By Sarah Anderson, PhD

In a study published in Science Advances, a team of scientists at UBC and the Fraser Health Multiple Sclerosis Clinic provide new evidence that latent infection with Epstein-Barr virus can prime the immune system for susceptibility to multiple sclerosis (MS). “Our findings have implications that therapeutic approaches to reduce, eliminate, or prevent Epstein-Barr virus infection could effectively lessen MS disease incidence,” said Marc Horwitz, Professor of Microbiology and Immunology at UBC and lead author of the study.

MS, a neurological disease resulting from autoimmune damage to neurons, is disproportionately prevalent in Canada. Investigation into this trend has revealed smoking, obesity, and low vitamin D levels to be risk factors, but the environmental element most strongly linked to MS is infection with Epstein-Barr virus. This common and contagious virus has infected about 95 percent of adults, remaining dormant in B immune cells for the rest of the host’s life.  

Longitudinal reports have revealed significant overlap between latent Epstein-Barr virus infection and development of MS, but because the virus only infects humans, mechanistic animal studies have been challenging. To develop a suitable animal model, the team injected mice with a collection of human immune cells known as peripheral blood mononuclear cells from one of three groups of human donors: healthy people that had not been infected with Epstein-Barr virus, healthy people that had been infected with Epstein-Barr virus, and people with MS that had been infected with Epstein-Barr virus. 

The researchers then induced experimental autoimmune encephalomyelitis, an animal pathology that simulates the neurological effects of MS, and evaluated symptoms such as motor imbalance, hind limb paralysis, and tail limpness. They found that the mice treated with blood cells from virus-positive donors were more susceptible to an MS-like disorder compared to the virus-negative group, with mice treated with cells from donors with MS exhibiting the most severe disease. They also found that the mice corresponding to virus-positive donors displayed significant deterioration of the protective myelin sheath surrounding neurons in the brain and spinal cord, a hallmark of MS. 

To get to the root of these differences, the team then stained and quantified the immune cells in the mice’s central nervous systems. They observed an increase in effector T cells that launch a cytotoxic, proinflammatory immune attack and a decrease in regulatory T cells that keep this immune response in check. While this shift in T cell populations makes sense while the body is actively fighting a virus, it appears to persist even after Epstein-Barr virus goes latent, throwing the immune system off balance. Long-term dysregulation of T cell responses could be one of several cofactors leading to the development of MS.

In creating mice that more closely capture the human immune system, “now we have a model where we can study a mechanism, but we can also study treatment,” Horwitz said. Scientists can use the model to evaluate MS therapeutics that target Epstein-Barr virus or its downstream effects, including drugs aimed at selectively eliminating B cells harboring the virus or reprogramming T cell activity. 

Having established their peripheral blood mononuclear blood cell-based approach, the researchers can generate a wide range of humanized mouse models by swapping out cells from individuals with desired disease characteristics. Horwitz plans to explore the virus’s role in autoimmunity more generally using mice developed from donors with other autoimmune disorders such as arthritis and lupus. “There's commonality across these diseases, and that commonality, I think, is Epstein-Barr virus,” he said. 

Horwitz is also interested in investigating how age at the time of infection influences T cell responses, as acquisition of Epstein-Barr virus later in life results in infectious mononucleosis and is more highly correlated with onset of MS. Drawing a comparison to a pedestrian getting hit by a car, he said, “If they would have walked across the street five minutes later, they would be fine. It’s the same thing with environmental insults and genetics: If the immune system is at a different point in time, it makes all the difference in the world.” 

The study was supported by the Multiple Sclerosis Society of Canada, the National Multiple Sclerosis Society, and the Canadian Institutes of Health Research.