Regulatory T-Cell Function Is Impaired in Celiac Disease

Granzotto, Marilena; Bo, Sara Dal; Quaglia, Sara; Tommasini, Alberto; Piscianz, Elisa; Valencic, Erica; Ferrara, Fortunato; Martelossi, Stefano; Ventura, Alessandro; Not, Tarcisio

doi:10.1007/s10620-008-0501-x

Cited by 55 publications

(51 citation statements)

References 27 publications

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“…Taken together, these findings confirmed the deficiency of the D2 isoform in down-regulating the Th17 master transcription factor. Previous studies have reported an increase in the number of T reg cells in CD patients and suggested that functional impairments in their suppressive function may be related to the onset of the disease [29][30][31][32]. The exact mechanisms that cause the altered regulatory activity of T reg cells in CD, however, are not understood fully.…”

Section: Discussionmentioning

confidence: 99%

“…While deficiencies in the population of T reg cells have been associated with other autoimmune diseases such as systemic lupus erythematosus (SLE) [28], CD is characterized by an increased number of FoxP3 1 cells in the lamina propria of the small intestine [29,30]. Several groups have shown that their suppressive function is impaired significantly [31][32][33], but the exact mechanisms behind these deficiencies are not understood fully. In the present study, we show that in CD patients the D2 isoform is overexpressed compared to FL in FoxP3-positive cells homing in the gut mucosa and that the intestinal microenvironment, characterized by high production of proinflammatory cytokines and specific microbial-derived metabolites, may contribute to this disequilibrium.…”

Section: Regulatory T Cells (T Reg ) Represent a Subset Of Cd4mentioning

confidence: 99%

See 1 more Smart Citation

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Serena

Shu

Camhi

et al. 2017

Clinical and Experimental Immunology

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SummaryCoeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (T reg ) are CD4 1 CD25 11 forkhead box protein 3 ( FoxP3 1 ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 D2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in T reg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 D2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-g and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Regulatory T Cells (T Reg ) Represent a Subset Of Cd4mentioning

confidence: 99%

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Serena

Shu

Camhi

et al. 2017

Clinical and Experimental Immunology

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“…Surprisingly, expression of FoxP3 was found to be reduced in patients with NCGS compared to CD, perhaps in the context of a generally reduced activation of adaptive immunity in NCGS relative to CD patients [63]. However, the overall expression of this and other messengers (e.g., TGF-β1, and IL-10) represents a rather controversial aspect of CD autoimmunity, because both downregulation and upregulation of FoxP3 and other T reg -dependent molecules have been reported in patients with CD and related autoimmune conditions (e.g., type 1 diabetes mellitus) [72][73][74][75][76].…”

Section: Non-celiac Gluten Sensitivitymentioning

confidence: 99%

Non-Celiac Gluten Sensitivity: Literature Review

Mansueto

Seidita

D’Alcamo

et al. 2014

Journal of the American College of Nutrition

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Key words: non-celiac gluten sensitivity, celiac disease, wheat allergy, food allergy, HLA, flow cytometric basophil activation test, innate immune response Background: A significant percentage of the general population report problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA), because they test negative both for CD-specific serology and histopathology and for immunoglobulin E (IgE)-mediated assays. Most patients report both gastrointestinal and nongastrointestinal symptoms, and all report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS).Aim: We attempt to define the current pathogenic, clinical, and diagnostic criteria of this "new" disease, to provide a practical view that might be useful to evaluate, diagnose, and manage NCGS patients.Methods: We reviewed the international literature through PubMed and Medline, using the search terms "wheat (hyper)sensitivity," "wheat allergy," "wheat intolerance," "gluten (hyper)sensitivity," and "gluten intolerance," and we discuss current knowledge about NCGS.Results: It has been demonstrated that patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. NCGS diagnosis can be reached only by excluding CD and WA. Recent evidence shows that a personal history of food allergy in infancy, coexistent atopy, positive for immunoglobulin G (IgG) antigliadin antibodies and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients.Conclusions: Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroups. Key teaching points:• Most patients report both gastrointestinal and nongastrointestinal symptoms, and all agree that there is an improvement of symptoms on a gluten-free diet.• NCGS diagnosis can be reached only by excluding celiac disease and wheat allergy.• Patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course.• A personal history of food allergy in infancy, coexistent atopy, positive IgG antigliadin antibodies (AGA) and flow cytometric basophil activation test, with wheat and duodenal and/or ileum-colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients.• Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroup. Abbreviations: CD = celiac disease, WA = wheat allergy, NCGS = non-celiac gluten sensitivity, GFD = gluten-free diet, IBS = irritable bowel syndrome, HLA = human leukocyte antigen, tTg = antitissue transglutaminase, AGA = antigliadin antibodies, EMA = endomysial antigen, DGP = deami...

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“…22 Support However, another study found evidence for reduced Treg function in CD, 32 and even if Treg cells are increased in CD, they do not seem to prevent CD from being associated with many autoimmune diseases. Co-infection or 'co-disease' may lead to a chronic inflammatory process with a concomitant increased CTLA-4 and PD-1 expression on immune cells, which is associated with decreased Th17 and Th1 responses.…”

Section: Mechanismsmentioning

confidence: 99%