Research Article: A viral trigger for celiac disease

Date Published: September 20, 2018

Publisher: Public Library of Science

Author(s): Judy J. Brown, Bana Jabri, Terence S. Dermody, Richard C. Condit.

http://doi.org/10.1371/journal.ppat.1007181

Abstract

Partial Text

Celiac disease (CD) is an autoimmune enteropathy that occurs in genetically susceptible individuals exposed to dietary gluten. CD occurs in approximately 1 in 133 persons in the United States [1], although most are undiagnosed. Young children with CD present with diarrhea and malabsorption, but CD is also associated with extraintestinal autoimmune disorders, infertility, miscarriages, and cancer [2]. Ingestion of gluten is the most important environmental factor that correlates with CD [3]. Accordingly, current treatment strategies are centered on maintaining a gluten-free diet, which is challenging for many with CD [4]. Because of the increasing prevalence of CD [5] and the consequences of misdiagnosis, it is essential to better understand CD pathogenesis.

Although 30–45% of the United States population has the CD risk alleles (HLA haplotypes DQ2 and DQ8), only 1% of the population develops the disease [1]. Therefore, unidentified triggers of CD must exist to cause the initial insult that breaks oral tolerance to gluten and establishes lasting pathogenic immune memory.

During lymphocyte development, B and T-cell receptor diversity is required to mount successful responses against pathogenic microbes. Immune tolerance selects against B and T cells that express receptors that recognize self-antigen and thus could harm the host. In the intestine, a unique type of immune tolerance, known as oral tolerance, induces local and systemic unresponsiveness following oral feeding and prevents unnecessary immune responses to food proteins. Following antigen feeding, oral tolerance prevents delayed-type hypersensitivity (DTH) responses by inhibiting T-cell proliferation, cytokine production, and serum antibodies against the food protein [12, 13].

The inhibition of oral tolerance by reovirus is strain specific [24]. Infection with reovirus T1L abrogates oral tolerance to fed antigen, as seen in CD, while infection with T3D-RV does not (Fig 1). Relative to infection with T3D-RV, T1L infection is associated with increased levels of inflammatory mediators, including type 1 IFNs and IFN regulatory factor-1 (IRF-1) [24], which are up-regulated in the intestinal mucosa of CD patients [26, 27]. Type 1 IFNs are not required for the differentiation of inflammatory food-specific TH1 cells. However, type 1 IFNs are required to inhibit conversion into Foxp3+ Treg cells, suggesting that these cytokines, although dispensable for development of inflammatory food-specific T cells, inhibit tolerogenic processes [24]. IRF-1, a transcription factor implicated in multistage regulation of TH1 immune responses and antiviral immunity [28], is required to induce reovirus-mediated, OVA-specific inflammatory TH1 cells, likely via stimulation of IL-12 in LP DCs [24]. These results suggest that the switch from tolerogenic to inflammatory DCs results from viral stimulation of type 1 IFN and IRF-1 and that viruses producing higher levels of these factors are more likely to irreversibly disrupt immune homeostasis in the development of CD.

Viral capacity to infect the intestine, avert host antiviral responses, and induce high levels of inflammatory cytokines may dictate whether a specific virus breaks oral tolerance. To test this hypothesis, T1L × T3D-RV reassortant viruses can be used to define the pathobiological properties associated with the abrogation of oral tolerance and identify specific viral gene products and functional domains that elicit such phenotypes. Although IRF-1 has been defined as a host factor required for the disruption of oral tolerance, other host factors have yet to be determined. Since apoptosis functions in accelerating clearance of reovirus in the intestine, studies using caspase inhibitors and mutant mice lacking apoptosis effectors should allow the role of apoptosis in prevention of reovirus-induced tolerance blockade to be clarified. It also will be important to understand the contribution of the intestinal microbiota in the differential host response displayed by T1L and T3D-RV. These studies will reveal underlying mechanisms by which viruses break oral tolerance to gluten in the development of CD.

 

Source:

http://doi.org/10.1371/journal.ppat.1007181