BackgroundCeliac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.MethodsCD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity.ResultsUnlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293).ConclusionsThis study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

Background: Enteropathy in coeliac disease (CD) is sustained by a gliadin specific Th1 response. Interleukin (IL)-10 can downregulate Th1 immune responses. Aim: We investigated the ability of recombinant human (rh) IL-10 to suppress gliadin induced Th1 response. Patients and methods: IL-10 RNA transcripts were analysed by competitive reverse transcriptionpolymerase chain reaction in duodenal biopsies from untreated and treated CD patients, non-coeliac enteropathies (NCE), and controls. CD biopsies were cultured with a peptic-tryptic digest of gliadin with or without rhIL-10. The proportion of CD80+ and CD25+ cells in the lamina propria, epithelial expression of Fas, intraepithelial infiltration of CD3+ cells, as well as cytokine synthesis (interferon c (IFN-c) and IL-2) were measured. Short term T cell lines (TCLs) obtained from treated CD biopsies cultured with gliadin with or without rhIL-10 were analysed by ELISPOT for gliadin specific production of IFN-c. Results: In untreated CD and NCE, IL-10 RNA transcripts were significantly upregulated. In ex vivo organ cultures, rhIL-10 downregulated gliadin induced cytokine synthesis, inhibited intraepithelial migration of CD3+ cells, and reduced the proportion of lamina propria CD25+ and CD80+ cells whereas it did not interfere with epithelial Fas expression. In short term TCLs, rhIL-10 abrogated the IFN-c response to gliadin. Conclusions: rhIL-10 suppresses gliadin specific T cell activation. It may interfere with the antigen presenting capacity of lamina propria mononuclear cells as it reduces the expression of CD80. Interestingly, rhIL-10 also induces a long term hyporesponsiveness of gliadin specific mucosal T cells. These results offer new perspectives for therapeutic strategies in coeliac patients based on immune modulation by IL-10.

These data suggest that CD4+CD25+Foxp3+ T cells are induced in situ by gliadin. However, their suppressor capacity might be impaired in vivo by IL-15; this phenomenon contributes to maintain and expand the local inflammatory response in CD.

These data indicate that gliadins contain peptides able to activate, through a TCR/HLA class I interaction, CD8-mediated response in intestinal CD mucosa and to induce the enterocyte apoptosis.

Mice fed a wheat-containing diet showed a higher incidence of diabetes, signs of small intestinal enteropathy and higher mucosal levels of proinflammatory cytokines.

Coeliac disease (CD) is a very common food‐sensitive enteropathy, which is triggered by gluten ingestion and is mediated by CD4+ T cells. In addition, alterations in the intestinal microbiota that is normally involved in the homeostasis of GALT (gut‐associated lymphoid tissue) seem to play a role in CD. In accordance with these findings, we previously reported that Lactobacillus casei can induce a strong enhancement of the T cell‐mediated response to gliadin without inducing enteropathy. In this study, we analysed the effects of L. casei administration in a mouse model of gliadin‐induced villous damage that was recently developed and involves the inhibition of cyclo‐oxygenase (COX) activities in gliadin‐sensitized HLA‐DQ8 transgenic mice. To address the issue, we assessed the weight loss, the intestinal cytokine pattern, the density of CD25+ cells and morphometry of the gut mucosa. We confirmed that COX inhibition in sensitized mice caused villus blunting, dysregulated expression of tumour necrosis factor (TNF)‐α and reduced gliadin‐specific IL‐2 production. Notably, the administration of probiotic strain induced a complete recovery of villus blunting. This finding was associated with a delay in weight decrease and a recovery of basal TNF‐α levels, whereas the numbers of CD25+ cells and the levels of IL‐2 remained unchanged. In conclusion, our data suggest that the administration of L. casei can be effective in rescuing the normal mucosal architecture and GALT homeostasis in a mouse model of gliadin‐induced enteropathy.

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The biological effects of interferon (IFN)-The major signal transduction pathway initiated by interferon (IFN)-␥ has been elucidated by a series of elegant biochemical and genetic studies. Binding of IFN-␥ to its receptor induces dimerization of the receptor chains, bringing together JAK kinases 1 and 2 that are activated by transphosphorylation. Activated JAK-1 and -2 then phosphorylate tyrosine residues within the cytoplasmic domains of the receptor subunits, which act as a docking site for a latent cytoplasmic protein, termed signal transducer and activator of transcription 1 (STAT-1). Phosphorylation of a C-terminal tyrosine (Y701) in STAT-1 facilitates interaction with the SH2 domain of a second STAT-1 molecule, mediating dimerization. STAT-1 can also be phosphorylated on a single serine residue (Ser-727) at the carboxy end of the molecule.