The results of preclinical research headed by a team at Karolinska Institutet have indicated how T cells that play a role in the immune system’s reaction to the common Epstein-Barr virus (EBV) can also cross-react with a protein in the brain, ultimately contributing to multiple sclerosis (MS). The team said the study provides new insight into the long-suspected link between EBV and MS.
“Our results provide mechanistic evidence that immune responses to EBV can directly damage the brain in MS,” said Olivia Thomas, PhD, assistant professor at the Department of Clinical Neuroscience at Karolinska Institutet. “It is a complex neurological disease, and it may be that the molecular mechanisms vary between patients.” Thomas is first author of the team’s published paper in Cell, titled “Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis.”
MS is a chronic inflammatory disease in which the immune system attacks the central nervous system and causes nerve damage. “Multiple sclerosis (MS) causes neurological disability in young adults, with an estimated 2.8 million patients worldwide,” the authors wrote. “MS is characterized by inflammatory lesions in the central nervous system (CNS) and usually presents clinically with a relapsing-remitting phenotype.”
It has long been known that everyone who develops MS has had an infection with the Epstein-Barr virus, a common virus that often infects young people, sometimes causing glandular fever but often without any obvious symptoms. Exactly how this virus contributes to MS has long been unclear. “Epstein-Barr virus (EBV) is the common cause of infectious mononucleosis (IM) and a prerequisite for MS,” the team continued.
Through their newly reported studies, part of which the investigators analyzed blood samples from people with MS compared with those of healthy controls, the researchers have now shown that when the immune system fights EBV, T cells that normally attack the virus can also react to a protein in the brain called Anoctamin-2 (ANO2). “… cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS),” they pointed out. This phenomenon is called molecular mimicry—immune cells mistaking the body’s own proteins for those of the virus. “Given the link between ANO2 antibodies and MS, we hypothesized that ANO2-specific T cells may also exist and cross-react with EBNA1 via molecular mimicry.”
Through their study, the team was able to isolate T cells that react to both the EBV protein EBNA1 and ANO2 from people with MS, demonstrating that these cross-reactive T cells are significantly more common in people with MS than in healthy controls. “Here, we show that ANO2-specific CD4+ T cells are more frequent in pwMS,” they stated. “Notably, the proportion of pwMS with ANO2-reactive T cells was much higher (∼57% of untreated pwMS) than previously reported for ANO2 antibody seropositivity (∼15%), further reinforcing the potential relevance of ANO2 cellular immunity in neuroinflammation.”
In addition, experiments in a mouse model showed that these cells can exacerbate MS-like symptoms and cause damage to the brain. According to the researchers, the results may help explain why some people develop MS after an EBV infection while others do not.
The study builds on previous research showing that misdirected antibodies after EBV infection may play a role. “The discovery opens up new treatments that target these cross-reactive immune cells,” suggested Tomas Olsson, PhD, professor, who led the study together with Andre Ortlieb Guerreiro-Cacais, PhD, associate professor, both at the Karolinska Institutet. “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.”
The team said their study offers “… first mechanistic evidence that EBNA1 CD4+ T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuroinflammation.” In their discussion, they concluded, “In this study, we demonstrate that over half of pwMS 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.”
