Celiac Disease Can Be Triggered By Mild Viral Infection Years Later

Infection with reovirus, an outwardly harmless virus, may play a role triggering the immune system response to gluten which leads to celiac disease, suggests research from the University of Chicago and the University of Pittsburgh School of Medicine.

The finding provides further evidence pointing to viruses in the development of autoimmune disorders such as celiac disease and type 1 diabetes, and raises the possibility that vaccines could one day be used to prevent these diseases.

Senior author Bana Jabri, MD, PhD, professor in the Department of Medicine and Pediatrics, vice chair for research in the Department of Medicine, and director of research at the University of Chicago Celiac Disease Center, said:

“This study clearly shows that a virus that is not clinically symptomatic can still do bad things to the immune system and set the stage for an autoimmune disorder, and for celiac disease in particular. However, the specific virus and its genes, the interaction between the microbe and the host, and the health status of the host are all going to matter as well.”

Digestive System Havoc

Celiac disease, an autoimmune disorder in which gluten in food can wreak havoc on the digestive system, affects one in 133 people in the United States. It is believed that only 17 percent of those have been diagnosed.

It is caused by an improper immune response to the protein gluten, found in wheat, rye, and barely, that damages the lining of the small intestine. There is no cure for celiac, and the only effective treatment is a gluten-free diet.

Science has known for some time that certain genes influence some people toward celiac. But the actual mechanisms behind inflammatory immune responses to gluten work remains poorly understood.

Jabri’s laboratory previously reported in a 2011 study that IL-15, a cytokine upregulated in the intestinal lining of celiac disease patients, can break oral tolerance to gluten. However, not all celiac disease patients overexpress IL-15.

In her latest study, a collaboration with Terence Dermody, MD, chair of the Department of Pediatrics at the University of Pittsburgh School of Medicine and physician-in-chief and scientific director at Children’s Hospital of Pittsburgh of UPMC, Jabri showed that intestinal viruses can induce the immune system to overreact to gluten and trigger the development of celiac disease.

Reovirus

Using two different reovirus strains, the researchers showed how genetic differences between viruses can change how they interact with the immune system. Both reovirus strains induced protective immunity and did not cause overt disease.

However, when given to mice, one common human reovirus triggered an inflammatory immune response and the loss of oral tolerance to gluten, while another closely related but genetically different strain did not.

Reoviruses, a family of viruses, are unique in that they lack lipid envelopes and package their genomes of discrete double-stranded segments of RNA within multi-layered capsids. Reovirus infection occurs often in humans, but most cases are mild or subclinical.

“We have been studying reovirus for some time, and we were surprised by the discovery of a potential link between reovirus and celiac disease,” said Dermody. “We are now in a position to precisely define the viral factors responsible for the induction of the autoimmune response.”

More Antibodies

The study also found that celiac disease patients had much higher levels of antibodies against reoviruses than those without the disease.

The celiac patients who had high levels of reovirus antibodies also had much higher levels of IRF1 gene expression, a transcriptional regulator that plays a key role in the loss of oral tolerance to gluten. This suggests that infection with a reovirus can leave a permanent mark on the immune system that sets the stage for a later autoimmune response to gluten.

Taken together, the study suggests that a reovirus infection could be an important beginning event for developing celiac. For example, in the United States, babies are usually given their first solid foods – often containing gluten – and weaned from breastfeeding around six months of age.

Children with immature immune systems are more susceptible to viral infections at this stage, and for those genetically predisposed to celiac disease, the combination of an intestinal reovirus infection with the first exposure to gluten could create the right conditions for developing celiac.

“During the first year of life, the immune system is still maturing, so for a child with a particular genetic background, getting a particular virus at that time can leave a kind of scar that then has long term consequences,” Jabri said. “That’s why we believe that once we have more studies, we may want to think about whether children at high risk of developing celiac disease should be vaccinated.”

The research was supported by the National Institutes of Health, the University of Chicago Celiac Disease Center and Digestive Disease Research Center Core, the Bettencourt Schueller Foundation, the Dutch Sophia Research Foundation, and the Austrian Science Fund.

Romain Bouziat, Reinhard Hinterleitner, Judy J. Brown, Jennifer E. Stencel-Baerenwald, Mine Ikizler, Toufic Mayassi, Marlies Meisel, Sangman M. Kim, Valentina Discepolo, Andrea J. Pruijssers, Jordan D. Ernest, Jason A. Iskarpatyoti, Léa M. M. Costes, Ian Lawrence, Brad A. Palanski, Mukund Varma, Matthew A. Zurenski, Solomiia Khomandiak, Nicole McAllister, Pavithra Aravamudhan, Karl W. Boehme, Fengling Hu, Janneke N. Samsom, Hans-Christian Reinecker, Sonia S. Kupfer, Stefano Guandalini, Carol E. Semrad, Valérie Abadie, Chaitan Khosla, Luis B. Barreiro, Ramnik J. Xavier, Aylwin Ng, Terence S. Dermody, Bana Jabri
Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease
Science, 2017; 356 (6333): 44 DOI: 10.1126/science.aah5298

Image: Daniel Nemecek, NIAMS Laboratory of Structural Biology, Alasdair Steven, Ph.D., Chief. RNA-packaged procapsid (protein shell) of the cystovirus, the double-stranded RNA bacteriophage Phi-6, that is used as a model system for the assembly and packaging of viruses of the eukaryotes such as the Reoviridae.

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