The initiation and prevention of multiple sclerosis

Abstract

Although strong genetic determinants of multiple sclerosis (MS) exist, the findings of migration studies support a role for environmental factors in this disease. Through rigorous epidemiological investigation, Epstein-Barr virus infection, vitamin D nutrition and cigarette smoking have been identified as likely causal factors in MS. In this Review, the strength of this evidence is discussed, as well as the potential biological mechanisms underlying the associations between MS and environmental, lifestyle and dietary factors. Both vitamin D nutrition and cigarette smoking are modifiable; as such, increasing vitamin D levels and smoking avoidance have the potential to substantially reduce MS risk and influence disease progression. Improving our understanding of the environmental factors involved in MS will lead to new and more-effective approaches to prevent this disease.

Figure 1

Time of Epstein-Barr virus seroconversion and multiple sclerosis onset in the 10 cases who were seronegative at baseline. Adapted from . These data are identical to, but presented in a different order than, origninal figure in . Vertical lines represent time of serum collection, blue circles mark the time of MS onset. The yellow bars represent the period of EBV seronegativity, and transition to green bars indicate seroconversion to EBV positivity.

Figure 2

Relative risk of multiple sclerosis by levels of EBNA IgG antibody titers. From

Figure 3

Potential mechanisms by which Epstein-Barr virus infection might contribute to the development of multiple sclerosis. Patients with MS show higher frequencies and activation states of self-reactive lymphocytes (red nuclei), in addition to impaired functions of regulatory immune compartments indicating a lower threshold for breakdown of self-tolerance to central nervous system (CNS) antigens. Strong innate immune activation during primary EBV infection (virions and viral DNA are depicted as red dots) could facilitate the activation and expansion of autoreactive and polyspecific (i.e. both autoantigen and viral antigen specific) T and B cells. These cells could be maintained in the presence of continuous antigen exposure. In addition, latent EBV infection confers B cell survival advantages and could rescue autoreactive B cells from apoptotic deletion during B cell development and differentiation. Homing of these rescued autoreactive lymphocytes, which have immunomodulatory and antigen-presenting functions on T cells, to the inflamed CNS might contribute to the immunopathology of MS.

Figure 4

In vivo effects in humans of vitamin D on the immune system observed in clinical trials. 25(OH)D level is that achieved with the vitamin D3 supplementation given in the trial. Yellow: ; Red: ^, ; Blue: ; Green: ; Pink: ; Orange: .

Figure 5

A) Change in prevalence of smoking behavior in men and women in Canada by birth cohort; B) Changing female:male sex ratio of multiple sclerosis by birth cohort observed in Canada and that expected from changing smoking behaviors, assuming a relative risk of smoking on MS among men=2.7. Adapted from .

Figure 5

A) Change in prevalence of smoking behavior in men and women in Canada by birth cohort; B) Changing female:male sex ratio of multiple sclerosis by birth cohort observed in Canada and that expected from changing smoking behaviors, assuming a relative risk of smoking on MS among men=2.7. Adapted from .