ECTRIMS 2023: New research may help explain EBV and MS link

Faulty immune regulation may be why certain EBV patients develop MS

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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New research by scientists in Austria may shed light on the link between the Epstein-Barr virus (EBV) and multiple sclerosis (MS), and explain why only some people infected with EBV — previously found to raise the risk of MS by 32 times — go on to develop the neurodegenerative disorder.

Distinct regulatory mechanisms within the body normally prevent the immune system’s attack against EBV from also causing an attack on healthy brain cells, according to researchers.

However, certain genetic variations in people, as well as variations between different strains of EBV and infections with other viruses, appear to make these quality control mechanisms less effective. These findings may help researchers to better understand why some people infected with EBV may develop MS while others do not.

Thomas Berger, MD, a professor at the Medical University of Vienna, discussed the findings at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) joint meeting, held last week in Italy.

His talk was titled “Ineffective Immune Control of Epstein-Barr Virus-Induced Autoreactive Responses is an Important Cause of Multiple Sclerosis.”

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Genetic variations may underlie link between MS and EBV

In MS, the immune system launches an attack that targets healthy cells in the brain and spinal cord. Exactly what initiates this self-targeting immune attack remains incompletely understood, but infection with EBV has been identified as one of the strongest risk factors for MS.

Previous research has shown that an EBV protein called EBNA1 has a similar structure to a human brain protein known as GlialCAM. It’s thought that, when the immune system targets viral proteins to fight off an infection, it also may accidentally attack similarly-shaped proteins in the nervous system, setting the stage for MS.

EBV is best known as the virus that causes infectious mononucleosis, commonly known as mono. It also often causes unspecific illnesses in childhood — in fact, the vast majority of people have been infected with the Epstein-Barr virus by the time they reach adulthood.

As EBV is very common, but MS is not, this has begged the question of why only certain people infected with EBV go on to develop the autoimmune disease.

“If MS occurs only in a small fraction of patients [who are] EBV-infected, then there have to be some additional factors — on the one hand, either to protect from autoimmune responses, or on the other hand, to trigger MS,” Berger said.

The researchers now sought to better understand what determines whether someone who develops an EBNA1-specific autoimmune response that can target GlialCAM will or will not go on to develop MS.

If MS occurs only in a small fraction of patients [who are] EBV-infected, then there have to be some additional factors — on the one hand, either to protect from autoimmune responses, or on the other hand, to trigger MS.

To that end, the team analyzed data from 270 MS patients who had blood samples available going back to the time they were first infected with EBV. That infection occurred a median of 8.2 years before the patients’ MS diagnosis. A matching set of 270 samples from healthy individuals also were analyzed.

The results showed that, following EBV infection, it’s fairly common to develop immune cells that are able to accidentally target the brain protein GlialCAM, as well as the viral protein EBNA1. Indeed, the initial immune responses targeting EBNA1 and GlialCAM were “completely similar” in people who did or did not go on to develop MS, Berger said.

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The researchers found, however, that there were notable differences in the activity of other immune cells that help to regulate the immune system. Specifically, compared with healthy controls, people who went on to develop MS had much lower levels of certain types of natural killer (NK) cells and cytotoxic CD8 T-cells.

As their names imply, these are types of immune cells that are able to kill other cells — and the researchers think these regulatory cells normally eliminate GlialCAM-targeting immune cells before they can cause problematic autoimmunity that gives rise to MS.

The scientists identified several factors that were associated with reduced activity of these regulatory cells. For one, the regulatory cells were less active in patients carrying certain variations of immune-regulating genes like KLRC2 and NKG2D.

Regulatory cell activity also was affected by specific strains of the EBV virus. In particular, some strains of Epstein-Barr are able to make human cells produce more of an immune-modulating protein called HLA-E, and people infected with these strains tended to have less activation of the regulatory cells.

Mutations in the gene that provides instructions to make HLA-E also were linked with differences in regulatory immune cell activity, as was previous infection with another type of common virus that can modulate HLA-E activity, called cytomegalovirus or CMV.

Taking these findings collectively, there is “a very clear distinction between the healthy control immune response as compared to MS patients,” Berger said.

“Specific virus but also host predispositions cause the ineffective control … of EBV-mediated autoimmune responses,” he added.

In statistical models, the scientists calculated that patients who had genetic risk factors and were infected with one of the EBV strains that upregulates HLA-E were up to 260 times as likely to develop MS, compared with people without these genetic factors infected with other EBV strains.

These findings may help to better explain the link between EBV and MS and why the virus only leads to the disease in some people. If future work validates these results, the discoveries may pave the way toward better monitoring for people at the highest risk of MS and also lead to new treatments aimed at stopping the disease from developing.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the 9th joint ECTRIMS-ACTRIMS meeting Oct. 11–13. Go here to see the latest stories from the conference.