Office of Research & Development
Office of Research & Development
New research links the Epstein-Barr virus to numerous autoimmune diseases. (Photo: ©iStock/Dr._Microbe)
April 18, 2018
By Tristan Horrom
VA Research Communications
A rheumatologist and biochemist, Dr. John Harley studies the genetic and environmental causes of inflammatory diseases.
Researchers with the Cincinnati VA Medical Center and the Cincinnati Children's Hospital Medical Center have found a link between a common virus and multiple autoimmune disorders. The researchers were able to show that a protein created by the Epstein-Barr virus binds to locations on human genes that are known to be associated with lupus.
The research was published in the April 16, 2018, issue of Nature Genetics.
The team analyzed genomic data with a new computer algorithm they created called RELI—short for Regulatory Element Locus Intersection. They found that the protein, EBNA2, has associations with lupus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. The study authors have dubbed these seven conditions the "EBNA2 disorders."
Dr. John B. Harley, one of the lead authors on the study, described the results as "astonishing." As the authors write in the paper, the results could provide "mechanisms possibly explaining the molecular and cellular origins of disease risk." The scientists believe that the strategy they used could have broad implications for all diseases: The researchers have identified more than 2,000 different bindings between various transcription factors and genome loci—only some of which involve the Epstein-Barr virus—possibly explaining molecular interactions involved in 94 different diseases.
"Our evidence is comparable to a strong circumstantial case. Maybe the jury would not be able to pronounce a guilty verdict...but virtually all of the jurors would be very suspicious that this virus did do the evil deed."
Epstein-Barr is one of the most common viruses in humans. Over 95 percent of all adult humans have life-long infections with the virus. It is the cause of mononucleosis, and is also associated with some forms of cancer and other conditions. The virus produces the transcription co-factor EBNA2, which binds to specific locations in the human genome—as many as 10,000 locations, according to some estimates.
Transcription factors are proteins that determine the expression of genes: They direct processes of cell growth, division, and death, and also cell migration and organization. They do this by "turning on and off" genes, controlling when that gene creates a product such as a protein. Epstein-Barr infects B cells—a type of white blood cell in the immune system. This may explain the association between Epstein-Barr and the EBNA2 disorders: All seven are autoimmune diseases, conditions involving an abnormal immune response to a normal body part.
In other words—if the link suggested by the results proves true—it is the body's immune and inflammatory response to the virus and to the infected cells that causes the conditions, rather than the virus directly. Harley explains that, since the Epstein-Barr virus is so prevalent, human bodies go to extraordinary lengths to try to control and eliminate it, and the virus has developed ways to hide from or avoid the immune system. He writes, "The intense host response against the virus has much potential to 'go off the rails' and waft toward a misdirected pathological response."
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The link between the Epstein-Barr virus and lupus has been shown by multiple research groups. The rates of infection with the virus were shown to be increased by as much as 50-fold in children with lupus, in a 1997 study by Harley and colleagues at the University of Oklahoma. Lupus patients have also been shown to have elevated Epstein-Barr virus loads in their blood.
The new study, however, does more than confirm an association; it shows a component of possible mechanism: the binding of EBNA2 to specific genes. While the new evidence is circumstantial, it provides a new starting point in the quest to understand how these diseases are generated. Currently, Epstein-Barr virus is accepted as a causal agent only for multiple sclerosis. Harley says it is "curious" that the same transcription factors associated with MS risk are also associated with the other EBNA2 disorders.
Scientists have long known that different variations of the same genes could be risk factors for various diseases. The results of this study may show how an environmental factor, the virus, can interact with these gene variants to cause different health conditions. Harley cautions, though, that more research is needed before scientists can definitively say that the virus causes the conditions. He likens the search for a disease cause to a criminal investigation, saying: "Our evidence is comparable to a strong circumstantial case. Maybe the jury would not be able to pronounce a guilty verdict, as if we were accusing the virus of a crime, but virtually all of the jurors would be very suspicious that this virus did do the evil deed."
It is not yet understood exactly how one form of a gene at a specific spot on a genome increases disease risk compared to a different form at the same spot. The link between where on the genome transcription factors bind and disease risk appear to be more than chance, suggesting that this binding is a mechanism for disease development. But Harley says that "proving that a possible mechanism is truly responsible for generating disease risk is a whole different problem."
While the results show that EBNA2 is associated with all of these conditions, the genes the protein is binding with differ for each condition. Depending on what gene variants a person has, the same virus could cause different conditions.
Harley believes that discovering the basic mechanisms underlying the virus’s effects on genes could lead to exciting advances. "If it means that Epstein-Barr virus causes these diseases, then it is information that is as valuable as knowing that M. tuberculosis causes pulmonary tuberculosis or that human immunodeficiency virus (HIV) causes AIDS," he wrote in an email.
Harley tempers the optimism with a realistic perspective on how long it might take to translate his lab’s basic science work into clinical treatments. Continuing his analogy to tuberculosis and AIDS, he notes: “In the first case it must have been 80 years between establishing the cause of pulmonary tuberculosis as M. tuberculosis and the discovery of effective therapy. For HIV the time between its discovery and effective therapies for AIDS was much shorter, probably about 15 years. I wonder how long it will be before we have effective therapies, vaccines, or preventive measures for Epstein-Barr virus."
Harley mentioned several ways that the findings could eventually lead to treatment advances. If this unexpected relationship between the Epstein-Barr virus and autoimmune diseases in fact proves to be the root cause for at least some of the patients with these diseases, then a vaccine could be developed. An effective vaccine would prevent disease altogether for at least some patients, even if the virus is not the only possible cause. The discovery could also redirect drug development for people with these diseases. Further research could focus on the specific gene loci interactions that cause each condition.
Developing new drug treatments or vaccines will take years more of further research. But figuring out the root causes of these conditions will point researchers in the right direction, says Harley. "We give the world a starting place for figuring out how these mechanisms operate by bringing the genetic loci together with Epstein-Barr virus nuclear antigen 2 (EBNA2)."
More studies are now being planned. For example, Dr. Matthew T. Weirauch, a principle investigator on this study, is working on a study to develop the observations as they specifically apply to multiple sclerosis along with the rest of the current team: Drs. Leah Kottyan, Mario Pujato, Xiaoting Chen, and Harley.
The research was supported by the National Institutes of Health, VA, Cincinnati Children's Hospital, and the University of Cincinnati. Harley points out that this project used data made available by thousands of scientists working on other investigations. "Without such a strong spirit of scientific generosity, this study, as well as many other important projects, would very simply not exist," he says.
View a Cincinnati Children's Hospital video about the research.
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