Researchers Find New Mechanism for Virus-Induced Autoimmunity

Researchers at Washington University School of Medicine in St. Louis have discovered that a viral infection can set a destructive process in motion that culminates in autoimmunity long after the infection has resolved and in a different location in the body. Their results, reported in the Journal of Experimental Medicine, describe a previously unknown way a virus can trigger autoimmunity.

Scientists have long suspected roseolovirus—a member of the herpesvirus family that has mild symptoms and many contract and resolve at a young age—of causing autoimmunity. The ubiquity of the virus, however, has made it difficult to establish prove.

To test the autoimmunity link, Wayne M. Yokoyama, MD, the Sam J. Levin and Audrey Loew Levin Professor of Arthritis Research, and colleagues infected newborn mice with murine roseolovirus.  The roseolovirus infected the subjects’ thymus, where T cells that are likely to damage the body’s own tissues are usually identified and eliminated. The process, called central tolerance, was disrupted by the virus. “T cells that shouldn’t leave the thymus get out, and they manifest months later in the stomach, causing an autoimmune disease in a location that was never infected with the virus,” Yokoyama says. 

Twelve weeks later, all of the mice had developed autoimmune gastritis, or stomach inflammation, though there were no signs of the virus in their stomachs. 

“It is very hard to find the culprit of a crime that was never even at the scene of the crime,” said Dr. Yokoyama. “As clinicians, we often look directly in the diseased tissue, and if we find no virus we conclude that the disease was not caused by a virus. But here we have a situation in which a virus is doing its damage someplace else entirely.”

If the virus was promptly eliminated with antiviral drug treatment in the first few days, while it was still actively replicating, the mice did not develop gastritis three months later. If, however, the researchers waited to give an antiviral until the mice were 8 weeks old—after the active infection had resolved but before the mice showed signs of stomach problems—the drug did no good at all, and the mice still went on to develop gastritis a few weeks later.

Scientists already knew that viral infection could lead to autoimmunity if some of the virus’s proteins happen to resemble normal human proteins. In those cases, antibodies meant to target the virus end up also reacting with normal human cells. Yokoyama and colleagues found that the mice with gastritis had developed antibodies against proteins on stomach cells. But they also had developed antibodies against a wide array of normal proteins associated with other autoimmune conditions. In addition, they had many T cells that targeted the body’s own normal proteins, and other changes to the T cell population that biased the immune system toward autoimmunity.

“We don’t think the autoimmune gastritis is the result of molecular mimicry because we observed such a broad autoantibody response,” says Tarin Bigley, MD, PhD, a fellow in pediatric rheumatology. “The observation that infected mice produced diverse autoantibodies, in addition to the anti-stomach autoantibodies, suggested that murine roseolovirus infection early in life was inducing a wide-ranging defect in the body’s ability to avoid targeting its own proteins. This is why we focused our studies on the impact of infection on central tolerance rather than molecular mimicry.”

The next step is to investigate whether a similar process occurs in people. “Human autoimmune disease also may occur via viral infection that gets cleared but leaves damage that can cause autoimmunity,” Yokoyama said. “But if so, there has to be some other factor that we don’t understand yet that makes some people more susceptible to the autoimmune effects of roseolovirus infection, because almost all people are infected, but most people do not get autoimmune diseases. That is a really important topic for further investigation.”