Multiple Sclerosis and the Epstein Barr Virus: Do MS risk genes indicate an EBV signature?

Abstract

A debilitating degenerative autoimmune disease, Multiple Sclerosis (MS) is characterised by demyelination of neurons in the central nervous system (CNS). The exact cause of MS is unknown; though MS is thought to arise in genetically susceptible individuals, elicited by environmental factors. Around 32% of disease risk is due to genetic factors; HLA-DR has the strongest association with MS. Other MS risk genes of interest here are CD40, a member of the TNFR superfamily, transcription factors ZFP36L2, EOMES and TBX2, the transcription factor regulator ZMIZ1, and RPS6KB1, which phosphorylates ribosomal protein S6 (RPS6). As 70% of MS risk cannot be explained by genetics; a large portion must be due to environmental factors. Here, we focus on two main environmental factors influencing MS risk; the Epstein Barr Virus (EBV) and Multiple sclerosis associated retrovirus (MSRV). Virtually all MS patients are seroconverted to EBV, and MS patients are found to have increased levels of anti EBNA-1 IgGs, an EBV latency protein. Salt serum levels will also be investigated. In this project, we confirm that anti EBNA-1 IgGs are increased in MS patients, independent of total IgG levels in the blood, alongside a significant association between anti EBNA-1 IgG levels with rs2516049, an MS risk SNP for HLA-DR. We found no significant association of the SNP most associated in MS; rs9271366. ZMIZ1, RPS6 and ZFP36L2 were associated with anti EBNA-1 titres and may contribute to the immune response to EBV. The MS protective allele of CD40 is associated with higher expression of CD40 in lymphoblastic cell lines (LCLs) derived by EBV transformation of B-cells, and culture of LCLs in the presence of CD40L reduces their proliferation a genotype dependant manner. This suggests that the protective allele of CD40 reduces MS risk by reducing EBV susceptibility. MSRVenv was previously found to be overexpressed in MS lymphocytes, were found to be expressed at very low levels in MS and healthy controls, with no statistically significant differences between them. No correlation between MSRVenv mRNA and anti EBNA-1 IgG titres suggests a lack of association between MSRVenv, MS and EBV. Here, we show that EBV is likely to contribute to MS risk by way of the MS risk genes of ZMIZ1, RPS6, ZFP36L2 and particularly, CD40. MSRV is unlikely to contribute to MS risk through EBV.