In multiple sclerosis (MS), our immune system mistakenly attacks myelin, or the sheath that covers the axon.
The axon is the projection that allows brain cells to send electric signals carrying information.
As the damage occurs, various functions — such as motor and cognitive functions and sight — are gradually impaired.
According to Atlas, an MS resource put together jointly by the World Health Organization (WHO) and the MS International Federation in 2008, on a global level, “the median estimated prevalence of MS is 30 per 100,000,” and the United States has one of the highest prevalences of MS cases.
What exactly causes MS is yet unclear, meaning that, currently, treatments focus on managing the symptoms of the condition rather than eliminating its biological triggers.
But emerging research from the University of Geneva and the Geneva University Hospitals — both in Switzerland — may have just brought us one step closer to understanding what drives the development of this disease.
“We decided,” explains senior researcher Doron Merkler, “to analyze the infectious factors [in MS] by studying the autoimmune reactions provoked by different pathogens.”
“This was to try to pinpoint an element that might influence the development of [MS] where there has been an infection,” he adds.
The team’s findings were published yesterday in the journal Immunity.
Viral pathogen triggers autoimmunity
Merkler and team decided to test out the immune system’s reaction to two different pathogens, or disease-causing bacteria — a viral and a bacterial one — to understand what might trigger a response consistent with the development of MS.
To do so, they worked with a mouse model, injecting each type of pathogen into healthy rodents.
What they noticed was that a certain type of white blood cell — CD8+ T lymphocytes — which play a key role in the body’s immune response, reacted in similar ways both to the viral and to the bacterial pathogen.
“We saw a quantitatively identical immune reaction from the lymphocytes called CD8+ T,” says first author Nicolas Page.
“However,” he adds, “only the mouse infected with the viral pathogen developed an inflammatory brain disease reminiscent [of MS].”
This observation led the scientists to examine gene expression in CD8+ T cells, to see how it was affected by the viral pathogen.
They found that the lymphocytes that had reacted to the bacterium expressed a particular DNA-binding factor, or proteins that help to organize DNA: TOX.
TOX contributes to the development of certain lymphocytes that then mount an immune response in reaction to foreign bodies that are perceived as threatening.
In this case, as Page further explains, they “found that the inflammation environment influences the expression of TOX in T lymphocytes, and that it could play a role in triggering MS.”
How does TOX lead to MS?
But how could the team decide whether TOX expression was, in fact, crucial in the development of an autoimmune disease such as MS? They thought that a good way of proving its significance was by repressing the DNA-binding factor in the CD8+ T cells of healthy mice.
What the researchers then noticed was, in Merkler’s words, that “although they received the viral pathogen, the mice did not develop the disease.”
Normally, our brains are well equipped to fend off autoimmune reactions that might damage the neurons and impact the central nervous system.
“Our brains have a limited regenerative capacity, which is why they have to protect themselves against the body’s immune reactions, which can destroy its cells by wanting to fight the virus, creating irreversible damage,” Merkler explains.
“The brain then sets up barriers that block the passage of T lymphocytes,” he adds.
However, when TOX is activated in CD8+ T lymphocytes, it renders the cells unable to receive some of the signals that the brain sends to prevent them from attacking healthy neurons. So, without this “memo,” the lymphocytes then mount an autoimmune response that targets the brain cells.
“This is an encouraging result for understanding the causes of the disease but there is still lots of work to be done to ascertain what really causes multiple sclerosis in humans,” says Page.
So, the next step from here for the research team will be to gain a better understanding of TOX’s role, and to see whether it might be involved in triggering other autoimmune diseases apart from MS, as well as certain types of cancer.
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