Prevention of MS Requires Intervention on the Causes of the Disease: Reconciling Genes, Epigenetics, and Epstein Barr Virus

Abstract

Prevention of multiple sclerosis requires intervention on modifiable causes of the condition making it necessary to establish what those causes are. MS is often stated to be a polygenic disease, with causal contributions from environmental factors and gene-environment interactions, implying an additive and independent relationship of these factors. Mechanistically there are no independent contributions of genes or environmental factors to traits. This model is unrealistic but still useful and underlies the concept of heritability, a foundational parameter in population genetics. However, it perpetuates a debate on an irreconcilable dichotomy about whether MS is primarily genetic or environmental. In particular, epidemiological evidence now exists for a causal, possibly even necessary, role for Epstein Barr Virus in MS. The additive model makes it unintuitive to reconcile MS as a genetic disease but also independently a viral illness. In this perspective it is argued that starting from a realistic interaction only model, based on broadly accepted biological premises, and working forward to explain why the classical additive model gives useful results, there is actually no paradox. An integrated approach using population genetic studies, immunology and molecular virology offers a particularly promising route to establish the elusive role of EBV in MS pathology, as EBV is a large and complex virus and its latency, dysregulated in most EBV-related pathologies, is hard to study in vivo. This approach may offer a route to prevention of MS altogether.

The interaction between Epstein–Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities

“…A combination of the HLA‐DRB1*1501 allele (the strongest genetic risk factor for MS identified by GWAS) and EBV infection increases the risk of developing MS by up to five times compared to either factor alone, 14,75,76 suggesting a synergic link between EBV molecular processes and MS risk genetic background 17 . Considering that B cells are the most common reservoir for EBV and EBV infection is a strong risk factor (32‐fold) for the development of MS, 14 it has been postulated that there is likely to be an interaction between EBV molecular processes and those MS risk loci which are active in B cells and drives (causality) or at least contributes to (near causality) MS pathogenesis 14,77 . In fact, the therapeutic benefit of targeting B cells may be a result of reducing the impact of EBV within these cells, although this has not been definitively proven.…”

“… 17 Considering that B cells are the most common reservoir for EBV and EBV infection is a strong risk factor (32‐fold) for the development of MS, 14 it has been postulated that there is likely to be an interaction between EBV molecular processes and those MS risk loci which are active in B cells and drives (causality) or at least contributes to (near causality) MS pathogenesis. 14 , 77 In fact, the therapeutic benefit of targeting B cells may be a result of reducing the impact of EBV within these cells, although this has not been definitively proven.…”