The MS-mononucleosis link
It has long been suspected that multiple sclerosis is caused by a virus, although there are several versions of the theory. It has been suggested that MS is directly caused by a virus, in the way that polio is. An alternative suggestion is that the body’s immune reaction to a viral infection is somehow different in people who develop MS compared to those who don’t.
High on the list of the usual suspects is the Epstein-Barr virus (EBV). EBV is a member of the herpesvirus family, which includes viruses that cause cold sores, chickenpox (and shingles), and Kaposi’s sarcoma (most commonly in people with HIV/AIDS). Herpesvirus also infects other mammals, birds, reptiles, amphibians and shellfish.
One thing for which herpes is notorious is its ability to evade detection by the immune system. Once an infection occurs, it’s typically for life. An example of this is chickenpox: after the initial infection (usually in childhood), the virus remains dormant for decades; but it can reappear as shingles if the virus becomes reactivated.
EBV (also known as human herpesvirus-4) commonly infects people during childhood, but often there are few symptoms and the infection goes undetected. However, when the virus is contracted in adolescence or adulthood, it can cause infectious mononucleosis (“mono”). This has been flagged as an MS risk factor: people who develop mononucleosis are 2-3 times more likely to develop MS later in life (Thacker and colleagues. Ann Neurol 2006;59:499-503).
EBV initially infects the tonsils. The primary target is B cells, a type of immune cell. Once infected, the B cells become activated, enter the circulation, and are distributed throughout the body. When these “memory B cells” eventually return to the tonsils, the B cell is destroyed (called the “lytic phase”), releasing viral particles that infect a new generation of B cells.
Like all viruses, EBV has the ability to interfere with the host cell’s DNA, coopting the genetic machinery it to produce viral proteins. The immune system normally detects viral proteins and attacks the infected cells. EBV avoids detection by switching off protein production and remaining dormant. So the only time it can be tagged by the immune system is when the machinery is turned on for cell division.
In healthy people, a type of immune cell, called CD8+ T cells, target viruses and are able to keep EBV infection under control. CD8+ cells produce a number of antiviral chemicals that enhance the antiviral response, including interferon-gamma (a type of interferon that differs from the one used to treat MS). Also important are CD4+ T cells, which recognize foreign invaders (as well as “self” proteins in people with autoimmune conditions such as MS).
So why don’t T cells keep EBV under control in people with MS?
A new series of studies has looked at this question by examining blood samples from people with MS and healthy controls (Pender and colleagues. Clin Transl Immunol 2017;5:e126). The first finding was that there was less of an immune response (of both CD8+ and CD4+) to EBV when people first developed MS. This phenomenon of a reduced antiviral response persisted throughout the lifelong course of MS – except during relapses (we’ll return to this point later on). In addition, as people with MS got older, they produced fewer CD8+ and CD4+ cells capable of controlling EBV. There was a relative increase in the number of immune cells capable of attacking infected B cells, but a deficiency in the number of immune cells capable of killing EBV while it was spreading in the tonsils.
What this means is that the immune system in people with MS may be mistargeted: it mounts a defence against the downstream target, but doesn’t turn off the flow of new virus. The long-term consequence is that the amount of virus steadily increases, which ultimately exhausts the T cells – which explains why there were progressively fewer T cells that could be detected in the study.
As mentioned, the situation was a little different during an MS relapse. Here, there was an expansion of the T cell populations, presumably in response to the increasing burden of virus. This immune activity may explain, in part, how an MS flare-up begins, and which culminates in inflammatory lesions and tissue damage in the brain. However, as T cells became exhausted, there was less of an immune reaction to the rising viral load, which may cast light on why relapses “burn out” over time in MS. This issue will need further examination.
The study raises a number of interesting questions about EBV and MS. It has been suggested that the impaired response to viral infection seen in MS may be genetically determined, and may be due to a relative deficiency in CD8+ cells (Pender MP. Neuroscientist 2011;17:351-367). An early study found that treating MS with interferon-gamma (the antiviral agent produced by CD8+ cells) increased the number of relapses, so this treatment was abandoned (Panitch and colleagues. Lancet 1987;1:893-895). It would be interesting to know what this agent was doing to the CD8+ cells, and whether there might have been a long-term benefit associated with a more aggressive antiviral approach.
Viral infections (such as the flu) are known to worsen MS symptoms, which may be due to the body’s impaired antiviral defences. Indeed, herpes zoster has been reported to flare up during MS relapses (Sotelo and colleagues. Clin Neurol Neurosurg 2014;119:44-48). Impaired defences could also explain why people with MS are more likely to develop viral infection/reactivation both on and off treatment.
It may be that therapies that target B cells, such as Lemtrada, ocrelizumab (in development) and Gilenya, may be beneficial because they are eliminating the pool of B cells infected EBV. Conversely, it is unclear if therapies that preferentially reduce the population of CD8+ cells, such as Tecfidera, will further impair antiviral immunity (Spencer and colleagues. Neurol Neuroimmunol Neuroinflamm 2015;2:e76).
As a final note, since EBV infects the tonsils, it could be hypothesized that surgically removing the tonsils (tonsillectomy) might improve things. In fact, the opposite appears to occur – population studies have reported that people who had a tonsillectomy during childhood or adolescence (but not adulthood) were 30% more likely to develop MS (Lunny and colleagues. BMC Neurology 2013;13:41). But it may be that the tonsils needed to be removed because the infection was more virulent or less controlled in people at risk of MS.
Whether EBV is associated with MS and, if so, how it contributes to the disease process are still unknown. Further research will be needed to determine if there are genetic underpinnings to the impaired antiviral immune response, if this impairment contributes to how MS develops, and whether treatments can specifically target this process.
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