Throughout our lives, many viruses sneak into our intestines, silently mount cellular invasions like tiny little Hannibals crossing the microbiological Alps, then just as quietly slip away unnoticed. Usually, those stealthy viral invaders are completely innocuous—decidedly unnoteworthy. But sometimes they inadvertently set off a lifetime of haywire immune responses and disease, according to a new study published Thursday in Science.

According to the authors of a new study, a stopover by one such covert reovirus in the gut of someone with a genetic predisposition for celiac disease can do just that, triggering the lifelong autoimmune disease. More specifically, the virus primes their immune systems to shut down regulatory cells that hold back overly aggressive immune responses. Then, when they eat gluten—a group of proteins found in wheat and other grains, such as barley and rye—their immune systems mistakenly treat the proteins as toxic and mount a damaging inflammatory response, leading to discomfort and gastrointestinal problems.

Though researchers had hints before that viruses were involved in the onset of celiac disease, the study offers the first detailed molecular mechanism for exactly how they are involved. And that information opens the door to the idea that vaccines could be used against those incognito viral infections as a way to thwart the disease all together.

In an accompanying editorial on the study, gastroenterologists Elena Verdu and Alberto Caminero of McMaster University in Canada go further: “The implications… expand beyond food sensitivities and celiac disease to possibly other autoimmune disorders where the triggering agent is still unknown,” they write.

Immune mishmash

To unravel the mechanism behind celiac disease, researchers at the University of Chicago and the University of Pittsburgh School of Medicine teamed up with colleagues to tease apart the immune minutia. The researchers had previous experience working with reoviruses—common viruses that infect us multiple times throughout our lives. At first, they didn't think they’d find a connection between reoviruses and celiac disease. But then the researchers noticed that an intestinal reovirus sparked different immune responses than another reovirus type that ignores intestinal cells.

In mouse and cell experiments, the researchers found that the intestinal reovirus caused cells to overproduce immune signals called type 1 interferons, which generally help regulate immune responses. This overproduction suppressed the creation of so-called regulatory T cells, which essentially maintain tolerance to potentially toxic or foreign substances—called antigens—in order to avoid overzealous autoimmune responses.

The researchers also found that, at the same time, the intestinal reovirus boosted cells’ production of a transcription factor called interferon regulatory factor 1. This, in turn, boosted the production of a type of T helper cell, called TH1 cells. These cells can activate strong adaptive immune responses when other cells in the immune system present them with antigens.

It just so happens that some people with celiac disease have a mutation that makes their antigen-presenting cells really good at binding gluten proteins. And, when they present gluten to those abundant TH1 cells while regulatory T cells are repressed, it sets up a permanent intolerance to gluten.

The scenario makes sense with what we know about celiac disease. Though those immune cell mutations are known risk factors, only 3 to 4 percent of people with those mutations go on to develop celiac disease. And, when the researchers of the new study looked for signs of reovirus infections in the serum and tissue of 160 people with celiac disease and in 73 people without the disease, they found that those with celiac disease were more likely to have anti-reovirus antibodies, meaning they’d been infected before.

“Overall,” Verdu and Caminero conclude, “the bulk of data indicate there are three factors responsible for the development of adverse reactions to dietary antigens: the antigen that triggers the maladaptive immune response [in this case gluten], the microbial milieu, and the genetic milieu.”

Science, 2017. DOI: 10.1126/science.aah5298 (About DOIs).