Antibodies against EBV and genetic factors raise MS risk: Study
Work supports 'molecular mimicry' between proteins in virus and in brain
Antibodies that target proteins from the Epstein-Barr virus (EBV) also can inadvertently attack proteins in the brain, which may help to explain the link between EBV and multiple sclerosis (MS), a new study shows.
Findings also indicate that antibodies targeting EBV as well as a person’s genetics both independently affect MS risk. As such, individuals with specific antibodies against EBV as well as genetics that predispose to MS are at substantially higher risk of developing the disease.
“A better understanding of these mechanisms may ultimately lead to better diagnostic tools and treatments for MS,” Tomas Olsson, a study co-author and neurology professor at the Karolinska Institutet in Sweden, said in a university news story.
The study, “Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls,” was published in PNAS.
EBV infection is quite common, while MS is not
EBV is best known for causing infectious mononucleosis (known as mono), but it most commonly causes nonspecific symptoms or no symptoms at all. Almost everyone is infected with EBV by the time they reach adulthood, with most people not knowing they’ve been infected.
Recent studies have shown that EBV infection is a key risk factor for developing MS — in fact, evidence suggests that MS can only develop in people who’ve been infected with EBV. It isn’t fully clear, however, how EBV infection leads to MS. It’s also not clear why MS is relatively rare, when the vast majority of humans have been infected with EBV.
One potential explanation for how EBV sets the stage for MS is so-called molecular mimicry. When viruses like EBV infect the body, the immune system makes proteins called antibodies that can target specific viral proteins to help fight the infection. But in some cases, antibodies targeting EBV proteins may also react with proteins in the brain, causing healthy brain cells to get caught in the crossfire.
Previous data specifically has suggested that an EBV protein called EBNA1 shares certain molecular structures with a brain protein called GlialCAM, such that antibodies targeting EBNA1 can accidentally attack GlialCAM.
Anti-EBV antibodies that can attack brain protein evident in MS patients
Building on these findings, the researchers profiled antibodies in 650 people with MS and 661 people without the disease from the Swedish Nationwide Epidemiological Investigation of MS (EIMS) cohort. They found that antibodies targeting EBNA1 were significantly more common in patients, supporting the idea that these antibodies increase a risk of MS.
Through detailed molecular tests, the researchers also showed that MS patients were more likely to have the specific types of anti-EBNA1 antibodies that inadvertently can also attack GlialCAM, lending support to molecular mimicry as a likely mechanism explaining this connection.
“Our study demonstrates in a large cohort of MS patients and matched population-based controls that elevated anti-EBNA1 and anti-GlialCAM antibody levels are associated with increased risk for MS,” the researchers wrote.
Besides EBV infection, genetics are known to play a role in MS risk. In particular, a genetic variant called HLA-DRB1*15:01 has been identified as a major risk factor for MS. In subsequent analyses, the researchers found that patients with antibodies targeting both EBNA1 and GlialCAM who also carried the HLA-DRB1*15:01 variant were more than nine times as likely to develop MS as people without these risk factors.
A different genetic variant called HLA-A*02:01 previously was linked with lower risk of MS. The researchers found MS risk to be significantly increased in patients who had antibodies against EBNA1 and GlialCAM, but did not have this protective genetic variant.
“The new findings provide another piece of the puzzle that adds to our understanding of how genetic and immunological factors interact in MS,” said Lawrence Steinman, MD, a study co-author at Stanford University.
Other brain proteins also may be antibody targets, increasing disease risk
In addition to GlialCAM, prior research also suggests that antibodies against EBNA1 may inadvertently target other brain proteins, including CRYAB and ANO2. Consistently, researchers in this study found that MS patients were more likely to have antibodies that can react with CRYAB and ANO2, and MS patients were more than twice as likely to have anti-EBNA1 antibodies that can react with more than one of these brain proteins.
These data support the idea that “molecular mimicry between EBNA1 and ANO2, CRYAB, and GlialCAM is likely an important molecular mechanism contributing to MS,” the researchers wrote.
The scientists now are planning additional studies to test when antibodies targeting EBV and these brain proteins might serve as initial MS biomarkers.
“If [the antibodies] are already present before the onset of the disease, they may have the potential to be used as biomarkers for early diagnosis,” Olsson said.
This study was supported by grants, including those from the Swedish Research Council, the Swedish Brain Foundation and Horizon Europe, and the National Institutes of Health.
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