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The immune system has an inherent contradiction in the way it functions – the major role of the immune system is to fight off the invasion of our bodies by bacteria, fungi, viruses and parasites; but in order to accomplish this, immune cells need to recognize our own tissues so that they can determine what is foreign when we have an infection.

In the case of T cells (the immune quarter backs as well as partly offense in the fight against infection) there are special receptors (T cell receptors, TCR) on their surface which recognize the major histocompatibility protein molecules (HLA) on surface of other cells they surveille. These HLA proteins are a genetic molecular signature which identifies our specific immune makeup (and there are a large variety of these molecules so it creates diversity, which helps boost resistance to infections and thus, helps us survive as a species). Recognition of these HLA molecules by the TCR, therefore, lets T cells recognize the signature of our own tissues. However, these HLA molecules also bind processed portions of proteins derived either from our own tissues or from foreign invaders and the TCR can read the signal from the combined molecules; but T cells are essentially activated only by the HLA/non-self – combination. So the duality of recognizing HLA with a signal from ourselves or from something else, allows us to have a safety check on T cells so that they go into action only against other organisms. If a T cell TCR recognizes a pathogen then the cell will go into action to defeat it. However, if T cells were to overreact to our own tissues then an autoimmune disease could result, as against just autoimmune recognition, which is a necessary phenomenon.

During our embryonic development T cells which react too strongly against HLA or our tissue molecules are eliminated in the thymus to prevent autoimmune disease (the Goldilocks principle). This process is incomplete and, therefore, a failsafe mechanism also exists where some T cells are trained to prevent other T cells from overreacting to produce an autoimmune disease. These are called regulatory T cells (Treg). It turns out that these cells, which also recognize our own tissues, may fail for a number of reasons and the result is over-reactivity to our own tissues beyond just recognition of our cells, and autoimmune disease may result. There is sufficient evidence that autoimmunity occurs in MS and some evidence points particularly to Treg not working properly, which results in a tissue specific autoimmune disease.

During the first 2 decades of our life the immune system develops and matures. Part of this process is driven by the infections we suffer as well as other types of environmental exposure. In fact, much of the way the immune system functions in adults is defined by these events. It is believed that one result of all these infections is enhancement of Treg function – so this helps in turn to prevent autoimmune disease. Similar to infections, a farm environment has both micro-organisms and other environmental stimuli which promote Treg – the result of 10,000 years of adaptation. Essentially, our immune systems became tuned to an inherently dirty and infection-ridden environment which characterized most of human history. With the advent of sanitation, better nutrition and vaccinations we now live in a cleaner world which does not challenge and define our immune systems (and particularly Treg) the way it did for eons.

The result of this environmental change has been an increase in the frequency of autoimmune diseases and allergies. This phenomenon has been most prevalent in the developed world but the rest of the world is catching up. In the case of allergies this process has been studied in children in the first 3 years of life. Investigators have been able to define that Treg function declines instead of increases as allergies develop in those children susceptible to them. The same faulty process is likely, with a longer time frame, in autoimmune diseases in adults such as MS. This phenomenon has been called “the hygiene hypothesis” of autoimmunity.

The prevalence (total presence) of MS in a population as well as the incidence (the number of new cases per 100,000 population per year) of MS has risen in parts of the world where MS is most common. And, MS might now be seen more frequently in developing areas of the world. Unfortunately, much of the medical literature has ignored these facts of immune function and has treated MS as some sort of mystery disorder instead as an autoimmune disease. While autoimmunity is not the only thing going on (progression is probably initiated by and results from inflammation but has its own trajectory of development) the data defining MS as an autoimmune disease are as solid as those for other conditions such as Type I Diabetes and Hashimoto Thyroiditis. Not only are populations in place affected by these environmental processes, but when migration before the age of 15 from areas of low prevalence to high prevalence occurs MS becomes more frequent in the migrant population (and the opposite is seen in movement from high to low prevalence areas, where the prevalence of MS in migrants goes down). Even migration from farms to cities in the same country increases the risk of developing MS. The pace of change is too rapid for genetic mutations (natural selection) to occur and produce these findings so it must be due to environmental change. Other than ancient Rome, the development of large cities with populations over 200,000 has only happened since the middle Ages and urbanization has accelerated even more recently driving this phenomenon.

Other factors which seem to affect the development of MS include order of birth (more in firstborn), obesity, diet (including the microbiome – the bacteria and viruses resident in the GI tract and modified by our diet) smoking, Vitamin D levels, sun exposure, temperate climates (MS is relatively uncommon in the Tropics than in more Northerly or Southerly Temperate zones. The infectious load including parasites is greater in the Tropics which might enhance Treg and protect from MS), number of child births and prior Infectious Mononucleosis (which is an immune mediated disease and perhaps a harbinger of things to come in some).

So it is no surprise that a recent paper has documented an increased incidence in Denmark (N Koch-Henriksen and others. Incidence of MS has increased markedly over six decades in Denmark particularly with late onset in women, Neurology 2018, Volume 90, Page 1001).

The incidence of MS (number of MS individuals per 100,000 population per year) was studied using data from 1950 to 2009 (Scandinavian health systems, like the Danish Multiple Sclerosis Registry, collect enormous amounts of health data which facilitates population studies). The analysis was done individually for women and men and groups from each decade were examined – e.g. 1950-1959 to 2000-2009. Overall the increase in incidence of MS was 114% in women and 30% in men over the 60yr period. The highest incidence occurred in women 50-64 years of age, suggesting that the provoking stimulus could either have occurred specifically later in life, or that an earlier stimulus for some reason took longer to have an effect on the development of MS. MS is seen more frequently in Scandinavian countries which are far North and the already high incidence might have made it easier to see the occurrence of change.

Not all of the factors related to MS could be evaluated in this study. Because this was a large study using available data, but not a direct evaluation of the immune system it is possible that the biological effects of specific factors could not be determined.

Smoking has been associated with an increased risk of developing MS as well as MS progression. Smoking decreased substantially in Denmark over the 60yr period evaluated and thus was not established as an overall cause of the increase in MS. This is interesting because smoking increases pro-inflammatory activity and may decrease Treg number and activity. If smoking contributed to the population’s development of MS there might have been a decline in incidence of MS in parallel with the decrease in smoking, rather than an increase over this period.

Obesity is associated with dysfunction of Treg activity in fat and generally in the body. We might have expected an increase in MS incidence as a result of rising obesity rates in Denmark. However, the time of onset of the increased incidence of MS preceded the increased rate of obesity in Denmark so increased obesity could not explain the findings.

A lack of sun exposure and low Vitamin D levels are associated with increased risk for developing MS as well as MS progression. Low Vitamin D levels in newborns is associated with a higher risk for MS, particularly if they are born in the winter. Vitamin D is a cofactor in inducing Treg but it does not work independently, and experimentally it requires the concurrent administration of cortisone. It is possible that Vitamin D has a different and more independent effect in newborns compared with adults, but there is no experimental evidence to show this. The incidence of MS did not correlate with month of birth so an effect of low Vitamin D at birth could not be confirmed in this study. Little attention has been given to evaluating the immunologic effect of sun exposure in MS. Sun exposure in and of itself will increase Vitamin D levels, but more importantly, exposure of skin to UV light promotes the development of Treg. These cells partly stay in skin but they also circulate and experimentally these cells can be seen to traffic to the brain. There have been no studies to determine if there is a differential effect of UV light on Vitamin D and Treg as far a controlling the immune system is concerned.

The incidence of Infectious Mononucleosis was not assessed in this study. In Scotland there has been a decline in Infectious Mononucleosis but there remains a very high incidence of MS (more so than the rest of the UK). This would argue against Infectious Mononucleosis contributing to the development of MS in the Scottish population, and possibly also in Denmark.

This study adds to previous ones and confirms the increased incidence of MS in many countries. It also demonstrates both the strength and the weakness of epidemiological studies which observe the occurrence of change or of different conditions in a population without actually examining the biological basis for the phenomena studied. It is surprising that some of the factors associated with the development of MS were not supported by the findings of this study. It is possible that the effects of these associated factors are only operative in a smaller subpopulation, and the effect of factors with influence on the development of MS would not have been revealed by looking only at the whole group.

The effect of infections on the development of MS was not assessed in this study. Thus, events with potentially a major impact on MS might not have been evaluated. It would have been important to determine whether there was a decline in infections over the 60yr time period, and if so, which infections were impacted. If infections were shown to decline along with the increase in MS, then the predictions of the hygiene hypothesis might be applicable to the causation of MS.

While the population gene pool in Denmark would not have changed greatly over the time studied, the interaction of certain genes with a changed environment might indicate a stronger genetic influence on MS than we had previously suspected. Given that there are many genes which have an association with MS, and given that the occurrence of these genes is higher in an already MS susceptible population, then an investigation of these factors might have been fruitful and have enlarged our understanding of both the impact of genes and environment on MS.

So, as we learn something new in science about MS, it provokes us to ask more questions, to dig deeper, in order to ultimately allow us to fully grasp what actually is going on.

What we critically need is to develop more experimental biologically based approaches to open up and expand our understanding of the cause of MS based on hard scientific data.

That is our mission at MSRI!