MS: the coming (r)evolution (Part 2)
In Part 1 we looked at the concept of progression independent of relapse activity (PIRA), and how it is forcing a rethink of the underlying disease mechanisms in MS. So let’s look at some of those mechanisms.
An important trigger for developing MS appears to be infection by the Epstein-Barr virus (EBV). A U.S. analysis of a military database found that almost everyone with MS become infected with EBV prior to developing their MS; exceptions to this rule were rare (Bjornevik and colleagues. Science 2022;375:296-301). Infection occurred about 5-7 years before MS developed. However, since over 90% of the population become infected with EBV at some point in their lifetimes but very few develop MS, this raises the questions of what EBV is doing, and why are some people more susceptible to MS?
The EBV story is complex and has not been fully worked out. There is some evidence that viral proteins resemble human proteins; the immune system can’t tell the difference and launches an immune attack on the body’s own tissues. People with MS, rheumatoid arthritis, lupus and other disorders may be more likely to develop an autoimmune response (Robinson WH. ECTRIMS-ACTRIMS 2023;O010). Alternatively, a person with MS may have an impaired immune response to the virus, which may be partially determined by genetics (Vietzen and colleagues. ECTRIMS-ACTRIMS 2023;LB1).
MS susceptibility is also influenced by environmental factors, such as obesity, low sun exposure, smoking and probably diet. Each of these factors isn’t sufficient to cause MS. But they contribute to a person’s risk of developing MS – just as risk factors for heart disease (obesity, smoking, diabetes, high blood pressure, etc.) raise the risk of having a heart attack without directly causing a heart attack.
Once the immune system becomes activated, immune cells enter the central nervous system and cause inflammation and tissue damage. Inflammation in the brain can be caused by many things, such as head trauma or infection. What differs in MS is that this inflammation doesn’t shut down; in fact, it triggers a second inflammatory response that continues to smoulder, causing chronic damage to nerve cells. A key player in this process are cells called microglia, which are the main line of immune defence in the brain. They consume damaged tissue and activate other immune cells, thereby directly and indirectly increasing immune-related damage to nerve fibres.
This chronic inflammation unleashes a cascade of problems: nerves misfire and break down; repair cells become damaged themselves; and the cell structures that power the healing process (the mitochondria that act like the AA batteries they resemble) no longer function effectively. Aging also comes into play: as people get older, they are less able to repair the accumulating damage that has occurred.
This cascade of events is like any complex mechanism (e.g. your computer, your car) where one problem can lead to any number of downstream effects. But there are two reasons for optimism. Just as a little preventive maintenance on your car can save you later misery down the road, intervening earlier in the disease process may be able to prevent problems later on. Secondly, as researchers gain a better grasp of the disease mechanisms involved, they can develop different treatments to specifically target these processes.
We’ll look at how the MS revolution is impacting the approach to treatment in Part 3.
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