Immunopathogenesis of multiple sclerosis : big roles for small RNAs

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and the leading cause of neurological disability in young adults. The exact cause of MS remains elusive despite enormous progress during the last decades in establishing the role of genetic and environmental risk factors. Epigenetic mechanisms, at the interface of genetics and environment, could provide the missing link and help understand the mechanisms underlying MS pathogenesis. The work presented in this thesis has aimed to understand the role of different epigenetic mechanisms, including DNA methylation and small RNAs, and in particular microRNAs (miRNAs), in the context of biological function or as diagnostic tools.

In Paper I we revealed DNA hypermethylation at the VMP1/MIR21 locus in CD4 T cells of MS patients compared to controls. Moreover we found lower expression of miR-21 and consequently an upregulation of its targets genes. Our functional investigation using murine MS-like disease further demonstrated that miR-21 deficiency at early stages of disease ameliorated disease severity. In contrast, deletion of miR-21 after onset of disease in CD4 T cells associated with disease. In Paper II we profiled circulating miRNAs in the cerebrospinal fluid (CSF) of MS patients showing higher levels of miR-150 compared to controls and highlighting its potential as a biomarker of early active disease. The biological function of miR-150 was further investigated in-vivo in Paper Ill, where miR-150 deletion alleviated and miR-150 overexpression aggravated disease. The observed phenotype was associated with the role of miR-150 in promoting pathogenic CD4 T cells subsets, potentially by affecting metabolic mechanisms. In Paper IV we profiled all classes of small RNAs in MS patients across the peripheral compartment including peripheral blood mononuclear cells and plasma as well as CNS compartment, CSF cells and cell-free CSF. MS patients displayed wide-spread changes in small nuclear RNAs, nucleolar RNAs, transport RNAs and miRNAs with striking opposing patterns between the peripheral and CNS compartments, emphasizing the enrichment of pathogenic cells in target organ.

Taken together, these studies highlight the significance of small RNA-mediated pathophysiological mechanisms and could give crucial insights into MS disease etiology, opening up potential avenues for new therapeutic approaches.

List of scientific papers

I. Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing­ remitting Multiple Sclerosis associates with lower miR-21 levels and concomitant up-regulation of its target genes. Sabrina Ruhrmann, Ewoud Ewing, Eliane Piket, Lara Kular, Julio Cesar-Cetrulo Lorenzi, Sunjay Jude Fernandes, Hiromasa Morikawa, Shahin Aeinehband, Sergi Sayols-Baixeras, Stella Aslibekyan, Devin M. Absher, Donna K. Arnett, Jesper Tegner, David Gomez-Cabrero, Fredrik Piehl and Maja Jagodic. Mult Scler. 2018, 24(10):1288-1300.
https://doi.org/10.1177/1352458517721356

II. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis. Petra Bergman, Eliane Piket, Mohsen Khademi, Tojo James, Lou Brundin, Tomas Olsson, Fredrik Piehl and Maja Jagodic. Neural Neuroimmunol Neuroinflamm. 2016, 3(3):e219.
https://doi.org/10.1212/NXI.0000000000000219

Ill. MicroRNA-150 controls experimental autoimmune encephalomyelitis by regulating CD4 T cell differentiation and function. Eliane Piket, Anna Olofsson, Lottie Williams, Lena Mrugalla, Marie N'diaye, Irena Lavrnja, William Nyberg, Alexander Espinosa, Lara Kular, Andre Ortlieb Guerreiro-Cacais and Maja Jagodic. [Manuscript]

IV. Small non-coding RNA profile across cellular and body fluid compartments from Multiple Sclerosis patients. Galina Zheleznyakova*, Eliane Piket*, Maria Needhamsen, Michael Hagemann-Jensen, Mohsen Khademi, Faiez Al Nimer, Patrick Scicluna, Omid Faridani, Tomas Olsson, Fredrik Piehl and Maja Jagodic. *These authors contributed equally to this work. [Submitted]