Are repeated attacks from the mono-virus making MS-patients sicker?

Multiple sclerosis (MS) is a serious chronic disease.

The disease occurs when the immune system damages the protective sheath that covers the nerve cells in the brain and spinal cord. This can in turn lead to a variety of symptoms, including impaired vision, paralysis, fatigue and difficulty remembering or learning.

Researchers have long suspected that multiple sclerosis is in some way related to the Epstein-Barr virus – the virus that causes mononucleosis. But whether the virus actually causes the disease has been difficult to determine.

Earlier this year, however, a ground-breaking US study concluded that the virus most likely is the main cause of MS.

Now Ludvig Sollid, a professor at the University of Oslo (UiO), launches a hypothesis that may expand our understanding even more.

According to Sollid, the Epstein-Barr virus is not only involved when the disease starts. It can also be a critical factor in maintaining the disease and exacerbating symptoms.

Viruses in several autoimmune diseases

The cause of autoimmune disorders, as the name implies, lies in the immune system. Cells from the immune system attack the body's own tissue.

But why do these cells go on the attack?

Scientists still have a lot to learn about this. Several recent studies suggest that viruses may play an important role in diseases as diverse as lupus, MS, rheumatoid arthritis, inflammatory bowel disease (IBD), celiac disease and type 1 diabetes.

There may be several reasons for such a link. One of them is that the immune system in some people is simply unable to distinguish between the virus and the body's own cells.

Triggering cause

Immune cells in your body protect you from infections by learning to recognize certain structures on the surface of the invading virus. This is how they can locate the virus and destroy it.

However, some of these structures may be very similar to parts of the body's own cells. Thus, the immune system sometimes misunderstands and begins to attack the body’s cells.

Traditionally, researchers have believed that some triggering factor affects the immune system so that it no longer distinguishes between the virus and our own cells. Once this happens, the immune system continues to react to this type of cell.

This is how a persistent immune response – and the resulting chronic autoimmune disorder - occurs.

But another possibility might be at work, Sollid believes. He is a professor at UiO’s Institute of Clinical Medicine and chief physician at the Department of Immunology and Transfusion Medicine at Oslo University Hospital.

He has written about this idea in the latest issue of the journal Science Immunology.

Celiac disease

Sollid has not done much research on multiple sclerosis. He has, however, been studying celiac disease, another autoimmune disorder, for many years. His experience from celiac research led him to new ideas about MS.

Celiac disease has a very special position among autoimmune disorders.

In the past, it was thought that the disease was purely a food intolerance. People with celiac disease suffer inflammation in the gut when they eat gluten, a protein found in wheat and some other grains.

But then researchers discovered that the disease has a number of features which suggest that it is a classic autoimmune disorder.

“We found very specific autoantibodies, for example,” Sollid says.

Autoantibodies are immune proteins that specifically mistake and attack a person’s own cells in the body.

“People with celiac disease also show signs of damage in the intestinal tissue,” which is characteristic of autoimmune diseases.

Studies looking for genes that predispose someone to celiac disease also show a picture that is very similar to what we see in classic autoimmune diseases like type 1 diabetes and arthritis, says Sollid.

But one factor breaks completely with the typical picture of a chronic autoimmune reaction: celiac disease can be stopped.

When patients avoid all foods with gluten, they can become and remain healthy. This must mean that the autoimmune reaction in these individuals is not maintained by the immune system itself, but by the foreign substance gluten.

Read more about Sollid's research on celiac disease:

• A pill for celiac disease will come soon, researchers believe
• New pill against celiac disease protects fully against the effects of gluten

Triggers and drivers

This finding is what made Sollid particularly interested in distinguishing between two factors in autoimmune diseases: triggers and drivers.

A trigger is an event that activates the disease process. Human beings are not born with an autoimmune disorder, but at some point something – one or more triggers – triggers the disease.

A driver, on the other hand, is a factor that maintains the disease so that it does not fizzle out over time.

“Gluten might be a trigger in celiac disease. But what’s absolutely certain is that gluten is a driver,” Sollid says.

By removing the driver, you can stop the disease. This fact has led Sollid to speculate whether the picture we see in celiac disease might not also apply to other autoimmune disorders.

In the Science Immunology article, Sollid argues that this may be the case in MS. Until now, researchers have thought that the Epstein-Barr virus might play a role in triggering the disease.

But, wonders Sollid, might it also be maintaining MS?

Virus hides in the body

Several clues could point in that direction, Sollid believes.

We know, for example, that the Epstein-Barr virus does not disappear from the body after a bout of mononucleosis. Instead, the virus hides inside immune cells called B cells. At some later time, the viruses can become active again and cause the cells to make more of the virus.

Could such reactivations trigger new reactions from the immune system, where antibodies attack both the virus and the protective sheath covering the body’s nerve cells?

A recent study also suggests that certain antibodies from MS patients do just this, and attack both the Epstein-Barr virus and a special protein in the central nervous system.

Another interesting fact is that one of the most effective drugs against MS removes B cells. These cells form the antibodies that damage the protective layer around the nerve fibres. They also happen to be the cells that act as hiding places for the Epstein-Barr virus.

Could it be that this medicine also works by removing B cells that harbour dormant virus cells?

If this is the case, it is also conceivable that B cell removal is part of the active mechanism when MS patients receive stem cell treatment. In this treatment, the patient receives cytotoxic drugs that break down all the immune cells in the body, including the B cells.

The treatment thus removes the immune cells that react to the Epstein-Barr virus and that can cause autoimmune reactions.

At the same time, the B cells where the Epstein-Barr virus hide are also removed.

Good hypothesis

Sollid is aware that this is only a hypothesis at the moment.

“I don’t know if the Epstein-Barr virus is a driver for MS, but the suspicion is there. I wrote about this to show that there are parallels to celiac disease,” he says.

Andreas Lossius, a neuroimmunologist at the University of Oslo, studies MS and the Epstein-Barr virus. He thinks Sollid's hypothesis is solid.

“We’ve been aware for a long time that a really strong overlap exists between the Epstein-Barr virus and multiple sclerosis. There’s a lot of research on this. But Sollid's point is to distinguish between triggering and driving factors,” Lossius says.

He surmises, “Maybe we’ve been too preoccupied with triggers and not enough with driving factors so far.”

Important for research on medicines

Transferring experiences like this from celiac disease could point MS research in new directions, Lossius believes. He says that other researchers have been onto similar ideas, but they haven’t been described explicitly, as Sollid is now doing.

“It’s important to formulate the ideas. Then we can start testing them and move forward,” Lossius says.

However, Lossius believes there’s a long way to go before we’ll know whether Sollid's ideas in fact hold up.

The research results we have today, like from the study on antibodies in MS patients, are not good enough to be able to say whether the Epstein-Barr virus is a maintenance factor in MS, he says.

But researchers will be able to test the idea in new studies. They could prove to be very important in developing medicines both to prevent MS and to treat disease that has already occurred.

Medicines and vaccines

One way to investigate Sollid’s hypothesis would be to treat MS patients with an antiviral agent that prevents the B cells from reactivating dormant viruses. Researchers do not currently have any medication that can do this with the Epstein-Barr virus, but they have succeeded at this with other viruses. HIV is a famous example.

If MS patient health improves with such drugs, it would signal that the Epstein-Barr virus really is a factor.

Another strategy might be to prevent the virus from making the surface parts of the virus that the body can confuse with its own cells, and which creates the autoimmune reaction.

Vaccine development could offer another interesting idea for treatment.

Lossius believes that Sollid's hypothesis raises important questions about preventing the development of MS by vaccinating the whole population against the Epstein-Barr virus.

“If the Epstein-Barr virus proves to be a trigger event, a vaccine containing the same components as the virus could also trigger the disease,” he says.

On the other hand, if the virus is primarily a factor that maintains disease activity, a vaccine that inhibits infection could have a good preventive effect.

Big questions

Sollid's idea does not only involve a more detailed understanding of the course of the disease in people with multiple sclerosis. In the broadest sense, he is questioning our basic understanding of autoimmune disorders.

What about autoimmune diseases such as lupus, type 1 diabetes, Sjøgrens syndrome and rheumatoid arthritis – might they also be maintained by viruses, bacteria or other environmental factors?

If so, we might consider whether what we today call autoimmune disorders would be better defined as chronic infections.

So far we have no clear answer for this. Sollid urges further research to look for this type of driver in more autoimmune disorders.

The answers we gain could ultimately lead to dramatic changes in how we understand and treat such serious diseases, he writes in his article.

Reference:

Ludvig M. Sollid: Epstein-Barr virus as a driver of multiple sclerosis. Science Immunology, 2022. (Summary)

———

Read the Norwegian version of this article at forskning.no