The prevalence of MS is not equally spread around the world, and is associated with latitude. Apart from some exceptions such as Sardinia, people living more closely to the equator are less likely to develop MS. Strikingly, when an individual moves before the age of 15 years old from for example Kenia (low MS prevalence) to the UK (medium MS prevalence), it will acquire the MS risk of his new home country. As the genetics of this individual obviously did not change, these migration studies are one of the most convincing arguments in favour of environmental factors as a trigger for MS. In addition, most countries have experienced a distinct increase of MS prevalence among women in the past few decades. This increase has been too fast to be explained by changes in genetic composition which take millions of years. Therefore, the increased prevalence of MS among women is likely to be explained by changes in lifestyle and environmental factors affecting women. Understanding environmental triggers is key in the light of MS prevention.
The usual suspects when it comes to environmental risk factors are:
- Smoking (passive and active): The more you smoke, the higher your future risk of MS becomes. The underlying hypothesis is that smoking-induced lung irritation triggers aberrant immune responses.
- Low vitamin D levels: Low vitamin D levels are the consequence of insufficient sun exposure, which is – for obvious reasons – more frequent when moving further away form the equator. Vitamin D is known to have an immune-regulatory function and is thus able to tone down inflammation.
- Adolescence obesity: The association is most strongest for a body mass index above 27. The most common explanation for this observation is the fact that obesity is characterized by a low-grade inflammation: increased levels of pro-inflammatory mediators are produced in fat tissue.
- Infectious Mononucleosis (caused by Epstein Barr Virus/EBV): Although EBV infection is very common in the general population, there is now more and more evidence that all pwMS have encountered the pathogen before ultimately being diagnosed. Some of the EBV proteins resemble myelin proteins leading potentially to aberrant immune responses.
Importantly, all of these lifestyle and environmental factors can be traced to their effects on the immune system (similar to the genetic risk factors) which strongly supports the argument that the peripheral immune system (B cells, T cells) has a primary role in driving MS. In addition, you can imagine that when Audrey would move from Kenia to the UK at the age of 10, she would would be much more likely to have started smoking in her teens, more likely to have gained some extra pounds fuelled by ‘Breakfast at Dunkin’ Donuts’ and less likely to have played outside catching sunrays. “La vie en rose!”
A new study from Xu et al. now adds another environmental risk factor to this list. In the walhalla of nation-wide studies Sweden, Xu et al. looked at whether any infection requiring hospital admission before the age of 20 years old would translate into a higher MS risk later in life. Interestingly, they found that only infections between the age of 11 and 19 years old conveyed into a higher risk of MS as opposed to infections before the age of 10. When analysing the infections according to site, especially infections of the central nervous system (e.g. meningitis) and respiratory infections (eg. pneumonia) could be linked to future MS risk. When analysing the infections according to the type of infection, especially bacterial infections and EBV were linked with future MS risk.
These are very interesting observations. However, there is no explanation (yet) on why for example brain infections in early life would increase the risk for MS later onwards. Potentially, an inflamed, leaky blood brain barrier would facilitate immune reactions against brain constituents such as myelin. It’s also unclear why the risk is mainly apparent between 11 and 19 years old and not before. From a mechanistical point of view, this age difference is not logical. Potentially, there is a lower threshold to register non-specific infectious events in babies/early life? Most importantly, the study does not answer the question whether mild versus serious and single versus multiple infectious events matter when it comes to your future MS risk. Does your future risk of MS increase when you have multiple pneunomia admissions compared to a single one? Do you need to be infected with EBV (which triggers a pro-inflammatory immune state) before the risk-increasing effect of other infections becomes relevant? What about the additive effect of for example adolescent obesity? This is what we could call the environmental domino-effect, and refers to the cumulative MS risk if one environmental factor (e.g. smoking, EBV) would be required to open up your immune system to potential damaging effects of other environmental triggers (eg. infection)? And remember: happy domino’s are the prettiest!
Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Brain. 2021 Mar 9;awab100. doi: 10.1093/brain/awab100. Online ahead of print.
Yin Xu 1, Kelsi A Smith 2 3, Ayako Hiyoshi 1, Fredrik Piehl 3, Tomas Olsson 3, Scott Montgomery 1 2 4Affiliations expand
- PMID: 33693538
- DOI: 10.1093/brain/awab100
The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections, such as of the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20 years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970-1994 were identified using the Swedish Total Population Register (n = 2,422,969). Multiple sclerosis diagnoses from age 20 years and hospital-diagnosed infections before age 20 years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11-19 years) and earlier childhood (birth-10 years) was estimated using Cox regression, with adjustment for sex, parental socioeconomic position, and infection type. None of the infections by age 10 years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21-1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06-1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11-3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13-1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30-1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections.
Keywords: CNS; Infection; adolescence; multiple sclerosis.