How infection can incite sensitivity to food

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Science  07 Apr 2017:
Vol. 356, Issue 6333, pp. 29-30
DOI: 10.1126/science.aan1500

Immune tolerance to dietary antigens is key to preventing undesirable responses to innocuous antigens ingested with food. On page 44 of this issue, Bouziat et al. (1) report how viral infection may break oral tolerance to dietary proteins. The findings provide an explanation for the known epidemiological association between viral infections and the onset of food sensitivities, such as celiac disease. The results are of great interest considering the recent increase in prevalence of food allergies and autoimmune disorders, which suggests an unknown environmental risk modifier.

Celiac disease is an autoimmune enteropathy, characterized by intestinal villus atrophy that globally affects 1 in 100 people. The condition is triggered by the ingestion of a group of proteins called, collectively, gluten, in individuals that carry the genetic susceptibility genes human leukocyte antigen–DQ2 (HLA-DQ2) or –DQ8 (2). Although genetic risk and exposure to dietary gluten are required factors for developing celiac disease, it will occur in only 3 to 4% of genetically predisposed individuals ingesting gluten.

There are two major inflammatory pathways involved in celiac disease (see the figure). One is an adaptive immune response involving the generation of T cells that produce interferon-γ (IFN-γ). The adaptive immune response also involves the differentiation of B cells into antibody-producing plasma cells. Both T cell and B cell events require presentation of a gluten peptide association with major histocompatibility complex (MHC) class II on the surface of antigen-presenting cells (3) (the human MHC is also called the HLA complex). In celiac disease, antigen presentation and generation of this adaptive inflammatory immune response is facilitated by deamidation of glutamine residues in gluten peptides by human transglutaminase 2, the enzyme against which autoantibodies are made in celiac disease (4). The second pathway, required for the development of intestinal atrophy in celiac disease, is activation of the innate immune response. Key cellular players are the intraepithelial lymphocytes found within the epithelial layer of the mammalian gastrointestinal tract. During the innate immune response, these cells become activated and transform into cytotoxic lymphocytes, driven by increases in cytokines such as interleukin-15 (IL-15) (5). The specific trigger of intraepithelial lymphocyte activation and transformation in celiac disease, and whether this trigger could contribute to breakdown of tolerance to gluten and autoimmune development, have remained elusive.

Epidemiological studies have shown a potential association between viral infection and the onset of celiac disease, particularly in childhood (6). In this context, Bouziat et al. observed that infections in mice with different reoviruses triggered protective antiviral T helper 1 (TH1) cell responses in specific gutassociated lymphatic tissue (Peyer's patches). However, the reoviruses affected immunity to dietary antigens at inductive and effector sites of oral tolerance differently. Those reoviruses that affected oral tolerogenicity caused changes in gene transcription in the gut mucosa at different locations. Indeed, Bouziat et al. show that a proinflammatory phenotype is induced in dendritic cells from mesenteric lymph nodes. Here, these antigen-presenting cells lose their capacity to promote tolerance towards the food antigens, and lead instead to a pathogenic T cell response. Because association of viral infections and autoimmune development has been reported mainly in childhood (6), one point of interest for future work will be to determine the role of timing of viral infection in conjunction with the initiation of a gluten-containing diet.

Provoking intolerance

Viral infection disrupts intestinal homeostasis and can promote both autoimmune responses and intolerance to dietary antigens (such as to gluten in celiac disease).


Reoviruses are double-stranded RNA viruses that infect humans frequently throughout their lifetime, but the infections are usually mild, without observable symptoms. The results of Bouziat et al. provide mechanistic proof linking viral infections, including subclinical ones, and the development of food sensitivities, such as celiac disease. The study also indicates that increased signaling by type 1 interferons and increased expression of the transcription factor interferon regulatory factor 1 (IRF1) are differentially implicated in blocking the conversion of T cells into regulatory T cells (Tregs, which maintain tolerance to self-antigens) and promoting the production of TH1 cells that respond to dietary antigens, respectively, after viral infection. Specifically, IRF1, whose expression is increased in children with celiac disease (7), could enhance TH1 cell responses to dietary antigens by promoting the production of IL-12 and IL-27 by dendritic cells. Both cytokines can spur the development of TH1 cells. By contrast, type 1 IFN signaling, which has been associated with celiac disease (8), is not directly required, but is likely to contribute to the increased expression of IRF1 following reovirus infection (9).

Reovirus could independently facilitate the adaptive immune response through human transglutaminase 2 activation, which increases the efficiency of peptide binding to a groove in the HLA protein. Bouziat et al. also studied the antireovirus antibody titers in patients with celiac disease at diagnosis and after treatment with a gluten-free diet. Patients with celiac disease tended to have higher antireovirus antibody titers, and among those individuals with high titers, higher levels of IRF1 expression were detected. Together, these results suggest that the presence of antireovirus antibody titers may be a biomarker of virus-host interaction that leads to long-lasting changes in immune homeostasis associated with high IRF1 expression. This is in agreement with the concept that viruses in general may leave a permanent mark on the transcriptional program of the host (10).

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. Investigation of microbiome alterations in heath and disease has dominated the past decade of biomedical research. Whereas clinical studies have shown associations, basic studies are beginning to show complex mechanistic interactions between the microbiome, diet, and inflammatory and metabolic conditions (11). Although the study by Bouziat et al. is centered on reovirus infections, the authors propose that other enteric viruses involving different signaling pathways could also trigger similar host responses to dietary antigens. This hypothesis is supported by the recent identification of opportunistic bacterial pathogens that colonize the small intestine of celiac patients and participate in gluten metabolism, affecting peptide immunogenicity and host immune response to gluten (12). Overall, the bulk of data indicate that there are three factors responsible for the development of adverse reactions to dietary antigens: the antigen that triggers the maladaptive immune response, the microbial milieu, and the genetic milieu.

The implications of the Bouziat et al. study expand beyond food sensitivities and celiac disease to possibly other autoimmune disorders where the triggering agent is still unknown. In the future, new strategies could be implemented to prevent autoimmunity and food sensitivities, through the monitoring and prophylactic intervention of common viral infections, some of which are currently considered clinically irrelevant.


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