Recent studies have shown that an Epstein-Barr virus (EBV) infection can be a precursor to multiple sclerosis; large, population studies have indicated that people who had the infection were far more likely to develop multiple sclerosis (MS) than others. Some work has indicated that 99 percent of MS patients carry EBV antibodies in their blood. Now, research has revealed how the virus can lead to this chronic inflammatory disorder. The findings have been reported in Nature.
The rate of MS is rising worldwide, though the reasons are unclear. An estimated 2.9 million people have been diagnosed with the disorder, about 40 people in 100,000. In MS, the immune system attacks a fatty sheath that surrounds nerve fibers called myelin, and the fibers themselves, causing inflammation and a variety of symptoms that can range from mild to debilitating. Attacks of weakness, fatigue, or numbness may come on quickly, persist for awhile, then go away before the cycle starts over. Over time, MS can get worse unless it's treated. There are many treatment options, but there is no cure.
EBV is a common type of herpesvirus that can cause mononucleosis and is spread through saliva. It's thought that most people will get an EBV infection at some point, so we don't yet know why some get MS because of it and most others don't.
This latest study has shown that about 25 percent of MS patients carry antibodies that can attach to a protein that is encoded by EBV, called EBNA1, as well as a human protein called GlialCAM (glial cell adhesion molecule), which is generated in the central nervous system.
"Part of the EBV protein mimics your own host protein," which happens to be the GlialCAM in myelin in this case, explained senior study author William Robinson, MD, Ph.D., a professor of immunology and rheumatology at Stanford. So when the immune system attempts to clear the virus and mounts an attack on EBV, it ends up targeting GlialCAM too, he added.
Study co-author Lawrence Steinman, MD, a professor of neurology at Stanford, suggested that this definitive proof that "a virus is the trigger for multiple sclerosis," will create new treatment options for patients.
MS patients carry antibodies to other viruses as well, so for a time, scientists were not sure whether EBV was involved in MS development, or it could be traced to other common viruses such as measles or varicella-zoster.
"Nobody really knows what causes autoimmune diseases, and for many decades, all sorts of different viruses have been hypothesized," Robinson said. "But when people did further mechanistic digging, everything fell apart, and it turned out that getting those other viruses didn't actually cause MS."
In MS patients, immune cells move to the central nervous system and generate antibodies that are revealed in a diagnostic test for MS as oligoclonal bands. In this study, the antibodies in those oligoclonal bands were analyzed, and the scientists determined they came from B cells. The B cells in patients' spinal fluid were then sequenced at the single-cell level. Extensive research showed that of the nine MS patients, six carried antibodies that would bind to EBNA1, the EBV protein, and eight of them had antibodies that would bind to a portion of EBNA1.
These results reveal a causative relationship, said Robinson, who was not sure before this study. "We all thought it was just kind of an artifact...but when we found these antibodies that bound EBV in the spinal fluid, produced by the spinal fluid B cells, it made us revisit the potential association that we'd dismissed."
Next, the researchers showed that these antibodies could also attach to GlialCAM. Additional work with animals provided further confirmation; in a mouse model of MS, an EBNA1 injection exacerbated the symptoms.
"EBV tricks the immune system into responding not only to the virus, but also to this critical component of the cells that make up the white matter in our brains," Steinman said. "To use a military metaphor, it's like friendly fire: In fighting the virus, we damage our own army."
This study underscores the need for caution when developing a vaccine for EBV; scientists would not want to trigger MS through an immune mechanism that was fighting the virus. It also suggests that when it comes to other autoimmune disorders with unclear causes, there may be viral triggers involved.
Sources: Stanford University Medical Center, Nature