In a study on mice published on February 28, 2022, in the Journal of Experimental Medicine, (“Disruption of thymic central tolerance by infection with murine roseolovirus induces autoimmune gastritis”), scientists at the Washington University School of Medicine in St. Louis demonstrated a new mechanism by which infection of newborn mice with roseolovirus (MRV)—a mouse herpesvirus highly related to the human roseoloviruses—induces autoimmune gastritis (AIG) in adult mice long after the infection has resolved. MRV is a recently discovered virus that infects the thymus and T cells in mice.

Human and mouse roseoloviruses are members of the herpesvirus family. The study suggests that human roseoloviruses warrant investigation as possible causes of autoimmunity in people.

“Viruses are associated with autoimmune disease but the most common way they are thought to cause autoimmunity is by cross-reactive immune cells. That is, when the body mounts an immune response to combat the virus, some of this response inadvertently also reacts with normal tissues, a sort of ‘damage by friendly fire’,” said Wayne Yokoyama, MD, professor of rheumatology at the Washington University School of Medicine and senior author of the study. “We don’t think this is the way MRV causes autoimmunity.”

Wayne Yokoyama, MD, professor of rheumatology at the Washington University School of Medicine, is senior author of the study. [Matt Miller/Washington University]
An earlier study showed infection with MTV (mouse thymic lymphotropic virus) in early life led to the development of gastric-specific autoantibodies and AIG later in life. Yokoyama said, “We wanted to follow up on this and dig deeper to determine why, particularly since we have new knowledge about how the thymus works, and new reagents since the previous paper was published.”

Risk factors for autoimmune diseases have been attributed to genetic and environmental factors but pinning down mechanisms has been difficult. Although earlier studies have proposed that human roseolovirus infections are a risk factor for autoimmune disease, defining a causal mechanism has proven elusive largely because nearly all humans get infected with at least one roseolovirus by the time they start kindergarten, making it hard to identify uninfected individuals for such studies. In addition, the virus usually stays dormant in humans after the initial infection, and a prolonged period elapses between an acute infection and the emergence of autoimmunity.

Mouse roseoloviruses disrupt the central tolerance processes in the thymus, resulting in self-destructive, autoreactive T lymphocytes in the circulation. [Wayne Yokoyama]
“It is very hard to find the culprit of a crime who was never at the scene of the crime,” said 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.”

In this study, the researchers probed the disruptive role of roseoloviruses on the development of central tolerance in the thymus—a thyme leaf-shaped lymphoid organ just behind the breastbone, where self-destructive T cells are identified and eliminated. The researchers showed, months after infection with the virus at neonatal stages, the mice developed an autoimmune disease of the stomach (AIG) driven by T cells that target the body’s own cells.

“This virus goes to the thymus where T cells undergo a process to select those cells useful for immune defense and get rid of T cells that are too likely to damage the body’s own tissues,” Yokoyama explained. “This whole process, called central tolerance, is affected. 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’s team including Tarin Bigley, MD, PhD, a fellow in pediatric rheumatology who is the first author of the study, infected newborn mice with mouse roseolovirus and found that three months later all infected mice developed autoimmune gastritis, or stomach inflammation, although the virus was not present in the stomach.

“We had previously determined the sequence of MRV and used this sequence to derive molecular probes to determine if it was present in autoimmune tissues,” said Yokoyama.

The researchers showed, if the virus was eliminated with antiviral treatment in the first few days following the viral infection while it was still actively replicating, the mice did not develop gastritis three months later.

On the other hand, if the researchers treated the infected mice with antiviral drugs at eight weeks, when the active infection had resolved, the mice still developed gastritis at three months.

“When central tolerance, is disrupted, autoreactive T cells get out into the body and autoimmunity results sometime later in adulthood. This autoimmunity is much broader than can be explained by cross-reactivity because the infection caused production of a very broad array of autoantibodies. Importantly, MRV is not in the stomach when there is autoimmune gastritis, and indeed, autoimmunity occurred long after the acute viral infection,” said Yokoyama.

It is already well accepted that when viral proteins resemble normal human proteins, viral infection can result in autoimmune diseases since antibodies meant to quell the virus end up reacting with normal human cells.

The researchers found that the test mice infected with mouse roseoloviruses that developed AIG produced antibodies against proteins on stomach cells and against a wide array of normal proteins associated with autoimmunity. The T cell populations in these mice were biased toward autoimmune responses.

“We don’t think the autoimmune gastritis is the result of molecular mimicry because we observed such a broad autoantibody response,” Bigley said. “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. Therefore, we focused our studies on the impact of infection on central tolerance rather than molecular mimicry.”

In future investigations, the team will explore whether a similar process occurs in humans. Yokoyama said, “[This study] raises the possibility that this mechanism may underlie association of autoimmunity with other viral infections in humans. However, the virus may no longer be present when autoimmunity occurs, so we will need better strategies to make this connection in humans, to open new ways to treat autoimmunity by targeting the virus.”

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