Infection with reovirus, a common but otherwise harmless virus, can trigger the immune system response to gluten that leads to celiac disease, according to new research from the University of Chicago and the University of Pittsburgh School of Medicine.
The study, published April 7, 2017 in Science, further implicates 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.
"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," said study 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. "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."
Celiac disease is an autoimmune disorder that affects one in 133 people in the United States, although 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.
Gluten is a dietary protein that is naturally poorly digested, and therefore more likely to engage the immune system than other proteins, even in people without celiac. However, the way inflammatory immune responses to gluten work remains poorly understood. In a 2011 study published in Nature, Jabri's laboratory reported 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.
The current 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, shows that intestinal viruses can induce the immune system to overreact to gluten and trigger the development of celiac disease. 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.
"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."
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.
The study suggests that infection with a reovirus could be a key initiating 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."
Jabri and her team, including postdoctoral researchers Romain Bouziat, PhD, and Reinhard Hinterleitner, PhD, are collaborating with graduate student Judy Brown and additional members of Dermody's team at UPMC to study the common critical features of host-viral interactions driving loss of tolerance to dietary antigens. Furthermore, Jabri and Seungmin Hwang from the Department of Pathology at UChicago are investigating the possibility that other viruses can trigger the same series of events. All together, their work provides more evidence that viruses can trigger development of complex immune-mediated diseases, and raises the possibility that vaccines targeting viruses infecting the intestine could be used to protect children at risk for celiac and other autoimmune disorders.
The study 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.
Additional authors include Jennifer E. Stencel-Baerenwald, Mine Ikizler, Andrea J. Pruijssers, Jason A. Iskarpatyoti, Solomiia Khomandiak, Nicole McAllister, Pavithra Aravamudhan, and Karl W. Boehme from Vanderbilt University; Toufic Mayassi, Marlies Meisel, Sangman M. Kim, Jordan D. Ernest, Ian Lawrence, Matthew A. Zurenski, Fengling Hu, Sonia S. Kupfer, Stefano Guandalini, and Carol E. Semrad from the University of Chicago; Valentina Discepolo from the University of Chicago and the University of Naples Federico II and CeInGe-Biotecnologie Avanzate, Naples, Italy; Léa M.M. Costes from the University of Chicago and Erasmus University Medical Center Rotterdam, Netherlands; Janneke N. Samsom from Erasmus University Medical Center Rotterdam, Netherlands; Mukund Varma, Hans-Christian Reinecker, Aylwin Ng, and Ramnik J Xavier from Massachusetts General Hospital, Harvard Medical School, the Broad Institute at MIT, and Harvard University; Valérie Abadie from the University of Montreal and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Canada; Luis B. Barreiro from the CHU Sainte-Justine Research Center, Montreal, Canada; and Chaitan Khosla and Brad A. Palanski from Stanford University.
About the University of Chicago Medicine
The University of Chicago Medicine & Biological Sciences is one of the nation's leading academic medical institutions. It comprises the Pritzker School of Medicine, a top 10 medical school in the nation; the University of Chicago Biomedical Sciences Division; and the University of Chicago Medical Center, which recently opened the Center for Care and Discovery, a $700 million specialty medical facility. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.