EBV virus may prime immune system to attack brain protein, leading to MS

New research suggests that the Epstein-Barr virus (EBV) might activate the immune system to inadvertently attack a brain protein called ANO2. These findings could help explain the link between EBV infection – which causes glandular fever – and the development of multiple sclerosis (MS) in some patients.

Daniel Jons, PhD, a scientist from the University of Gothenburg in Sweden, presented these findings at a joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis, conducted virtually and in Milan this week.

In people with MS, the immune system, which usually defends against foreign invaders, mistakenly targets healthy brain tissue. Although the exact cause of this self-directed immune response remains unknown, researchers have identified a strong connection between EBV infection and an increased risk of developing MS. Virtually all MS patients have a history of EBV infection.

EBV is most commonly known for causing infectious mononucleosis (mono), but it can also lead to mild, nonspecific illnesses or even remain asymptomatic. A significant portion of the population has been exposed to EBV by the time they reach adulthood.

The theory suggests that EBV might set the stage for MS through a phenomenon called cross-reactivity. In essence, certain components of the EBV virus structurally resemble molecules found in healthy brain cells. When the immune system mounts an attack against EBV, it generates antibodies and other molecules that can attach to specific viral components. However, these can also attach to brain proteins with similar structures, leading to an immune assault on the brain.

Research has suggested that an EBV protein called EBNA1 closely resembles a brain protein called GlialCAM. Studies have shown that MS patients often have antibodies against EBNA1, and these antibodies are detectable before the earliest signs of nerve damage in individuals who later develop MS. Additionally, some MS patients have antibodies targeting Anoctamin2 (ANO2), a protein present on nerve cells and other brain support cells. There is evidence that an immune attack against certain EBV proteins may inadvertently provoke an attack on ANO2 due to cross-reactivity, similar to the way EBNA1 antibodies trigger an attack on GlialCAM.

In this study, researchers examined stored blood samples from individuals who developed MS in the years leading up to their diagnosis. The study encompassed data from 669 MS patients and an equal number of control subjects without MS, obtained by linking information from the Swedish MS register with other Swedish databases.

It was observed that individuals with a history of EBV infection who later developed MS had detectable EBNA1 antibodies roughly 10 to 15 years prior to the initial onset of MS symptoms. Notably, anti-EBNA1 antibodies were detectable years before any notable increase in serum neurofilament light chain (sNfL), a marker for nerve damage. Elevated sNfL levels were only seen about five to ten years before the onset of MS. Among the subset of MS patients who did not test positive for anti-EBV antibodies, there was no increase in sNfL levels before the onset of MS.

According to Jons, “An increase in [EBNA1 antibodies] occurs before the start of preclinical neuroaxonal [nerve fiber] damage.”

Antibodies targeting the ANO2 protein were found in both patients and controls. However, regardless of whether individuals had MS, virtually everyone with anti-ANO2 antibodies also tested positive for anti-EBNA1 antibodies.

“In a subgroup of presymptomatic MS,” Jons noted, “an increase in [anti-ANO2 antibodies] appeared at or shortly after [anti-EBV antibodies].”

Statistical analysis demonstrated that anti-ANO2 antibodies were significantly more prevalent in individuals who later developed MS compared to controls (16.7% vs. 10%), and individuals with antibodies against both ANO2 and EBNA1 were twice as likely to develop MS compared to those with only EBNA1 antibodies.

Similarly, among patients with anti-EBNA1 antibodies, those with antibodies against ANO2 had approximately 26% higher levels of the nerve damage marker sNfL on average.

These findings suggest that an immune response directed against EBV, which inadvertently also targets ANO2, could potentially contribute to the development of MS in a subset of patients.