Scientists uncover possible missing link between 'mono' virus and multiple sclerosis

For years, scientists have known that the virus behind "mono" dramatically raises the risk of multiple sclerosis (MS), a disease in which the immune system attacks nerve cells. But while most people are exposed to the mono virus by adulthood, only a few develop MS, raising the question of why.

Now, researchers have uncovered a possible reason why most people infected with the mono virus never develop MS: a specific immune-system gene may mediate their risk.

The mono virus — called Epstein-Barr virus (EBV) — infects more than 90% of people by adulthood, although it usually causes no symptoms. In some people, it can trigger infectious mononucleosis, better known as mono, causing fever, swollen lymph nodes and fatigue.

Despite EBV's widespread presence, very few people exposed to the virus go on to develop MS, a chronic condition that affects the brain and spinal cord. Now, scientists have identified a specific genetic variant that may help explain this disparity. They published their results April 7 in the European Journal of Neurology.

"The findings … could offer clues as to why only a small fraction of people develop MS despite the fact that over 90% of the global population are infected with EBV," Lisa Kiani, a senior editor of Nature Reviews Neurology, wrote in a summary of the study.

Related: $3 million Breakthrough Prize goes to scientists that completely changed our understanding of multiple sclerosis

The team found that people who carry a genetic variant called HLA-E*01:01 are more likely to develop MS than people without the variant, but only if they have previously had mono.

The gene HLA-E is thought to influence the immune system by interacting with white blood cells, which help defend the body against infections and abnormal cells. A 2023 study published in the journal Cell found that many people with MS have previously been infected with variants of EBV that boost production of the protein that this gene encodes. This molecule can help harmful, self-destructive cells evade detection and destruction by the immune system.

For the current study, the researchers examined data from more than 487,000 people from the UK Biobank, a biomedical database and research resource that includes data from 500,000 U.K. adults. They examined whether individuals carried the HLA-E*01:01 gene variant and reviewed their medical histories to see if they had ever been diagnosed with infectious mononucleosis.

The group also accounted for other known MS risk factors, like smoking, childhood obesity and other genetic markers. The findings showed that people with the HLA-E*01:01 variant who had previously had mono were much more likely to develop MS than those who carried the variant but never had mono, or those with a different version of the same gene.

In other words, the combination of the genetic variant and mono appeared to work together to raise the risk of developing MS. This may be because this specific version of the HLA-E gene may raise the risk of MS by weakening the immune system’s ability to control EBV infection.

For people who carried two copies of the variant — one from each parent — and had a history of mono, these factors accounted for 65% of their risk of MS, lead study author Andrea Nova, a postdoctoral researcher at the University of Pavia, told Nature Reviews Neurology.

"This finding further supports the idea that genetic susceptibility is necessary for IM [infectious mononucleosis] to act as a risk factor for MS, and vice versa," Nova said.

The findings could play an important role in improving early detection and treatment of MS. In theory, by screening for the HLA-E*01:01 genetic variant, doctors may be able to identify people at higher risk of developing the disease down the line, especially if they’ve had mono. This could enable earlier diagnosis and prompt treatment, which is key to slowing long-term damage. Early intervention can significantly improve a person’s overall health and quality of life.