Transcriptome Profiles From Relapsing-Remitting Multiple Sclerosis Patients Show Aberrant Immunological Phenotypes Compared With Healthy Controls

Objective: To use Next-Generation RNA Sequencing to identify differences in gene-expression profiles associated with relapsing-remitting multiple sclerosis (RR-MS). Background: Multiple Sclerosis is a common neuroinflammatory disorder where genetic variants have been shown to affect the risk of disease heritability. These include MHC related alleles as well as IL-2, IL-7 receptor alpha and CTLA-4. Observational studies using microarrays have shown that the transcriptome profiles of MS patients differ from controls with respect to inflammatory and immunological processes. tested this hypothesis by undertaking an unbiased differential expression analysis of peripheral blood mononuclear cells (PBMCs) from RR-MS patients and healthy Methods: Blood samples were taken from 10 RR-MS patients and 8 age- and sex- matched controls. Total RNA was isolated from freshly harvested peripheral blood mononuclear cells (RINu003e8 for all samples). RNA was sequenced using the Illumina HiSeq platform, aligned using TopHat and counts calculated using HTSeq. Differential expression analysis was performed using DESEq2 (padj cut-offs u003c0.01). Results: We discovered 198 differentially expressed genes in RR-MS patients compared to controls (padj u003c 0.01). Of these, 89 were significantly increased and 109 were significantly decreased. The potentially relevant genes that were elevated had a role in cytokine production (NLRP3 and IL5RA respectively), antigen processing (CTSS), leukocyte migration (CD244) and regulation of type I interferon production (UBC). Most interestingly, significantly decreased genes included those implicated in myelination (PLLP) and NF-kappaB signalling (TSPAN6). Conclusions: This study demonstrates that the transcriptome profiles of RR-MS patients differ from controls and that many implicated genes have inflammatory and immunological functions as well as roles in myelination. The use of next-generation sequencing can provide insight into the dynamic pathways involved in MS pathogenesis and may help to further understand the genetic components of disease susceptibility. Disclosure: Dr. Porter has nothing to disclose. Dr. Arie has nothing to disclose. Dr. St. John Nicholas has received personal compensation for activities with Bayer Pharmaceuticals Corporation as a speaker, and Biogen Idec as a principal investigator, researcher, speaker and for serving on the advisory board. Dr. Matthews has received personal compensation for activities with Biogen, Novartis, Ixico, transparency Life Sciences, and Adelphi Communications. Dr. Matthews has received research support from GlaxoSmithKline and Biogen.