There are three general disease patterns that may be classified as MS phenotypes. Upon initial onset of the disease, the majority of patients^[9] will be classified as relapsing-remitting multiple sclerosis (RRMS). Disease progression between periods of relapse is usually minimal, although the attacks themselves can cause a person to become more disabled.

Secondary progressive multiple sclerosis is usually seen as an initial RRMS diagnosis, but unlike RRMS, these patients will see a gradual worsening of symptoms (some of which are shown in Figure 3) with or without relapses. The third pattern, primary progressive multiple sclerosis, is a steady increase in disability from disease onset and has the worst prognosis. This accounts for about 10% of MS cases^[10] from initial diagnosis. While vitamin D supplementation may be a viable treatment option for all of these MS subtypes, the efficacy is not well understood. Current and pending trials are primarily looking at people with RRMS, as it is the most common diagnosis.

Symptom prevalence in MS

Reference: Richards et al. Health Technol Assess. 2002.

While more than 100 genes^[11] have been associated with MS, it is hard to say just how predictive these markers are without taking into account environmental and lifestyle variables. Someone carrying the genes associated with increased risk of MS may never develop the disease. Alterations in the HLA-DRB1 gene^[12] have shown the strongest associated genetic risk factors for MS. HLA-DRB1 genes play a role in the immune system, which may help to explain why the pathology of the disease is closely tied to dysfunction of certain immune system components like interleukin-17. Currently, there are no reliable tests available for predicting the risk of MS. While ensuring adequate vitamin D levels is always a good idea, there is no conclusive evidence that it can decrease the risk of developing MS.

While there are theories that MS prevalence is related to lifestyle factors, such as vitamin D status, other researchers have examined the disease through the lens of the “hygiene hypothesis”, the popular idea that modern society’s germophobia and obsession with sanitation have caused immune systems to overreact and develop allergies or autoimmunity.

Some researchers believe that humans have altered the natural environment for^[13] the billions of bacteria living in our guts in a quest for cleanliness. It is possible that this altered microbiome is associated with the increase in some autoimmune diseases that has been observed over the past half century.

Furthermore, it has been established that there is a gut-brain connection^[14] between microbiota and the central nervous system (CNS), and cross-talk between them affects a wide variety of bodily processes, from food intake to mood. Researchers have also shown a clear link between manipulation of gut microbiota in mice and the development and progression of experimental autoimmune encephalomyelitis (EAE), a disease induced in mice to study CNS inflammation and degeneration similar to that experienced by humans with MS. As shown in Figure 1, germ-free mice and those treated with antibiotics experienced delayed onset of EAE. Additionally, mice fed oral probiotics experienced varying effects on disease progression, both beneficial and harmful, depending on the strain.

Figure 1: Mice and EAE, non-probiotic observations

Reference: Wang, Y, Kasper, L. Brain Behav Immun. 2014 May.

However, successful pharmacological mouse treatments extended to human trials have had mixed results. While a few were effective, some exacerbated illness in study participants.

Epstein-Barr virus (EBV) is an incredibly prevalent virus that infects over 90% of people globally. It is most commonly known for causing infectious mononucleosis, also called “mono”.^[15] Research has found mounting evidence of a connection between EBV and MS, most notably some that suggests EBV may be an important trigger for MS onset. A 20-year epidemiological study of over 10 million U.S. military personnel found that EBV infection was associated with a 32-fold increased risk of developing MS.^[16] Using multiple blood samples drawn both before disease onset and afterward, the researchers found that early markers of MS disease activity consistently began after EBV exposure, but not before. Out of the entire cohort, 955 people were diagnosed with MS and only 1 person did not demonstrate a history of EBV infection (indicated by a lack of EBV-specific antibodies in the blood). This is in line with previous research finding that over 99% of people with MS had EBV-specific antibodies.^[17]

Further supporting the link between EBV and MS is the finding of several cross-reactive antibodies that attack both EBV proteins — most notably EBV nuclear antigens (EBNA) — and central nervous system proteins involved in MS.^[15][18][19] This is a phenomenon called molecular mimicry, which is when a molecule from a foreign invader (in this case, EBV) looks very similar to a molecule in the human body and therefore antibodies generated against the virus may also inappropriately attack human tissues. These EBNA-specific antibodies have been found to be elevated in people with MS compared to people without the disease and are associated with an increased risk of MS development.^[20]

So, why is MS so uncommon when EBV is so prevalent? This likely depends heavily on genetics, particularly variations in the gene HLA-DRB1.^[15] This gene controls how viral proteins are presented to the immune system upon infection, which may promote the generation of cross-reactive antibodies, meaning that many people who are infected with EBV won’t necessarily generate them. There is also evidence that other genetic variants that affect how the immune system responds to EBV may play a role.^[21]