In the Journals

Celiac disease triggered by common reovirus

An asymptomatic infection with a common but innocuous reovirus can trigger the immune system’s inflammatory response to gluten and lead to the development of celiac disease, according to new study results.

These findings support the role of viruses in the development of celiac disease and other autoimmune disorders, and suggest that vaccines could be developed to prevent them, investigators concluded.

“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,” 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 in a press release. “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.”

Jabri and colleagues first used a mouse model to compare the immune interactions between two closely related but genetically different strains of reovirus — type 1 Lang (T1L), which naturally infects the intestine and disrupts immune homeostasis, and type 3 Dearing (T3D), which does not. They engineered a strain of T3D allowing the virus to infect the intestine, and found that while both T1L and the engineered T3D strains induced protective immunity and did not manifest disease, T1L triggered the initiation of T helper 1 immunity against dietary antigens and induced the loss of oral tolerance to gluten.

Then, to directly explore the role of reovirus in the development of celiac disease in humans, the investigators compared anti-reovirus antibody titers in patients with celiac disease and healthy controls. Celiac patients had significantly higher levels of these antibodies against reoviruses compared with controls (P = .06), and those with high titers showed significantly increased expression of the IRF1 gene — a transcriptional regulator linked to loss of oral gluten tolerance — compared with those with low titers. These findings suggest that reovirus infection “may leave a permanent mark” on the immune system, which could predispose an at-risk child to develop an autoimmune response to gluten later in life.

“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 in the press release. “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 colleagues plan to further study the immune system interactions of these viruses and others and their role in triggering the loss of tolerance to dietary antigens, according to the press release.

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

Disclosures: Healio Gastroenterology was unable to confirm the researchers’ relevant financial disclosures at the time of publication.

An asymptomatic infection with a common but innocuous reovirus can trigger the immune system’s inflammatory response to gluten and lead to the development of celiac disease, according to new study results.

These findings support the role of viruses in the development of celiac disease and other autoimmune disorders, and suggest that vaccines could be developed to prevent them, investigators concluded.

“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,” 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 in a press release. “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.”

Jabri and colleagues first used a mouse model to compare the immune interactions between two closely related but genetically different strains of reovirus — type 1 Lang (T1L), which naturally infects the intestine and disrupts immune homeostasis, and type 3 Dearing (T3D), which does not. They engineered a strain of T3D allowing the virus to infect the intestine, and found that while both T1L and the engineered T3D strains induced protective immunity and did not manifest disease, T1L triggered the initiation of T helper 1 immunity against dietary antigens and induced the loss of oral tolerance to gluten.

Then, to directly explore the role of reovirus in the development of celiac disease in humans, the investigators compared anti-reovirus antibody titers in patients with celiac disease and healthy controls. Celiac patients had significantly higher levels of these antibodies against reoviruses compared with controls (P = .06), and those with high titers showed significantly increased expression of the IRF1 gene — a transcriptional regulator linked to loss of oral gluten tolerance — compared with those with low titers. These findings suggest that reovirus infection “may leave a permanent mark” on the immune system, which could predispose an at-risk child to develop an autoimmune response to gluten later in life.

“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 in the press release. “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 colleagues plan to further study the immune system interactions of these viruses and others and their role in triggering the loss of tolerance to dietary antigens, according to the press release.

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

Disclosures: Healio Gastroenterology was unable to confirm the researchers’ relevant financial disclosures at the time of publication.

    Perspective

    Benjamin Lebwohl

    The prevalence of celiac disease has increased markedly in recent decades, and this has led to interest in identifying environmental risk factors for its occurrence, with the ultimate goal of developing prevention strategies targeting individuals at high risk.

    Although there have been a number of proposed environmental risk factors in recent years, the present study is notable for its systematic method of demonstrating the molecular mechanism by which reovirus causes intestinal immune activation in response to dietary antigens in general, and then by gluten in particular. The investigators then followed their studies of mice by examining titers of reovirus antibodies in patients with celiac disease, which were elevated compared to healthy controls.

    This translational study makes a convincing case that reovirus can contribute to the development of celiac disease. But with this significant research advance comes a number of questions. How do we square these findings with previous studies that support the hygiene hypothesis (i.e. the notion that increased sanitation and decreased exposure to pathogenic microbes) has contributed to the rise in celiac disease? What additional cofactors are necessary besides dietary gluten and reovirus for the development of celiac disease? What are the key structural or functional features of reovirus that allow it to contribute to celiac disease risk? Answering these questions will allow us to develop and test future efforts to prevent celiac disease

    • Benjamin Lebwohl, MD, MS
    • Director of Clinical Research
      The Celiac Disease Center at Columbia University

    Disclosures: Lebwohl reports no relevant financial disclosures.