Professor Feature — The Multiple Sclerosis Mystery: Closer to an Answer
Dr. Devin Stauff
Most of us know that smoking cigarettes is a major risk factor for developing lung cancer and that a coronavirus causes COVID-19. Many of us assume that scientists have figured out the cause of most of the important diseases out there. However, there are still many diseases without a known cause. Linking up disease with risk factors or causative agents is essential when it comes to preventing disease.
One particularly devastating disease without a definitive cause is the autoimmune disease multiple sclerosis (MS). In healthy individuals, the immune system only attacks invaders like viruses and bacteria. In MS, the immune system loses its ability to differentiate ‘self’ from ‘non-self’ and starts attacking components of the cells in our central nervous system that form the protective myelin sheath around nerve cells. This causes permanent damage to the nerves, leading to a host of symptoms including numbness, weakness and even paralysis. With an estimated global prevalence of about 35 cases per 100,000 people, MS affects many lives (1). Studies point to risk factors including being female, having a family history of MS, and even living in high or low latitudes with low year-round sunlight. What is missing is a single dominant predisposing factor that points to a means of treating or preventing MS.
One risk factor for MS that has been discussed in the scientific literature since the early 1980s is somewhat surprising: infection with Epstein-Barr virus (EBV), the cause of infectious mononucleosis or ‘mono’ (2). EBV is a highly infectious virus that is transmitted by saliva. It infects B cells and usually causes minor or asymptomatic infection. It also infects most of us by the time we are adults and is associated with several rare malignancies. Although many excellent studies across the past four decades point to a connection between EBV infection and MS, one challenge when it comes to determining whether there is a causal link is the fact that nearly everyone becomes infected with EBV by adulthood. How can you link infection with disease if almost everyone has been infected but not everyone has the disease? One way would be to perform a ‘longitudinal analysis’ by determining whether people who develop MS had become infected with EBV recently before their MS diagnosis. But how are you going to do this if you rarely know when someone became infected with EBV in the first place? You can’t go back in time to collect blood samples in the years before their MS diagnosis.
A recent paper published in the journal Science in January 2022 solves this conundrum using a brilliantly designed experiment and the perfect data set (Bjornevik et al., Science 2022; 3). Here, the authors collaborated with the US military to track health data of military personnel. The authors focused on recruits that developed MS during the tracking period. They were then able to determine their EBV infection status before and after diagnosis. To do this, the authors took advantage of the fact that all US military recruits are screened for infection with human immunodeficiency virus (HIV) at the beginning of their service and every other year afterwards. Serum from these blood draws is archived; this allowed the authors to pull samples of serum out of the freezer and test for anti-EBV antibodies to determine whether incoming recruits who developed MS were EBV negative before their diagnosis and, if so, whether their MS diagnosis coincided with the recruits becoming EBV positive. Most importantly, their sample size was over 10 million individuals; they needed a huge sample size because of the low prevalence of EBV-negative individuals and the low prevalence of MS.
Their data are striking. Out of the 10 million recruits included in the study, 801 individuals with adequate prior serum samples were diagnosed with MS. Of these, only 35 were EBV-negative at their first blood draw. 34 of the 35 became infected with EBV by the third blood draw; all 35 eventually became infected with EBV before they were diagnosed with MS. The length of time between EBV infection and MS onset was always less than 10 years (median = 5 years). Importantly, in the control group (initially EBV-negative individuals who never developed MS), only about half became infected with EBV. These data allowed the authors to calculate a ‘hazard ratio’: According to their data, you are 35-fold more likely to develop MS if you have been infected with EBV. This is an exceptionally large hazard ratio, one that is in the ballpark of the hazard ratio for the development of lung cancer in individuals that smoke a pack of cigarettes every day for 16+ years (4).
The argument could now be made that MS should be thought of as one of many post-infection ‘sequelae’ — pathological conditions that appear months, years, or decades after an infection. Indeed, several other autoimmune or autoimmune-like diseases have turned out to be sequelae associated with infectious agents. For instance, Campylobacter infection predisposes individuals to the neurological disease Guillain-Barré syndrome and Streptococcus pyogenes infection can lead to rheumatic heart disease. How is it that a virus like EBV can cause the immune system to attack your nervous system? One possibility is something known as ‘molecular mimicry’, a process whereby pathogens produce factors that mimic their host in an effort to cloak or camouflage themselves and appear more host-like. When the immune system does kick in, host molecules are caught in the crossfire, causing autoimmune disease. There is evidence for this type of mechanism in MS (5).
Knowing that EBV infection plays a dominant role in the development of MS is important for understanding and possibly preventing MS. However, keep in mind that nearly everyone in the World becomes infected with EBV but relatively few develop MS. Now the question shifts from “What causes MS?” to “What causes only a few people with EBV to develop MS?”. Perhaps unique aspects of the course of EBV infection or a person’s immune response to the virus play a role in predisposing someone to MS. It is also possible that the many other risk factors associated with MS exert their activity on the immune system and its response to EBV, tipping the response towards autoimmunity in certain individuals. More research needs to be done to answer this question.
Are there any practical applications to this work? The most obvious would be to develop an EBV vaccine. If such a vaccine is effective at preventing EBV infection, it could dramatically decrease the incidence of MS, similar to how the measles vaccine reduced the incidence of a deadly neurological condition associated with naturally acquired measles (6). In fact, the biotech company Moderna (the same company that developed one of the coronavirus vaccines) has developed an mRNA-based EBV vaccine and initiated phase I clinical trials in January 2022 (7). However, it is unlikely that an EBV vaccine will move at the incredible pace of Moderna’s COVID vaccine. As we’ve seen, MS is relatively rare and there is typically a gap of several years between EBV infection and the onset of MS, so it could be a decade before anyone knows whether the vaccine prevents MS. Nonetheless, the firmly established EBV-MS link means that this strategy is feasible and could dramatically decrease the incidence of a devastating neurological disease sometime in the future.
References:
1. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, Robertson N, La Rocca N, Uitdehaag B, van der Mei I, Wallin M, Helme A, Angood Napier C, Rijke N, Baneke P. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020 Dec;26(14):1816–1821. doi: 10.1177/1352458520970841. Epub 2020 Nov 11. PMID: 33174475; PMCID: PMC7720355.
2. Warner HB, Carp RI. Multiple sclerosis and Epstein-Barr virus. Lancet. 1981 Dec 5;2(8258):1290. doi: 10.1016/s0140–6736(81)91527–0. PMID: 6118702.
3. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296–301. doi: 10.1126/science.abj8222. Epub 2022 Jan 13. PMID: 35025605.
4. Hansen MS, Licaj I, Braaten T, Langhammer A, Le Marchand L, Gram IT. Sex Differences in Risk of Smoking-Associated Lung Cancer: Results From a Cohort of 600,000 Norwegians. Am J Epidemiol. 2018 May 1;187(5):971–981. doi: 10.1093/aje/kwx339. PMID: 29087432.
5. Kuerten S, Lanz TV, Lingampalli N, Lahey LJ, Kleinschnitz C, Mäurer M, Schroeter M, Braune S, Ziemssen T, Ho PP, Robinson WH, Steinman L. Autoantibodies against central nervous system antigens in a subset of B cell-dominant multiple sclerosis patients. Proc
Natl Acad Sci U S A. 2020 Sep 1;117(35):21512–21518. doi: 10.1073/pnas.2011249117. Epub 2020 Aug 18. PMID: 32817492; PMCID: PMC7474673.
6. Griffin DE. Measles virus persistence and its consequences. Curr Opin Virol. 2020 Apr;41:46–51. doi: 10.1016/j.coviro.2020.03.003. Epub 2020 May 5. PMID: 32387998; PMCID: PMC7492426. 7. https://www.clinicaltrialsarena.co
