Genetic and environmental risk factors in multiple sclerosis

Question 1

Why does the geographical distribution of multiple sclerosis hints towards involvement of environment?

Answer 1

MS varies geographically, the more you move away from the equator the bigger the chance of having MS
The northern hemisphere is the most affected => lack of vitamin D and UVB radiation (vitamin D can actually prevent MS from happening)

Question 2

Is time an important factor for the geographical distribution of multiple sclerosis?

Answer 2

Yes => much bigger risk of having MS if you move to a riskier area before the age of 15

Question 3

What is the viking theory in multiple sclerosis?

Answer 3

=> genetic component to MS

• Origins traced back to the Vikings who colonized Northern Europe where MS isvmost pronounced
• ‘Viking genes’ make people particularly susceptible to MS
• MS carried by European colonists and settlers to North America, Australia and New Zealand

Question 4

Does multiple sclerosis run in families?

Answer 4

Yes

Question 5

Is there a variation in risk of multiple sclerosis between ethnic groups?

Answer 5

Yes, northern europeans are much more at risk

Question 6

What is the ratio of heritability of multiple sclerosis?

Answer 6

1/3 = environnement 
2/3 = genetics

Question 7

What are the 3 environmental risk factors that we are sure plays a role in multiple sclerosis susceptibility?

Answer 7

1. Anti-EBNA IgG seropositivity (latent mononucleosis)
2. Infectious mononucleosis
3. Smoking

Question 8

With what does anti-EBV nuclear antigen 1 (EBNA1) has sequence similarity and what does that cause?

Answer 8

• The sequence similarity is with anoctamin 2 (ANO2), expressed in human brain
• It causes an ANO2 reactive epitope
  => molecular mimicry

Question 9

How much does smoking increase the risk of multiple sclerosis, can it get better and what is the difference with Snuff?

Answer 9

Increase risk of 50-60%
If stoped, ex-smokers get better after 5 years => meaning that there is something that is actively susceptible to MS
But Snuff has a protective effect on MS => probably because it is not nicotine itself that is bad but the smoke

Question 10

Which type of antigen presentation is associated with multiple sclerosis?

Answer 10

MHC class 2

Question 11

Is there an interaction between environmental and genetic risk factors for multiple sclerosis?

Answer 11

Yes, there is a synergic interaction between smoking and the DRB1 gene (risk gene)

Question 12

How does smoking contribute to multiple sclerosis risk?

Answer 12

Smoking causes pro-inflammation which leads to T-cell receptors to recognize unknown antigens and break of tolerance

Question 13

What are the hypothetical mechanisms of action for vitamin D in multiple sclerosis?

Answer 13

• Dampens activation of myelin-specific Th1 and Th17 cells that drive CNS inflammation
• Attenuates demyelination and induce re-myelination
• Stimulates microglia activation => promotes clearance of myelin debris and favors re-myelination

Question 14

What can be said on the risk factors going through the threshold to cause multiple sclerosis?

Answer 14

To go through the MS threshold it will take a combination of risk factors, no risk factor can cause it alone