Study Details How Epstein-Barr Virus Reactivation May Lead to MS Relapses
In This Article
- Although Epstein-Barr virus (EBV) may play a role in the onset of multiple sclerosis (MS), its contribution to MS relapses is not clear
- Mass General Brigham investigators found EBV lytic reactivation, which on average precedes MS relapses by two to three months, can set off a chain of events that culminates in a flareup
- The findings could pave the way to predictive blood tests and new therapeutics for MS
Mounting evidence has suggested that Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS) and may play a role in MS onset. How EBV contributes to MS relapses, though, is not fully understood.
Subscribe to the latest updates from Neuroscience Advances in Motion
A team of Mass General Brigham investigators is working to unlock this mystery. Using a longitudinal biobank and a variety of modalities, they showed that EBV lytic reactivation precedes MS relapses—typically by two to three months.
“This reactivation causes certain genes to be expressed by host B cells, where EBV primarily lives, and by EBV itself,” says Mass General Brigham neurologist Tanuja Chitnis, MD, FAAN, senior author of the study. “Those genes produce proteins which, in turn, interact with MS risk genes to make the B cells very inflammatory and unleash an immune cascade that can drive individual flareups.”
The study was recently published in Nature Medicine.
Leveraging data From the CLIMB study
Dr. Chitnis has been conducting MS research for over 25 years, with understanding the mechanisms of MS one of her main goals. For the past decade, she has been involved in work to identify biomarkers associated with MS relapses.
One such study found neurofilament light chain, which is a marker of axonal or neuronal damage, was associated with MS relapses. She was also involved in subsequent studies that showed a temporal association between neurofilament light chain and relapses.
“Through all of this, I became interested in the relapse mechanisms of MS,” Dr. Chitnis says. “Clearly, just correlating with relapses was not sufficient. We wanted to both understand what causes relapses and potentially identify predictors of relapses.”
For the new study, Dr. Chitnis and her colleagues leveraged data from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) study at Brigham and Women's Hospital. This large-scale, long-term study of more than 2,000 patients with MS aims to identify predictors of future disease course when patients are at the beginning of their illness and to determine the effects of treatment on disease progression and accumulation of disability. Each year, besides having neurological exams and MRIs, CLIMB participants donate blood samples.
Pre-relapse samples are usually difficult to find, identifiable only retrospectively when a clinically stable patient happens to suffer a relapse after a routine blood draw. Some CLIMB participants happened to give a sample shortly before a relapse occurred. Dr. Chitnis and her team were able to identify those samples and then pair each with a sample from the same patient who was in a remission state about a year later.
By using single cell RNA sequencing (a large-scale analysis of gene expression in individual cells) and several other modalities, the investigators uncovered differences in some cells two to three months pre-relapse compared to the remission state.
“In contrast, we found that cells taken exactly at the time of a relapse were not all different compared to the remission state,” Dr. Chitnis notes. “The fact that the action was happening a little while before relapse actually makes sense from an immunological standpoint, as the immune system needs some time to activate and rev up.”
Interaction of EBV and MS risk genes
A crucial question underlying the study was this: Given that most people are infected with EBV by age 25, why do only some people develop MS and experience MS relapses? Exploring the interaction between EBV reactivation and the more than 200 MS risk genes pointed to a possible explanation.
The investigators found reactivation of MS risk genes was occurring in specific subsets of B cells called ABC-like memory B cells. These ABC cells expanded pre-relapse in 21 of 23 patients studied and displayed signs of EBV activity on their surface.
“Only in those people with MS risk genes, the EBV reactivation interacts with those risk genes to cause very pro-inflammatory B cells that then lead to the attack,” Dr. Chitnis says.
When discussing immediate clinical implications of the study for managing patients experiencing a relapse, Dr. Chitnis outlines two scenarios. For patients already receiving disease-modifying treatment, clinicians should consider initiating a course of IV steroids to subdue the inflammation. And for patients not already on disease-modifying treatment, clinicians should consider starting it.
Dr. Chitnis encourages clinicians to continue using the array of therapies available to treat patients with MS and prevent attacks. “But what this study does is open up possibilities for new treatments targeting EBV-specific mechanisms that need to be identified and then tested through clinical trials,” she says. “That could lead to more targeted, precise treatments. And then we could start thinking about strategies to prevent MS altogether.”
The study authors acknowledge that given the observational design of the study, they have not proven EBV reactivation causes relapses. However, according to Dr. Chitnis, they are working to further validate the many biomarkers they have identified that were elevated pre-relapse with the hopes of developing a blood test in the near future. They are also looking at new therapeutics that could suppress EBV activation or target the specific cells affected by EBV reactivation.
“I believe we’re entering a whole new phase of investigation into MS and potential new therapeutics,” Dr. Chitnis concludes. “Having studied MS for so long, I think we’re starting to get at the nidus of what causes the disease. And understanding the true cause of the disease could lead to a cure.”