifying the culprits in neurological autoimmune diseases

“…[ 79 ], showed differences in the methylation of HLA-DRB1 in CD4 + T cells, whereas Ewing et al. [ 80 ], showed more methylation changes in B cells and monocytes than in T cells. Additionally, there is evidence in the brain of MS patients of changes in DNA methylation such as hypomethylation in peptidyl arginine deaminases (PADI) 2, an enzyme involved in the citrullination of the myelin basic protein (MBP), which favors the breakdown of myelin in MS patients.…”

Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions

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Effectiveness of a combination therapy of traditional Chinese medicine and CO2 laser treatment for condyloma acuminatum

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