Boston / Berlin / Bochum. The suspicion had existed for a long time: But now a large US study clearly shows that the extremely widespread Epstein-Barr virus is the main cause of multiple sclerosis. An infection with the pathogen increases the risk of the autoimmune disease by about a factor of 32, the researchers report in the journal “Science”. The virus is by far the most important cause of the disease – and probably also a necessary precondition.
“This work is the last piece of the puzzle,” says the head of the multiple sclerosis outpatient clinic on the Mitte campus of the Berlin Charité, Klemens Ruprecht. “The results practically leave no doubt as to a causal relationship.” However, it is also clear that the vast majority of those infected do not develop multiple sclerosis.
Almost everyone gets the Epstein-Barr virus at some point
Because around 95 percent of all people become infected with the Epstein-Barr virus (EBV), which belongs to the herpes viruses, in the course of their life – mostly in childhood. The infection, which is usually transmitted via saliva, usually has no symptoms, but can cause Pfeiffer’s glandular fever in adolescents and adults – sometimes also called kissing disease or student fever because of the way it is transmitted. The disease is accompanied by fever, tiredness, a sore throat and swollen lymph nodes, but in most cases it heals.
For decades, researchers have suspected a connection between an EBV infection and later multiple sclerosis (MS). In the incurable autoimmune disease, which, according to the German Multiple Sclerosis Society (DMSG), affects around 250,000 people in Germany, the immune system in the central nervous system destroys the protective myelin sheaths that surround the nerve fibers. This leads, among other things, to sensory disturbances, visual impairment and movement problems up to paralysis, which can severely limit the quality of life of those affected.
Research team examined US military
Now the team led by the epidemiologist Alberto Ascherio from Harvard University examined the role of EBV on the basis of data from more than 10 million young employees of the US armed forces who had been regularly screened for HIV between 1993 and 2013. 955 participants were diagnosed with MS while working in the military. In the stored blood samples from these patients, the researchers looked for antibodies against EBV and other viruses in order to determine which pathogens the patients had been in contact with before the onset of the disease.
First, the researchers examined the last blood sample taken before the onset of the disease in 801 of the MS patients. All but one patient had antibodies to EBV, meaning they had previously been infected with EBV. The time between infection and diagnosis varied widely, averaging an estimated 7.5 years.
In the only patient whose blood samples did not contain EBV antibodies, the researchers still do not rule out an infection with the pathogen. It is possible that the participant only became infected after the last blood sample was taken or that no appropriate antibodies were formed. It could also be a misdiagnosis of MS, they write.
EBV infection is a cause, not an accompanying phenomenon
The authors assume that infection with the virus increases the risk of multiple sclerosis by a factor of 32. This strongly suggests that the pathogen is a cause of the disease – and not just an accompanying phenomenon.
This is all the more true as the researchers also examined the blood samples for antibodies against other viruses – for example the cytomegalovirus, which is also a herpes virus and which, like EBV, is transmitted through saliva. The team found no connection here.
MS expert: “The study is a milestone”
Other known MS influencing factors could not explain the increase in the risk by a factor of 32, the researchers write. The next largest risk factor, the gene variant HLA-DR15, increases the probability of the disease threefold. And the authors also consider it unlikely that there are as yet unknown risk factors of the order of magnitude of EBV.
“The study is a milestone,” says Ralf Gold, Director of the Neurological Clinic at St. Josef Hospital at the Ruhr University Bochum (RUB) and Chairman of the Medical Advisory Board of the German Multiple Sclerosis Society (DMSG). “There is no getting around the results.” The results match, among other things, data on the spread of multiple sclerosis on the Faroe Islands: after British soldiers were stationed there towards the end of the Second World War, the number of cases rose significantly.
Comment: EBV infection is necessary, but not sufficient on its own
However, the exact mechanism is unclear, as William Robinson and Lawrence Steinman from Stanford University in California write in a “Science” comment. “Almost everyone is infected with EBV, but only a small fraction will develop MS,” they point out. “So other factors such as genetic susceptibility are also important for the development of the disease.” An EBV infection is necessary, but not enough on its own to cause the disease.
MS is to be seen as a rare late complication of an EBV infection, says the Charité expert Ruprecht. The current study says nothing about the mechanism. “But if we want to better understand how MS develops, that is the central question.”
A large number of conjectures are currently circulating. This includes, for example, that a misdirected immune response against the virus ensures that the body’s defenses are directed against components of nerve tracts. But that alone does not convince Ruprecht in view of the widespread distribution of the virus: “EBV has to cause a specific change in people who later develop multiple sclerosis, to flip a molecular switch,” the neurologist suspects.
Is there a connection with the B cells of the immune system?
Presumably this change affects the B memory cells of the immune system. There are various indications that these B cells are involved: above all, the fact that the virus infects these cells and remains there for life.
The suspicion is further supported by a very new therapy: antibodies that are directed against CD-20, a protein on the surface of these B cells. The antibodies kill such B cells in the peripheral blood. “This therapy is very effective, which shows that the B cells are central to MS,” emphasizes Ruprecht.
The “Science” commentators Robinson and Steinman write that several studies have already found EBV-infected B cells in the brains of MS patients. They also refer to the effectiveness of the CD20 antibodies: “The clearly improving effect of the B-cell breakdown in MS clearly proves a central role of the B-cells in the pathophysiology of the disease.” At the same time, they point to two weaknesses of the therapy: one could not get enough antibodies across the blood-brain barrier. In addition, they did not reach the B cell precursors that do not have CD20.
Research team: EBV vaccination could prevent MS
Ascherio’s Harvard team therefore emphasizes that the Epstein-Barr virus must be targeted directly, for example through vaccinations, to protect against multiple sclerosis. “The extremely low risk of MS in EBV-negative individuals suggests that the vast majority of cases of MS are caused by EBV and could potentially be prevented by appropriate vaccination,” they write. Vaccination could also protect against EBV-related cancers such as Hodgkin lymphoma and Burkitt lymphoma.
However, a vaccine is not yet in sight. And Ruprecht urges caution: “An EBV vaccination would be the ultimate solution to prevent multiple sclerosis – but only if it provides reliable and permanent protection against infection.” Even in this case it would take decades In conclusion, it would be clear whether such a vaccine would actually protect against MS.
If a vaccine does not prevent an EBV infection, but only postpones it, the vaccination could even prove to be counterproductive, explains Ruprecht. Because the later in life a person becomes infected with the Epstein-Barr virus, the higher the risk of Pfeiffer’s glandular fever – and also of multiple sclerosis. “If an EBV vaccination in infancy would only prevent infection for a period of 10 to 20 years, this could paradoxically lead to the incidence of multiple sclerosis even increasing.”