Epstein-Barr Infection Raises Risk of Lupus, 6 Other Autoimmune Diseases, Study Suggests

Infection with the Epstein-Barr virus (EBV) that causes mononucleosis can increase a person’s risk of developing any of seven major autoimmune diseases, including systemic lupus erythematosus, new and possibly ground-breaking research indicates.

The study, “Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity,” published in the journal Nature Genetics, shows that a protein produced by the Epstein-Barr virus, called EBNA2, binds to multiple locations along the human genome that are linked with these seven autoimmune disorders.

These findings imply that EBV affects human health much more than previously thought, the researchers noted. The seven diseases linked to the EBNA2 protein are lupus, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, and Type 1 diabetes.

“Now, using genomic methods that were not available 10 years ago, it appears that components made by the virus interact with human DNA in the places where the genetic risk of disease is increased,” John B. Harley, MD, PhD, director of the Center for Autoimmune Genomics and Etiology, or CAGE, at Cincinnati Children’s Hospital and the study’s first author, said in a press release.

EBV is quite common, affecting more than 90 percent of the adult population in the U.S. Similar to chickenpox or oral herpes virus, it remains with an infected person throughout life.  

The virus spreads primarily through saliva, and in most cases, it causes no symptoms, being effectively controlled by the immune system. But in some cases it can lead to mononucleosis, also called the “kissing disease,” a condition characterized by extreme fatigue. For unknown reasons, infection with EBV can in rare cases trigger some types of cancer.

EBV behaves like an immune system hijacker. In an infected person, EBV mostly invades B-cells, the immune system cells responsible for producing antibodies critical to defending against viruses, bacteria and other foreign materials.

After entering B-cells, EBV takes control of their functions, altering them to survive and replicate.

Previous research found a link between EBV infection and lupus. In children, the virus can lead to a 50-fold increased risk for developing lupus.

Reasons for this link are not known, but the new study provided an important clue. A specific EBV protein, together with human molecules called transcription factors, bind to regions in the genome involved in the development of lupus and the other six autoimmune diseases.

Transcription factors are small proteins that bind to gene control centers, turning them off or on. They act as orchestrators of gene expression, controlling which ones should be active and which ones silent, so that each cell works as it should and properly responds to its environment.

After analyzing 136 data sets obtained from human cells, researchers found that EBNA2, an EBV protein, binds to almost half of the genome locations associated with a risk of lupus development. The same locations are also bound by a certain group of human transcription factors.

Importantly, data indicate that the presence of EBV increased the binding of those transcription factors to lupus-associated genome locations.

When analyzing genomic locations associated with the other autoimmune diseases, EBNA2 was seen to bind to a relevant proportion of these as well.

In fact, together with EBNA2, a group of transcription factors binding to regions associated with higher disease risk, was shared across all seven autoimmune disorders.

Computational analysis identified a set of 47 transcription factors binding to a total of 142 risk genetic locations.

The results support the hypothesis that B-cells infected with EBV are more prone to alter the expression of a certain group of genes linked to a heightened autoimmune disease risk. The genetic risk variants are specific for each disorder, but a group of transcription factors can, together with EBNA2, provide a common mechanism in several of these diseases.

It is not now possible to determine the proportion of cases of a given autoimmune disease caused by an EBV infection, particularly as that proportion will likely vary according to the disease.

“The impact of the virus is likely to vary across the diseases,” Harley said. “In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases.”

But the discovery of EBNA2 as a player in multiple autoimmune disorders adds to an understanding of the mechanisms behind these diseases, and may help in designing therapies to treat them.

Researchers are looking for compounds, some already approved for other conditions, able to block activity in high-risk transcription factors discovered in this study.

Four of the top 20 transcription factors that bind with EBNA2 can be targeted by at least one available drug, the researchers report.

“These results offer promise for the development of future therapies for manipulating the action of these proteins in individuals harboring risk alleles,” the team wrote in the study.

“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders,” Harley says.

These findings “could lead to therapies, ways of prevention, and ways of anticipating disease that don’t now exist,” added Leah Kottyan, PhD, the study’s senior author and a CAGE member.