Researchers identify brain protein linking EBV to MS damage
Study provides more evidence EBV immune responses can harm MS brain
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• Epstein-Barr virus (EBV) infection is linked to multiple sclerosis (ms) brain damage.
• T-cells mistake brain protein ANO2 for EBV protein, damaging myelin-producing cells.
• Future treatments may target these cross-reactive immune cells, EBV vaccines, or antiviral drugs.
A brain protein called anoctamin-2 (ANO2) has emerged as a new piece of the puzzle linking Epstein-Barr virus (EBV) infections to multiple sclerosis (MS), according to a study.
Researchers found that immune T-cells from people with MS can mistake ANO2 for an EBV protein, triggering a cross-reactive response that directly damages myelin-producing cells and worsens the disease in mice.
The study provides further evidence that molecular similarities between EBV and brain proteins can cause cross-reactivity that drives brain damage, and also shows that T-cells are implicated in those cross-reactive immune responses.
“Our results provide mechanistic evidence that immune responses to EBV can directly damage the brain in MS,” Olivia Thomas, PhD, assistant professor at Sweden’s Karolinska Institutet and the study’s first author, said in a university news story.
The study, “Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis,” was published in Cell.
Growing evidence of EBV-MS link
EBV is a common herpesvirus that is best known for causing infectious mononucleosis, although it also causes many nonspecific childhood illnesses. About 95% of adults have been infected with the virus at some point in their lives, and the vast majority don’t know it.
There’s an increasing body of evidence that EBV infection is necessary for developing MS, meaning all MS patients have had a previous EBV infection. However, the exact mechanisms linking EBV to MS remain to be fully elucidated.
In previous studies, a mechanism called molecular mimicry has emerged as a possible explanation. In this process, antibodies generated against EBV proteins, such as EBNA1, can also recognize and bind to proteins in the nervous system, including ANO2, GlialCAM, and CRYAB.
As a result, when the immune system is trying to fight EBV, it accidentally launches an immune response that damages the myelin sheath, the protective coating on nerve fibers that is lost in MS.
However, self-directed antibodies don’t account for all clinical and immunological manifestations of MS, and evidence from humans and rodent models of MS supports a role for immune T-cells.
“We hypothesized that ANO2-specific T cells may also exist and cross-react with EBNA1 via molecular mimicry,” the researchers wrote.
The team analyzed T-cells isolated from the blood of MS patients and healthy people matched for age and sex, who served as controls. Results showed that T-cell responses against ANO2 were significantly higher in MS patients than in controls, with 57% of patients showing ANO2-specific T-cell responses.
Multiple regions of the ANO2 protein were targeted by T-cells, predominantly a type of T-cell called helper T-cells that produced IFN-gamma, a pro-inflammatory signaling protein. These anti-ANO2 T-cell responses were also significantly correlated with anti-ANO2 antibody levels.
The researchers found T-cells that cross-reacted with both ANO2 and the viral EBNA1 protein in MS patients, including those carrying a form, or allele, of an HLA gene called HLA-DRB1*15:01, the strongest genetic risk factor for MS. HLA genes encode proteins that help the immune system distinguish between infecting microbes and the body’s own cells.
“We … present the first evidence that T cells from HLA-DRB1∗15:01 carriers can target both ANO2 and EBNA1,” the team wrote.
The researchers treated mice with ANO2 fragments before inducing MS disease. This exacerbated disease severity and duration, as well as relapse frequency, with a trend toward earlier disease onset. Further experiments confirmed that the anti-ANO2 T-cell response, rather than anti-ANO2 antibodies, was responsible for the increase in MS severity in mice.
In experiments to understand how ANO2 autoimmunity exacerbates disease, the team showed that ANO2 localizes to cells lining blood vessels and was detected in three brain areas. When researchers transferred anti-ANO2 T-cells into MS mice, the cells migrated to regions with high ANO2 levels.
When the team cultured various cell types from mouse brains, the highest ANO2 levels were observed in mature oligodendrocytes (MOLs), the cells that produce myelin. ANO2-specific T-cells were found to directly target ANO2-expressing MOLs.
“We demonstrate that over half of [MS patients] have T cell responses to ANO2, which highlights the potential of targeting these cells for diagnosis or MS therapies, either by depletion or ANO2 immune tolerance,” the researchers wrote. “ANO2 autoreactivity also has the potential to serve as a biomarker for disease severity.”
The study points to “new treatments that target these cross-reactive immune cells,” said Tomas Olsson, PhD, a neurology professor at Karolinska who led the study with Andre Ortlieb Guerreiro-Cacais, PhD, an associate professor at the institute. “Since several EBV vaccines and antiviral drugs are now being tested in clinical trials, the results may be of great importance for future preventive and therapeutic efforts.”
