Vitamin D supplementation and antibodies against the Epstein-Barr virus in multiple sclerosis patients

We read with great interest the recently published article by Salzer et al. in Multiple Sclerosis Journal that aimed to investigate the relation between circulating antibody levels against the Epstein-Barr virus (EBV), vitamin D and the risk of multiple sclerosis (MS). 1 In particular, the authors have further strengthened the known positive association between antibodies against the EBV antigen EBNA1 and the risk of developing MS later in life.1,2 Interestingly, the association was especially evident in younger individuals, in which an inverse correlation between anti-EBNA1 antibody and 25-hydroxyvitamin D levels was also found.1 Studies have shown that a poor vitamin D status is itself associated with an increased risk of MS later in life.3,4 We believe the findings of Salzer et al. are of great importance since they suggest the presence of a link between vitamin D deficiency and EBV infection in the aetiology of this complex disease. We collected serum samples from 15 relapsing– remitting MS (RRMS) patients who were supplemented with 20,000 IU/day vitamin D3 for 12 weeks.5 We measured their circulating antibody levels against EBNA1 using the Liaison® quantitative chemiluminescent assay.6 We found that the initial antibody levels (mean=77.98, SD=37.16) were significantly reduced after vitamin D supplementation (mean=62.27, SD=28.05) (mean difference=15.72; 95% confidence interval (CI)=3.37–28.07; paired T test p=0.016). The effect of vitamin D was particularly strong in those patients with the higher antibody levels, and a positive correlation was present between pre-supplementation antibody levels and their decrease following supplementation (Pearson’s rho=0.66, p=0.007) (Figure). It is important to note that this observation appears to be specific for anti-EBNA1 and/or for other specific antibodies, since we could not find any change in total immunoglobulin (Ig)-load and B cell differentiation profile after vitamin D supplementation in these patients.7 This study has several limitations. The inverse correlation between vitamin D status and EBV antibody titres observed by Salzer et al. was seen in individuals aged less than 26 years and with physiological vitamin D status. The 15 RRMS patients we studied were older (median=35.15, range=25.47–49.36), treated with beta interferon and reached supra-physiological levels of vitamin D. Despite these differences, our findings suggest that the negative correlation between vitamin D status and circulating antibody levels against EBV observed by Salzer et al. may not be a chance finding and that the link between these two factors could be causal. Notably, vitamin D has well-described antibacterial and antiviral roles and is able to modulate antibody production by plasma cells.8–10 Individuals with high serum vitamin D levels are also less likely to have EBV shedding in saliva.11 Furthermore, latitude is a major determinant of vitamin D status, and we have previously shown that EBV seroprevalence positively correlates with latitude in the MS as well as the general population.12 Finally, in relation to the potential therapeutic use of vitamin D in MS, we hypothesise that a stratification of MS patients based on baseline anti-EBNA1 antibody status may highlight differences in the immunological and perhaps also clinical response to vitamin D supplementation. We believe future studies are needed to understand how vitamin D influences the production of antibodies against EBV, the immune response against this virus and whether this mechanism is specific to EBV or shared with other viruses such as cytomegalovirus and varicella zoster virus. These studies will elucidate how these two environmental factors are linked in the causal cascade leading to MS and how we can program future effective strategies of disease prevention. 494494 MSJ191210.1177/1352458513494494Multiple Sclerosis JournalDisanto et al. 2013