“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, M.D., Ph.D., professor
in the department of medicine and pediatrics, 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 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 a weak immune response to the protein gluten,
found in wheat, rye and barley, which 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, M.D., chair of the Department of Pediatrics at the Pitt 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,” commented 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, Ph.D., and Reinhard Hinterleitner, Ph.D., 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, Ph.D., 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 Core Center, the Bettencourt Schueller Foundation, the Dutch Sophia Research Foundation, and the Austrian Science Fund.