3.5 The initiation and prevention of MS (Ascherio et al. 2012)

Question 1

3 environmental factors for MS

Answer 1

1. Infection with Epstein Barr virus (EBV)
2. Low levels of vitamin D
3. Cigarette smoking

These factors could account for a large proportion of cases in the regions of highest MS incidence, and thus provide a promising foundation for MS prevention.

Question 2

Genetics and environment

Answer 2

Primarily a disease of young adults, prevalence peak in individuals in late 20s and early 30s –> decline, becoming rare at 50+ years.
- High heritablility (siblings= 20 to 40 times the risk)
- Genetic risk: HLA-DRBI*1501 allele
- 80-90% of MS pat’s have negative family history.

Question 3

Migration

Answer 3

There is a change in MS risk with migration from a high latitude region to a low latitude region.

They younger the age at immigration, the lower the risk, which suggests that environmental exposure early in life could be important in determining MS risk.

Question 4

Epstein-Barr virus (EBV)

Answer 4

Ook wel human herpesvirus 4= a ubiquitous double-stranded DNA virus that is transmitted primarily via saliva.

Infection with EBV is common and usually asymptomatic in the first years of life, but often causes infectious mononucleosis (IM) when the infection occurs in adolescence or adulthood.
This is often the case in countries with higher socio-economic status and hygiene.

Early EBV exposure is common in the tropics and low-income countries, which means that IM is rares in these areas.

The risk of MS is 2 to 3 times higher in people with a history of IM.
So, older age at EBV infection is a risk factor for MS.

Question 5

Hygiene hypothesis

Answer 5

Good hygiene in childhood is the most common link between IM and MS. This suggests that EBV-negative people should have high MS risk, but MS risk is actually extremely low in them.

This doesn’t contradict the hypothesis: increase hygiene and thus reducing exposure to infections in early childhood can only increase the risk of MS after EBV.

Relation of EBV and MS= even though infection increases the risk of MS, most people with the virus do not develop MS.

Question 6

Potential mechanisms

Answer 6

Mechanisms of MS and EBV are not understood.

Possible scenarios:
- Activation and expansion of autoreactive T cells and B cells during infectious mononucleosis (syndrome of strong immune activation), or EBV-mediated immortalization of B cells, which leads to autoantibody production and antigen presentation to pathogenic T cells.
- The constant re-stimulation of cells by autoimmune tissue inflammation may contribute to MS.
- In EBV, anti-EBNA antibodies are developed that cause higher MS risk.

Question 7

Implications for prevention and treatment

Answer 7

• In theory: a vaccine that confers strile immunity to EBV could protect against MS, but such a vaccine is not under development.
• MS risk can be reduced by voluntary early exposure of children to EBV
• DNA polymerase inhibitors: target lytic infection but not latent infection

Question 8

Vitamin D

Answer 8

Geography of MS correlates stronily with the duration and intensity of UV radiation from sunlight, which is the primary source of vitamin D.

MS is less common among coastal populations that have greater exposure to UV light and a higher intake of fatty fish.

Study: MS risk was 31-40% lower in women who regularly took vitamin D.

Question 9

Serum 25(OH)D levels

Answer 9

Directly reflect vitamin D status.

Optimal vitamin D levels are at least 75 nmo/L and low levels of vitamin D are usually <30nmo/L.

One study: strongly suggests that high levels of serum 25(OH)D in young adults could reduce MS risk, independently of vitamin D status during childhood.

Question 10

UV light exposure

Answer 10

UV light has also direct effects on the immune system.

The lower MS risk among individuals with high levels of 25(OC)D is mediated by vitamin D, rather than other effects of UV light.

Question 11

Mechanisms of vitamin D

Answer 11

• Statistically sign increase from 5% to 6% in the proportion of regulatory T cells was observed when given vitamin D supplements
• Reductions in anti-inflammatory cytokine production and MHC presentation by antigen-presenting cells.
• Also enhancing effect on microbicidal responses and ability to reduce risk of respiratory infections, which are known triggers of MS relapses and may have some influence on MS risk.

Question 12

Cigarette smoking

Answer 12

MS risk in smokers is 50% higher, and risk is directly associated with smoking duration and intensity.

The relative risk of smoking inmen compared to women is 2:7.
Women are smoking more, as men are smoking less.
This might explain the increasing female:male ratio in MS.

MS progresses faster among smokers.

Question 13

Mechanisms cigarette smoking

Answer 13

• Effects on demyelination
• Disruption of the blood-brain barrier
• Immunomodulatory effects (stimulates/supresses immune system)
• Increased nitric oxide and nitric oxide metabolites

The observation that tabacco smoking, but not Swedish tabacco snuff, is strongly associated with an increased MS risk, suggests that combustion or inhalation are required for toxicity.

Question 14

Integration of risk factors

Answer 14

EBV or markers of immune response to EBV, insufficient vitamin D and smoking independently increase MS risk.

The strongest non-genetic risk factor for MS is the level of anti-EBNA antibodies.

MS risk can be reduced by vitamin D supplements, smoking cessation and exposing children to EBV.
Exposing children to EBV however is not a desirable solution.