Are Viruses Causing Celiac Disease? UChicago’s Celiac Disease Center Investigates

In their most recent issue of their e-newsletter, Impact, University of Chicago’s Celiac Disease Center published an article on some of their current research into the cause of celiac disease. The Celiac Disease Center, founded by Dr. Stefano Guandalini who is also a member of CDF’s Medical Advisory Board, is committed to studying celiac disease and is always looking for the cause and cure.

 

by Valentina Discepolo, MD

Celiac disease is a complex multifactorial disorder arising from gluten ingestion in genetically susceptible individuals, who carry the HLA-DQ2 and/or HLA-DQ8 predisposing alleles. As with most multifactorial disorders, celiac disease is the result of the interplay between genetic and environmental factors that cooperate to induce an immune-mediated response that results in the small intestinal damage (increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy) typically found in active celiac patients, and in the various systemic and autoimmune features of the disease.

HLA alleles explain only about 35% of the genetic susceptibility to celiac disease, while the remainder is due to numerous non-HLA genes. Recently, 13 new loci have been identified to be associated with celiac disease, bringing the number of known celiac-associated susceptibility loci to 40. In those regions, more than 115 non-HLA genes have been found to be associated with celiac disease, although they contribute only modestly to the overall disease risk. Almost 30 genes are implicated in the immune response, and some of are involved in the inflammatory response against viruses, reinforcing the central role of immune dysregulation in celiac disease pathogenesis and suggesting that immune response to viral infections may play a role in the development of the disease. Interestingly, many of the susceptibility genes are shared with other autoimmune disorders (e.g. type 1 diabetes), supporting the concept that other autoimmune disorders may share common pathogenic pathways with celiac disease. This further supports the idea that understanding the immunological response in the gut of celiac patients may help elucidate general mechanisms involved in autoimmunity.

The immune system can be typically classified into the innate and the adaptive branches that cooperate together to protect organisms against infections from pathogens and preserve healthy conditions. The inflammatory reactions arising in the small intestine of celiac patients involve both sides of the immune system. Typically the innate immune system is responsible for providing the first fast response against viruses and other pathogens. In celiac disease, the innate response has been shown to have a pivotal role, although the respective role of each of those subsystems in inducing tissue damage (villous atrophy) is still unclear. Each branch could be activated by several factors, such as food antigens (mainly gluten), foreign pathogens and commensal microbiota; nevertheless the specific contribution of each of those elements has not been fully elucidated yet.
The major environmental factor that triggers celiac disease is gluten. Other unknown environmental factors may also be contributing to celiac disease in susceptible individuals. Viral infections, in particular enteroviral infections, such as rotavirus, have been associated with an increased incidence of celiac disease and other autoimmune disorders. Several candidate genes identified in celiac patients have been found to be related to the response to viral infections. However, the immunological events behind this association have been poorly dissected.

The University of Chicago Celiac Disease Center has been investigating the mechanisms through which viral infections, in particular gastrointestinal viruses, can contribute to the inflammatory response occurring in celiac disease. One crucial concept is that in healthy individuals the intestinal mucosal immune system continuously samples what comes in contact with our intestine (foreign as well as indigenous microbes and food antigens) and decides what to tolerate and what to fight. In other words, there is a dynamic and continuous balance between regulatory (promoting tolerance) and inflammatory (promoting inflammation) responses towards antigens in the gut. This balance could be disrupted by several events, most of which are still unknown, leading to an inflammatory response against antigens normally tolerated by most healthy individuals. The mechanisms through which this phenomenon occurs are not completely clear. It seems that in genetically susceptible individuals, some environmental factors may disrupt the balance between tolerance and inflammation and enhance an inflammatory response that, once started, could be self-perpetuating and would need the removal of the causative agent (in celiac disease gluten) to be switched off.

Another factor that might contribute to disrupt the balance required for tolerance towards gluten in the intestinal mucosa of celiac patients. is viral infections. Viruses are able to enhance some immune molecules that normally contribute to viral clearance in the host tissue. One group of these molecules, named type-1 interferon (type-1 IFN), may well be related to autoimmune diseases. In fact, it has been hypothesized that viral infections may trigger celiac disease through the induction of type-1 IFN. However the mechanism through which their increased expression is maintained over time is still unclear.
To confirm the ability of viruses to trigger celiac disease, we studied biopsies of celiac patients looking for increased expression of innate immune markers and trying to correlate those with viral infections. Interestingly, we observed that type-1 IFN are highly increased in many of these patients, probably due to multiple gastrointestinal infections that together enhance activation of the innate immune system. This continuous stimulation could lead to a loss of tolerance towards gluten and the development of the disease in a subset of individuals. Those cytokines are able to induce a break of oral tolerance also in animal models, further reinforcing the concept that viral infections could play a role in this process.
In addition, we were able to demonstrate that not all patients with celiac disease are equal from an immunological point of view. Thus we started to sub-phenotype patients based on their “immunological signature” and we are using now this tool to understand how the natural history of the disease may differ across patients
carrying different signatures.
Although this research project is still ongoing, it is already very encouraging. We believe that it will prove helpful for different reasons. First of all, understanding the several “immunological signatures” of patients will help us design individualized therapy for each patient subgroup. Moreover, correlating different immunological signatures with the disease outcome will allow us to implement personalized preventive strategies for subjects at risk to develop celiac disease (such as relatives of celiac patients and individuals affected by other autoimmune conditions associated with celiac disease) based on their signature. Finally, if we can demonstrate that specific viral infections are strongly associated with celiac disease development, we can promote early vaccination against gastrointestinal viruses (such as, for example Rotavirus) to reduce the incidence of celiac disease in defined at-risk populations. Hopefully these studies will advance our knowledge of celiac disease and will change the way we classify patients. In the near future, they will contribute to improving the way we treat them and, more importantly, the strategies we use to prevent disease onset in at-risk individuals.