Mild Viral Infection May Trigger Celiac Disease Years Later

Ricki Lewis, PhD

April 10, 2017

Infection with the relatively innocuous reovirus may interfere with tolerance to food antigens and set the stage for — if not directly cause — celiac disease in genetically susceptible individuals, data from mice suggest.

The findings, published April 6 in Science, may have implications for preventing celiac disease.

"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. 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," said senior author Bana Jabri, MD, PhD, from the University of Chicago Celiac Disease Center in Illinois, in a university news release.

Celiac disease arises from a highly specific autoimmune reaction to peptides derived from dietary gluten proteins. It affects 1 in 100 people worldwide who have human leukocyte antigen DQ2 or DQ8 variants, which can direct an inflammatory T helper 1 (TH1) immune response against gluten proteins in wheat. Only 3% to 4% of people with these genotypes who eat gluten develop celiac disease.

The recent increase in prevalence of celiac disease and food sensitivities and allergies has suggested that an environmental factor might link the two. In addition, the fact that genetically similar populations can have wildly different incidences of celiac disease supports an environmental hypothesis.

Epidemiological studies have associated several familiar viruses with later development of celiac disease, including hepatitis C virus, adenovirus, enteroviruses, and rotavirus. Timing suggests a role for an environmental influence too: children typically begin to eat cereal at about age 6 months, a time when maternal immune protection wanes and the child's immune system encounters a world of viruses.

The new investigation takes a long-needed experimental approach that links the common but little-known reovirus, which causes few if any symptoms, to later celiac disease. The mechanism that Romain Bouziat, PhD, a postdoctoral researcher at the University of Chicago, and colleagues deduced from experiments in mice supports the epidemiological association of viral infections with later celiac disease in humans.

The researchers scrutinized the immune responses of mice fed gluten and infected with either of two reoviruses that differ in several respects, including tropism to the small intestine. Strain 1Lang (T1L) naturally infects the intestine. A second strain (type 3 Dearing, or T3D) does not naturally infect the intestine, but the investigators engineered a variant of T3D that does (T3D-RV).

Both viral strains evoked a TH1 response in Peyer's patches, as well as an antibody response, but T1L had a stronger effect and altered gene expression in the dendritic cells that are involved in tolerance to dietary antigen.

Further experiments in the mice confirmed that interaction between the T1L strain of reovirus and the immune system blocks tolerance to dietary antigens on gluten peptides, and instead launches a pathogenic TH1 autoimmune response.

To examine the possible link in humans, the researchers compared 160 people with celiac disease, some of whom followed a gluten-free diet, with 73 control patients. People with the disease had significantly higher antireovirus antibody titers than those without celiac disease.

In addition, individuals with celiac disease who were on a gluten-free diet and had high antireovirus antibody titers also had elevated levels of interferon regulatory factor 1, which induces dendritic cells to produce the cytokines that evoke the misplaced TH1 immunity. Although the increase in levels of the antibodies and interferon regulatory factor 1 was not linear, the researchers hypothesize that interferon regulatory factor 1 serves as a "permanent mark" on the immune system that reveals increased risk for celiac disease.

The investigators conclude that "viruses eliciting proinflammatory immune responses to dietary antigen alter immune homeostasis and in particular endow DCs with proinflammatory properties at sites where oral tolerance is induced." They call for identification of other viruses that can affect oral tolerance of food antigens and development of a vaccine to prevent celiac disease, and perhaps other autoimmune conditions.

A perspective by Elena F. Verdu, MD, PhD, and Alberto Caminero, PhD, from McMaster University places the findings in the context of information about the human microbiome. "The study of Bouziat et al. highlights the importance of microbial components as additional environmental triggers in the development of chronic inflammatory and autoimmune disorders," they write.

Dr Verdua and Dr Caminero also outline the "three factors responsible for the development of adverse reactions to dietary antigens: the antigen that triggers the maladaptive im¬mune response, the microbial milieu, and the genetic milieu."

The editorialists and the investigators call for special attention to common viral infections considered harmless because their effects are subclinical, as these viruses may set the stage for future celiac disease and perhaps other autoimmune conditions.

The researchers and commentators have disclosed no relevant financial relationships.

Science. 2017;356:29-30, 44-50. Article abstract, Perspective extract

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