EBV and MS

EBV and Multiple Sclerosis

Research into the etiology of multiple sclerosis (MS) has revealed several risk factors. Prior infection with Epstein - Barr virus (EBV), specifically infectious mononucleosis, is one of the strongest associations (RR=2 compared to general population).  People with MS are more likely to be EBV seropositive (>99%) than healthy controls (85-95%). This pertains to pediatric onset MS as well:  around 5% of MS occurs before the age of 18 years. In this group, over 80% of cases had serological evidence of past EBV infection compared with 42-64% of age matched controls. This would seem to indicate that prior infection with EBV is a significant risk factor, but not a prerequisite for MS, as previously supposed.

One nefarious quality of EBV infection is the virus’s ability to down-regulate antigen presentation on APCs. With low expression of antigen peptides, T cells have limited activation. This was demonstrated using lymphoblastoid cell lines. Yet there is something different about B cells of MS patients. In vitro, EBV infected B cells of MS patients have a higher rate of spontaneous immortalization than EBV infected B cells of controls.

HLA subtype, specifically HLA DRB1*15 is also associated with a higher risk of MS. This appears to be additive with prior EBV infection. Those individuals with this HLA subtype and history of IM have a ten-fold higher risk of MS than person who are DRB1*15 negative and have no history of IM.

There appears to be a dose-response relationship, with higher titers of EBV specific antibodies associated with an increased risk of developing MS.  Antibodies to EBV nuclear antigen-1 have the highest odds ratio. Among pediatric MS patients, one epitope was disproportionally represented when compared to their parents and siblings. This epitope has already been linked with the highest MS risk in adults: the combination of being HLA-DRB1*15 positive and having increased antibody reactivity to this segment was associated with a 24 fold increased risk for MS!

Vitamin D has also been linked to EBV and MS risk. Epidemiologic data has shown that pediatric patients with vitamin D level greater than 75 (defined as “sufficient”) have greater levels of anti-EBNA1 than controls. If causal, the mechanism likely involves the Vitamin D Response Element (VDRE) at the promoter region of vitamin D responsive genes.

Together these offer clues to the pathogenesis of multiple sclerosis, but the true picture of susceptibility is undoubtedly much more complex.

Lucas, RM, Hughes, AM et al. Epstein-Barr Virus and multiple sclerosis. J Neuro Neurosurg Psychiatry 2011; 82:1142-1148.