Two recent articles have focused on the possible relationships between rotavirus infection and celiac disease (CD). The first study (1) is a prospective investigation into the natural history and the environmental triggers of diabetes and CD autoimmunity in genetically predisposed individuals. The authors found that frequent rotavirus infection predicted a higher risk of CD autoimmunity. However, infections were not diagnosed on the basis of clinical symptoms but were estimated by the number of increases in rotavirus antibody titers between clinic visits. Furthermore, only HLA-DR3–positive subjects were considered to be genetically predisposed to CD. The second study (2) aimed to clarify the role played by infectious agents in eliciting the autoimmune response in CD. It was based on a random peptide library approach, a strategy that was successfully implemented for the identification of other disease-related autoantigens. In this case a peptide sequence was found to be specifically recognized by sera from untreated patients with CD. This sequence shared a high degree of homology with the rotavirus serotype 1 major neutralizing protein VP7, but also with HSP60, desmoglein, Toll-like receptor 4 (TLR4), and in particular with tissue transglutaminase. In fact, antibodies to this peptide sequence (and to VP7) bind to endomysium; more important, these anti-tissue transglutaminase autoantibodies were shown to have functional consequences on TLR4 activation and epithelial cell permeability.
These 2 studies brought up a number of relevant points pertaining to the pathogenesis of CD: the autoimmune features of the disease and the mechanisms of autoantibody induction; the biological activities of these autoantibodies and their contribution to the induction of mucosal damage; the environmental factors involved in the risk of developing the disease in genetically susceptible individuals, in particular the possible role of viruses and their ability to activate innate immunity mechanisms, setting the stage for the induction of adaptive gliadin-specific immune response; and perspectives opened in the area of prevention.
CD can be considered to be an autoimmune disease because of the presence of autoantibodies in both the sera (3) and the intestinal mucosa of patients (4). Of note, CD is also associated with a high prevalence of concomitant autoimmune disease (5). The mechanisms leading to the development of autoimmunity in CD are largely unknown, and whether this is a direct consequence of gluten ingestion is unclear (6,7). Furthermore, the mechanisms leading to the formation of autoantibodies, in particular anti-tissue transglutaminase antibodies, in CD are still obscure. Several hypothesis have been proposed: upregulation of tissue transglutaminase in inflamed sites may generate additional antigenic epitopes by cross-linking or deamidating external or endogenous proteins; unmasking of cryptic epitopes has also been hypothesized in the context of an inflamed environment where antigen processing and presentation may be more efficient; help for the production of autoantibodies given by gliadin-specific T cells in the mucosa has been advocated to explain why these autoantibodies are dependent on the presence of gluten in the diet (8); and molecular mimicry has emerged as a possibility from the study by Zanoni et al (2). Interestingly, rotavirus infection has been associated with pancreatic islet autoimmunity via a mechanism of molecular mimicry (9).
The possible role of these autoantibodies in the pathogenesis of celiac intestinal lesions has not been elucidated. Autoantibodies to TG2 partly inhibit enzyme activity (10). CD serum immunoglobulin A has been found to inhibit epithelial cell differentiation in a 3-dimensional fibroblast–epithelial cell coculture model (11). More recently, antibodies to surface TG2 have been shown to control some of the effects mediated by gliadin peptide p31-43 (12). Data from our laboratory suggest that these antibodies have a proliferative effect on the intestinal epithelial cells and uptake of gliadin peptides by epithelial cells (13). Zanoni and colleagues envisage a new biological action of anti-tissue transglutaminase antibodies on the activation of innate immunity.
The 2 articles also shed light on the environmental factors involved in the disease risk for genetically susceptible individuals. The relevance of the environment in CD should be little given the strong role played by genetics; however, some evidence, such as that in these articles, suggests a role for it and is indicated by the high disease concordance in monozygotic twins (14). Among the environmental risk factors, gluten has been the only one to be considered. In children prone to CD exposure to wheat, barley, and rye in the first 3 months or in month 7 onward significantly increased their risk for developing CD-associated autoantibodies, compared with exposure at 4 to 6 months (15). Nonetheless, apart from gluten (in particular the modes of introduction into the diet during the first year of life) it is possible that infectious agents play a role. In the 1980s a 12-amino acid sequence homology was found between A-gliadin and the E16 protein from the human adenovirus type 12 (16). More recently epidemiological observations on the seasonal pattern of incidence of CD have sustained the hypothesis of a viral infection triggering the disease (17). Rotavirus, as seems obvious from the articles by Stene et al and Zanoni et al, is a good candidate.
The scenario that can be envisioned is that the contact with gluten at a time when there is ongoing intestinal inflammation, altered intestinal permeability, and type I and type II interferon production, upregulation of HLA-DQ2 and HLA-DQ8 on dendritic cells, will increase the risk for developing CD, at least in a subset of individuals. At the same time, the phenomenon of molecular mimicry may trigger autoimmunity. The possibility that these antibodies, among their other biological activities, may modulate the innate immune response through activation of TLRs, is a new, intriguing observation.
Attention has been directly increasingly at the possibility of preventing CD. The strategies envisaged are mainly focused on feeding patterns in the first year of life (breast-feeding, amount and timing of gluten introduction). These observations pointing to a possible role played by rotavirus in the pathogenesis of CD open perspectives on prevention strategies in this new era of rotavirus vaccination. Further studies are needed to exclude any risk for inducing autoantibodies by mechanisms of molecular mimicry. However, it is possible that protecting infants genetically predisposed to CD from repeated infection by the wild-type virus may interfere with the activation of innate immunity and with the consequent adaptive gliadin-specific immune response eventually leading to the disease. Large prospective studies in genetically prone subjects will provide the answer.
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