When John Harley lost a friend to lupus while in medical school, he vowed to get to the bottom of the disease, a chronic autoimmune disorder that causes fatigue, joint pain, skin rashes, and sometimes death. Now, some 40 years later, Harley says he’s found a “smoking gun.” The Epstein-Barr virus (EBV), which infects some 90% of Americans, may cause changes in gene expression that dramatically increase a person’s chance of getting lupus and six other autoimmune disorders, a new study by Harley and colleagues shows.
“The work is paradigm-shifting in the way we think about genetic susceptibility and the interaction between genetic risk and the environment,” says Amr Sawalha, a geneticist and rheumatologist at the University of Michigan in Ann Arbor who was not involved in the study.
Scientists have known for decades that EBV, which causes an infectious disease named mononucleosis or “kissing disease,” is also linked to several autoimmune disorders, including multiple sclerosis and rheumatoid arthritis. And children infected with EBV are up to 50 times more likely to eventually develop lupus, which currently has no cure. But an explanation for the links remained elusive.
Scientists also know dozens of gene variants that increase people’s risk of lupus. Harley, now a rheumatologist at the Cincinnati Children’s Hospital Medical Center in Ohio, suspected that after infection with EBV, the proteins that the virus uses to switch on its own genes might also preferentially interact with these risk-increasing variants in the patient’s DNA. So Harley’s team compared three sequencing datasets that show where EBV proteins land on the genome in B lymphocytes, the immune cells that run interference against the virus when someone becomes infected.
The team assessed five EBV proteins. One of those, called Epstein-Barr virus nuclear antigen 2 (EBNA2), interacts with nearly half of the genetic risk loci associated with lupus in people with European ancestry, they found. (The other four EBV proteins had no interaction with the variant genes.) The team then extended its analysis to include genetic risk variants associated with hundreds of illnesses beyond lupus. EBNA2 increases the risk of developing six other autoimmune diseases, the team reports today in Nature Genetics, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes.
The work is the first to show a possible mechanism for how environmental factors such as infections alter genetic risk to make some individuals more susceptible to inflammatory disease than others, Sawalha says. But some researchers want more tangible proof because the study relies on associations found in massive data sets. “Show me the biology,” says George Tsokos, a rheumatologist at Beth Israel Deaconess Medical Center in Boston. Tsokos nevertheless calls the work a “paradigm shift.” It implies that an EBV vaccine, if it were ever developed, could prevent not just kissing disease, but many other disorders, similar to the way the human papillomavirus vaccine reduces cervical cancer risk.
The findings also point to the potential for new therapies for lupus and other autoimmune disease based on inhibiting the action of EBNA2 or other human proteins that bind to DNA at the same loci along with the viral protein, the researchers say.
*Correction, 17 April, 12:05 p.m.: An earlier version of this story misidentified John Harley as a pediatrician. He is a rheumatologist.