Greater immune ‘misdirection’ against EBV found in MS: Study

People with multiple sclerosis (MS) have elevated immune responses to more proteins of the Epstein-Barr virus (EBV) than previously thought, according to a new study.

EBV-specific immune T-cells isolated from MS patients could also respond to multiple proteins found in the brain, particularly those associated with myelin, the protective coating around nerve fibers that’s damaged in MS.

“The discovery of the link between Epstein-Barr Virus and Multiple Sclerosis has huge implications for our understanding of autoimmune disease, but we are still beginning to reveal the mechanisms that are involved,” Graham Taylor, PhD, study co-lead and an associate professor at the University of Birmingham, in the U.K., said in a press release.

“Our latest study shows that following Epstein-Barr virus infection there is a great deal more immune system misdirection, or cross-reactivity, than previously thought,” Taylor added. “Knowing this will help identify which proteins are important in MS and may provide targets for future personalised therapies.”

The study, “Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis,” was published in the journal PLOS Pathogens.

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EBV infection common in childhood, carried for life without symptoms

EBV infection, which is present in about 90% of people by the time they reach adulthood, is commonly acquired in childhood as a silent infection and is carried for life by most people without experiencing symptoms.

However, if the first infection occurs in adolescence or later, it may cause infectious mononucleosis (IM), also known as mono or “kissing disease,” marked by fever, sore throat, rash, fatigue, and an enlarged liver or spleen.

The virus infects B-cells, which are immune cells that produce antibodies. In an initial stage of infection, the virus is actively reproducing and may cause symptoms, but it then lies dormant inside B-cells for the rest of a person’s life or until an event triggers a new infection cycle.

EBV infection is a likely prerequisite for MS. Emerging evidence suggests virtually all people with MS have been infected with the virus and that the neurological condition is caused by EBV-specific immune cells that erroneously target the brain and spinal cord.

Exactly how EBV contributes to MS is unclear, but recent studies suggest some viral proteins are very similar to certain brain proteins, so immune cells end up damaging brain tissue when trying to fight off the virus.

To investigate further, Taylor and colleagues examined immune responses to EBV in people with relapsing-remitting MS and healthy individuals with a previous EBV infection but no history of IM, who were matched for age, sex, and the HLA-DRB1*1501 MS genetic risk variant — the strongest genetic risk factor for MS.

There was also a third group of people who developed IM, whose blood samples were collected 4-6 months after the resolution of symptoms.

Genetic analysis showed MS patients and healthy controls had a similar viral load. In contrast, the post-IM group had elevated viral levels, which was expected due to a recent infection, the researchers noted.

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MS patients had elevated antibody responses to EBV proteins

In line with previous studies, MS patients had elevated antibody responses to EBNA1, an EBV protein produced during the latent phase, compared with the other two groups.

However, these patients also had more frequent antibody responses to several other viral proteins, including EBNA2, EBNA3A, EBNA3B, EBNA3C, and VCA, indicating a “broader dysregulation of EBV-specific [antibody] responses in MS than previously acknowledged,” the researchers wrote.

“Our study has two main implications,” Taylor said. “First, the findings give greater weight to the idea that the link between EBV and multiple sclerosis is not due to uncontrolled virus infection in the body. Second, we have shown that the human immune system cross-recognises a much broader array of EBV and central nervous system proteins than previously thought, and that different patterns of cross-reactivity exist.”

The migration of immune T-cells into the brain and spinal cord is thought to be a key driver in MS-related inflammation. Moreover, MS patients have high levels of T-cells in their spinal fluid that specifically target cells infected with EBV.

Now, the researchers showed EBV-specific T-cells from MS patients, and also from healthy individuals, could respond to multiple brain proteins associated with myelin.

“Our detection of cross-reactive T-cells in healthy individuals suggests that it may be the ability of these cells to access the brain that is important in MS,” said Olivia Thomas, PhD, study co-lead, from the Karolinska Institute, in Sweden.

“Although our work shows the relationship between EBV and MS is now more complex than ever,” Thomas added, “it is important to know how far this cross-reactivity extends to fully understand the link between them.”