ACTRIMS 2025: Immune profiles imply EBV reactivation in relapses
Study: Immune cells show distinct gene activity just before symptom worsening
Immune cells from people with multiple sclerosis (MS) exhibit distinct gene activity just before patients have a disease relapse, according to recent research.
The observed immune perturbations, which are no longer observed by the time the relapse is actively underway, are consistent with the body’s response to a reactivation of Epstein-Barr virus (EBV), a common virus that’s now widely recognized as a leading MS risk factor.
The findings were presented in a talk at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2025 that’s being held Feb. 27-March 1 in Florida and virtually.
“We are really observing a robust, pre-relapse immune signature that exists at least up to 90 days in some cases prior to a relapse,” Devin King, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said in the presentation titled, “A Pre-Relapse Immune Signature Implicates EBV Reactivation in Multiple Sclerosis Attacks.”
The signatures are “consistent with the host cell responding to EBV activity,” King said.
MS is an autoimmune disease where the body’s own immune system mistakenly launches inflammatory attacks that damage the brain and spinal cord. In Relapsing-remitting MS (RRMS), periods of new or worsening symptoms associated with active inflammation, called relapses, are separated by periods of remission, where symptoms ease. The molecular mechanisms that drive MS relapses aren’t completely understood.
Immune alterations before a relapse
King referred to the case of a woman with MS who had blood samples collected before and after a relapse to explain the rationale for the recent study. Gene activity analyses of the woman’s immune cells suggested there were immune alterations just before the relapse that weren’t there during remission.
Inspired by these early findings, King and his colleagues performed a larger study to systematically catalogue immune cell changes that happen around the time of an MS relapse. This could help scientists better understand the mechanisms that drive these attacks.
“The ultimate goal is to identify blood-based biomarkers from these signatures,” King said.
Immune cells were collected from the blood of 15 adults with RRMS who had matched samples collected in the three months before a relapse or during a relapse, and during remission. A group of 21 healthy people matched for age and sex were also included as controls.
The cells were subjected to single-cell RNA sequencing, a technique that comprehensively profiles gene activity in individual cells. From this, an atlas of data from more than 300,000 cells was generated.
Analyses suggested a “whole host of statistically robust cell perturbations” in the pre-relapse samples relative to the remission samples, according to King. Such profiles weren’t seen in healthy people.
These gene activity alterations were mostly seen in immune B-cells and certain types of monocytes, which are cells from the innate immune system that help to fight infections.
The changes were dampened by the time an active relapse was underway, which was defined as the period within a week of having new symptoms accompanied by MRI-confirmed inflammatory disease activity. The changes were instead replaced by “a little bit of a different set of immune signatures,” King said.
Similar observations were made using a different sequencing approach on samples from a larger group of 71 MS patients.
Changes related to virus-related processes
Additional analyses indicated these pre-relapse immune signatures were related to virus-associated processes. In particular, the observed profile seemed consistent with the body’s response to the reactivation of EBV.
Most adults have been infected with EBV at some point in their lives, but it usually doesn’t cause severe illness or any symptoms at all, and most won’t know they’ve had it. But a landmark study published in 2022 found that a history of EBV infection raised the risk of developing MS by 32 times. Various studies thereafter have aimed to understand this link.
EBV infects immune B-cells and, even after the initial infection has resolved, the virus lives in those cells in a latent state for the rest of a person’s life. It can, however, spontaneously reactivate at any time. Previous research has suggested that EBV reactivation might trigger inflammatory immune activity that drives relapses.
In response to the virus, B-cells continuously alter their gene activity, according to King. Analyses indicated that EBV-induced gene activity within B-cells was markedly increased before an MS relapse.
Moreover, gene activity related to BZLF1 — a gene involved in EBV reactivation — was increased within B-cells during the pre-relapse period and returned to normal shortly before the relapse occurred. Similar changes in gene activity related to LMP1, a gene associated with latent EBV, were seen in monocytes, peaking about a month before the relapse.
“This really is a phenomenon that is preceding the relapse and then largely disappears once the relapse is underway,” said King, who added that, while the findings suggest a possible role for EBV reactivation in MS attacks, it can’t be definitively established if this is the true cause of patients’ relapses without more research.
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