Multiple Sclerosis
patients, the mean 25(OH)D level was 43nmol/L, which is in the insufficient range for bone health.45
A Finnish study reported that mean
25(OH)D levels during the summer (June through September) were significantly lower in newly diagnosed MS patients compared with healthy individuals living in the same region (58 ± 3nmol/L versus 85 ± 8nmol/L; p=0.022).46
An Australian study of 145 adult
Viral Exposures Background
Three studies have reported that 25(OH)D levels in adult MS patients are lower at times of relapse compared with periods of clinical disease remission.46–48
Finally, vitamin D concentrations have also been variably linked to MRI evidence of MS disease activity.47,51
Pathobiologic Insights
The effects of vitamin D in the experimental autoimmune encephalomyelitis (EAE) animal model of MS provide insight into the role of vitamin D in MS biology. In this model, injection of 1,25-dihydroxyvitamin D [1,25(OH)2D] prior to disease induction can prevent the clinical manifestation of symptoms and the development of characteristic pathologic lesions.51,52
If given at the onset of clinical
symptoms, treatment with 1,25(OH)2D resulted in an improvement of clinical symptoms,53
with more of an effect in female animals.54 The
mechanisms that underlie these observations may involve vitamin D-mediated interleukin-10 (IL-10) cellular signaling pathways,55 monocyte CNS entry or accumulation,56,57 cell apoptosis.58
reduced or induction of inflammatory
There have been conflicting reports of the ability of UV light exposure prior to EAE induction to prevent clinical symptoms in this model.59,60
In human cell cultures, 1,25(OH)2D modulates monocyte functions, including antigen presentation, inhibits autoreactive T-cell activation by dendritic cells, and induces the action of regulatory T cells.61–63 Production of pro-inflammatory cytokines such as interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and IL-2 are inhibited by 1,25(OH)2D, whereas levels of anti-inflammatory cytokines such as IL-10 are enhanced.48,61,63–69
Vitamin D-related Genetics
Several MS susceptibility loci have been identified in the human genome, with the most robust association being with specific alleles of the human leukocyte antigen (HLA) locus on chromosome 6.70
Recently,
a vitamin D response element (VDRE) was found in the promoter region of HLA-DR1 that was absolutely conserved in HLA DRB1*15 haplotypes, the major genetic risk haplotype for MS.71
Vitamin D receptor binding
sites have now been identified in 2,776 locations across the human genome, affecting the expression of 229 genes, including loci implicated as risk genes for MS.72
These studies provide an interesting conceptual
means whereby genetic susceptibility and environmental exposures may interact to increase MS risk.
98
A recent meta-analysis that included a total of 18 case-control and prospective cohort studies found that the risk for adult-onset MS is particularly high for individuals that have experienced clinical IM with a combined relative risk for 2.17 (95% CI 1.97–2.39).83
Similarly, in a
Canadian cohort of 14,362 individuals with MS and 7,671 spousal controls, people with MS were twice as likely to report a history of clinical IM than their spousal controls (OR 2.06, 95% CI 1.71–2.48).84
A
model has been proposed in which adult-onset MS risk is negligible in individuals not exposed to EBV, is intermediate in those with serologic evidence of remote EBV infection without clinical signs, and highest in those individuals who have experienced IM.85
US NEUROLOGY
EBV seropositivity appears to increase greatly the risk for adult-onset MS. A nested case-control study of US military personnel identified 10 initially seronegative patients with an eventual diagnosis of MS and 32 seronegative controls who did not develop MS. During the follow-up period, all 10 individuals who developed MS became seropositive for EBV prior to onset of clinical symptoms of MS, with an estimated mean time between primary EBV infection and MS diagnosis of 5.6 years (range 2.3 to 9.4 years). In this study, no person who remained seronegative for EBV developed MS in adulthood.78
Four prospective studies have shown that in EBV seropositive adults, the likelihood of future MS diagnosis increases as a function of higher concentrations of anti-EBNA complex and EBNA1 antibody titers.79–82
A study of 110 children with either a first attack of demyelination or established MS, reported a mean 25(OH)D level in this cohort of 57.3nmol/L (22.9ng/L) and found that each 25nmol/L increase in adjusted 25(OH)D level was associated with a 34% reduction in number of subsequent relapses (incidence rate ratio of 0.66, 95% CI 0.46–0.95).50
patients with relapsing–remitting MS (RRMS) showed a small but statistically significant inverse relationship between serum 25(OH)D level and risk for relapse in the subsequent six months with a hazard ratio of 0.91 (95% CI 0.85–0.97) for every 10nmol/L increase in serum 25(OH)D.49
The powerful impact of infection on host immune behavior, the frequent similarity in structure of microbial proteins and human tissue antigens, and the noted difference in host response to specific pathogens as a function of age at exposure has led to many hypotheses linking MS and infection. The general upregulation of immune responses to any infection has been considered as potentially important in increasing the likelihood of MS relapse.73
However, it could be argued that the most
compelling link between MS and a specific pathogen exists for Epstein–Barr Virus (EBV).
EBV is a DNA virus in the herpes group that has a widespread geographic distribution and infects more than 90% of individuals by adulthood.9,74,75
Primary infection is often asymptomatic in younger children, but when infection occurs later in childhood or adolescence the result is clinical infectious mononucleosis (IM) in 40–50% of cases. Following a primary infection, EBV remains latent in B cells and persists throughout life. In tonsils, the virus can periodically become reactivated, resulting in viral shedding and transmission may then occur to other individuals through infected saliva. EBV expresses viral capsid antigen (VCA) and early antigen (EA) during active infections, and the EBV nuclear antigen (EBNA) 1–6 and latent membrane protein (LMP) 1, 2a, and 2b during chronic infections.9,76
Epidemiology
Similarities in the geographic distribution, age at onset, association with socioeconomic status (SES), and predilection for individuals of particular ethnicities between IM and MS first raised the idea that EBV could be involved in MS pathogenesis.9,74,77
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