In a recent post, I reported on a massive retrospective examination of military personnel records that strongly implicated the ubiquitous Epstein-Barr virus (EBV-the agent of infectious mononucleosis) as a major risk factor for the development of multiple sclerosis (MS). What was lacking in this epidemiological study was a mechanism by which EBV could physically initiate a process leading to MS many years after viral infection. It has long been proposed that MS is an autoimmune disease where the immune system attacks the brain to cause the damage that becomes MS. One speculation is that EBV infection in some people might trigger the induction of antibodies that attack the brain, but the direct proof was elusive. A paper published in the journal Nature now provides evidence of antibodies that bind both an EBV protein (called EBNA1) and a host brain protein known as GlialCAM, providing a direct link between the virus, the immune system, and the brain.
When EBV or any other organism infects us, these invading organisms will express proteins that don’t exist in our bodies. The presence of these foreign proteins elicits an immune response that includes the production of antibodies that bind the foreign proteins. Antibody binding will impair the function of the target proteins and can lead to the destruction of cells that are expressing these proteins. During a viral infection, such antibodies are critical to fighting the invader in two ways. First, antibodies that bind to viral surface proteins (like the SARS-CoV-2 spike protein) will cover the virus particle with antibodies and prevent these shrouded virus particles from being able to infect cells. Such antibodies that bind to viruses and block infection are called neutralizing antibodies. The second way that antibodies work is by binding to viral proteins that are expressed on the surface of infected cells. Binding of the antibodies triggers events that cause the targeted cells to be destroyed. Since the infected cells are trying to make and release thousands of new viruses, destroying these cells prevents further virus production, similar to blowing up a munitions factory to prevent it from making new weapons. This combination of antibody effects is critical to recovery from viral diseases. The problem arises when antibodies generated in response to an infection inadvertently recognize and bind one of our own cellular proteins. These anti-viral antibodies then attack not only the virus proteins but also normal cells expressing the cross-reacting protein, an event that can damage and destroy normal cells leading to an autoimmune disease. The Nature paper examined antibodies found in the cerebrospinal fluid (CSF) of 9 individuals with MS. Using sophisticated molecular techniques they found that 6 of the 9 patients had antibodies that bound the viral EBNA1 protein and also bound a small region on the host GlialCAM protein. The GlialCAM protein is expressed by a type of brain cell called an astrocyte, a cell with many functions, including helping with electrical transmission within the brain. The existence of these cross-reacting antibodies is consistent with a possible mechanism whereby EBV infection produces antibodies that could attack astrocytes in the brain to cause damage and disease. To more directly test this hypothesis, the author used a mouse model of MS. In this model, mice exposed to pieces of the EBNA1 protein (a process that should elicit anti-EBNA1 antibodies) showed a worsening of their condition. These results are consistent with anti-EBNA1 antibodies contributing to the disease state in these mice. However, as exciting and intriguing as these results are there are still several caveats with this work. First, the number of patients tested in this study was small and the chosen patients were selected for high antibody levels in their CSF. Given these two limitations, it is hard to generalize the current results to the broader community of MS patients. Next, only 2/3 of the tested patients showed cross-reacting antibodies. MS is a complex illness and there may be multiple mechanisms that all lead to the disease, thus EBV and cross-reacting antibodies could be important only in a subset of patients. Lastly, the portion of the GlialCAM protein that is bound by the anti-EBNA1 antibodies is actually inside the astrocyte, not on the cell surface. This location is confounding since it isn’t clear how the antibodies would ever gain access to this intracellular portion of GlialCAM. Thus, while this is a tantalizing study, much additional work will be needed to understand what, if any, role these anti-EBNA1 antibodies play in human MS cases.