Abstract
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.