Impaired Control of Effector T Cells by Regulatory T Cells: A Clue to Loss of Oral Tolerance and Autoimmunity in Celiac Disease?

Hmida, Nedia; Ahmed, Mélika Ben; Moussa, Amel; Rejeb, M. Ben; Said, Yosra; Kourda, Nadia; Meresse, Bertrand; Abdeladhim, Maha; Louzir, Hechmi; Cerf‐Bensussan, Nadine

doi:10.1038/ajg.2011.397

Cited by 96 publications

(72 citation statements)

References 35 publications

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“…In this study we report a higher expression of the alternatively spliced isoform FOXP3 D2 in the intestine of CDA patients compared to non-coeliac controls, while no differences were seen in the expression of FOXP3 FL. Conversely to what was previously reported in the literature [33], our data on CDGF showed a higher expression of both FOXP3 isoforms in this group of patients. Interestingly, however, we found that in CDA patients the relative amount of FOXP3 D2 in the gut mucosa was higher than the FL, while HC subjects and CDGF patients presented a similar expression of both isoforms.…”

Section: Discussioncontrasting

confidence: 56%

“…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%

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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: Discussioncontrasting

confidence: 56%

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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“…A human study reported that there were HLA-DQ2.5-restricted, gluten-reactive T R1 cells present in gut biopsies of CD patients, but not control subjects (12). Other human studies reported that LPLs expressing Foxp3, CD25, and CD4 were present at higher frequencies in UCD patients than in control subjects (13,14), and that CD may evolve because of T lymphocytic resistance to suppressive T REG (14). Ag specificity of the presumed T REG was not ascertained in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…However, such cells were not observed in healthy subjects. Further, it has been demonstrated that there is increased expression of Foxp3 and increased numbers of CD4 + T REG (CD25 + Foxp3 + ) in the smallbowel biopsy specimens of CD patients compared with control subjects (13,14).…”

mentioning

confidence: 99%

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Christophersen

Risnes

Bergseng

et al. 2016

The Journal of Immunology

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Celiac disease (CD) is an HLA-associated disorder characterized by a harmful T cell response to dietary gluten. It is not understood why most individuals who carry CD-associated HLA molecules, such as HLA-DQ2.5, do not develop CD despite continuous gluten exposure. In this study, we have used tetramers of HLA-DQ2.5 bound with immunodominant gluten epitopes to explore whether HLA-DQ2.5+ healthy individuals mount a specific CD4+ T cell response to gluten. We found that gluten tetramer-binding memory cells were rare in blood of healthy individuals. These cells showed lower tetramer-binding intensity and no signs of biased TCR usage compared with gluten tetramer-binding memory T cells from patients. After sorting and in vitro expansion, only 18% of the tetramer-binding memory cells from healthy subjects versus 79% in CD patients were gluten-reactive upon tetramer restaining. Further, T cell clones of tetramer-sorted memory cells of healthy individuals showed lower gluten-specific proliferative responses compared with those of CD patients, indicating that tetramer-binding memory cells in healthy control subjects may be cross-reactive T cells. In duodenal biopsy specimens of healthy control subjects, CD4+ T cells were determined not to be gluten reactive. Finally, gluten tetramer-binding cells of healthy individuals did not coexpress regulatory T cell markers (Foxp3+ CD25+) and cultured T cell clones did not express a cytokine profile that indicated immune-dampening properties. The results demonstrate that healthy HLA-DQ2.5+ individuals do not mount a T cell response to immunodominant gluten epitopes of CD.

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“…In CD and CD-related autoimmune diseases a resistance of effector T lymphocytes to suppression by adaptive T reg cells has been demonstrated and has been proposed to explain the loss of immune homeostasis and development of autoimmune responses. Although percentages of CD4+ CD25+ FoxP3 + intraepithelial and lamina propria lymphocytes were significantly higher in patients with active CD compared to healthy controls, proliferation and IFN-γ production of intestinal T lymphocytes were significantly less inhibited by autologous or heterologous T reg cells in CD patients than in controls [70]. Several T reg cells have been found to be important for oral food tolerance: T H 3 cells, a population of CD4+ cells that produce transforming growth factorbeta (TGF-β); T regulatory type 1 (Tr1) cells, which secrete IL-10; CD4+ CD25+ regulatory T-cells, which express the transcription factor forkhead/winged-helix transcription factor box protein 3 (FoxP3); CD8+ suppressor T-cells; and gammadelta T-cells.…”

Section: Non-celiac Gluten Sensitivitymentioning

confidence: 92%

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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Impaired Control of Effector T Cells by Regulatory T Cells: A Clue to Loss of Oral Tolerance and Autoimmunity in Celiac Disease?

Abstract: Our results indicate that effector T lymphocytes from active CD become resistant to suppression by Tregs. This resistance might cause loss of tolerance to gluten, but also to self-antigens.

Cited by 96 publications

References 35 publications

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

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

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Non-Celiac Gluten Sensitivity: Literature Review

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