Exploring the genomic and transcriptomic landscape of immune cells in multiple sclerosis : towards better biomarkers, diagnosis and treatment

The overall aim of this thesis was to determine the changes in gene regulation taking place in immune cells during the course of Multiple Sclerosis. Over 200 MS-associated SNPs have been identified from GWAS studies. These regions were found to be primarily in the non-coding regions of the genome and point to the vast immune system as the leading cause of MS. Inferring their function therefore has been a challenge. In addition, a complex interaction of genetics and environment has been proposed. This leads to the unresolved question associated with specific changes in the immune system that can lead to disease.

In order to resolve the role of the immune system in MS, we applied an array of high-throughput genomic and transcriptomic profiling techniques to identify specific changes in specific immune cells. MS being a complex immune mediated neurological disease, makes inference of regulation dependent changes in gene expression a challenge. By integrating different layers of evidence we are able to propose multiple interactions taking place within and across immune cells. We also find evidence that confirms previous findings in MS related to the increased activity of T and B cells. In addition, we identify multiple new genes, chromatin regions and DNA-methylated regions with differential activity primarily in T and B cells.

Collectively the results from these studies highlight the multiple factors leading to the dysregulation of the immune system in MS and the specific cells associated with pathogenesis. These studies also provide a resource for hypothesis building, validation of other studies and application of newer integration methodologies in a complex immune disease such as MS.

List of scientific papers

I. Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of Multiple Sclerosis patients. Fernandes SJ, Morikawa H, Ewing E, Ruhrmann S, Joshi RN, Lagani V, Karathanasis N, Khademi M, Planell N, Schmidt A, Tsamardinos I, Olsson T, Piehl F, Kockum I, Jagodic M, Tegnér J, Gomez-Cabrero D. Sci Rep. 2019 Aug 19;9(1):11996.
https://doi.org/10.1038/s41598-019-48493-7

II. Paired analysis of chromatin and expressed genes in four immune cell-types in the blood of Multiple Sclerosis patients. Fernandes SJ, Ericsson M, Khademi M, Olsson T, Gomez-Cabrero D, Kockum I, and Tegnér J. [Manuscript]

III. Single cell transcriptomics of paired blood and cerebrospinal fluid of multiple sclerosis patients with special focus on the immune repertoire. Fernandes SJ, Radpour S, Thimappa M, Al Nimer F, Gyllenberg A, Piehl F, Gomez-Cabrero D, Kockum I and Tegnér J. [Manuscript]

IV. Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. Ewing E, Kular L, Fernandes SJ, Karathanasis N, Lagani V, Ruhrmann S, Tsamardinos I, Tegner J, Piehl F, Gomez-Cabrero D, Jagodic M. EBioMedicine. 2019 May;43:411-423.
https://doi.org/10.1016/j.ebiom.2019.04.042