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

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          Summary

          Coeliac 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 +CD25 ++forkhead box protein 3 (FoxP3 +) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, 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 Δ2 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)‐γ 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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          Author and article information

          Contributors
          afasano@mgh.harvard.edu
          Journal
          Clin Exp Immunol
          Clin. Exp. Immunol
          10.1111/(ISSN)1365-2249
          CEI
          Clinical and Experimental Immunology
          John Wiley and Sons Inc. (Hoboken )
          0009-9104
          1365-2249
          12 January 2017
          March 2017
          : 187
          : 3 ( doiID: 10.1111/cei.2017.187.issue-3 )
          : 490-506
          Affiliations
          [ 1 ] Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition Center for Celiac Research, Mucosal Immunology and Biology Research Center Boston MA USA
          [ 2 ] Graduate Program in Life Sciences, University of Maryland School of Medicine Baltimore MD USA
          [ 3 ] Celiac Center, Division of Gastroenterology, Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston MA USA
          [ 4 ] Department of Gastroenterology Massachusetts General Hospital Boston MA USA
          [ 5 ] European Biomedical Research Institute of Salerno (EBRIS) Salerno Italy
          Author notes
          [* ]Correspondence: Alessio Fasano, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, 175 Cambridge Street, Boston, MA 02114, USA. E‐mail: afasano@ 123456mgh.harvard.edu
          Article
          PMC5290237 PMC5290237 5290237 CEI12911
          10.1111/cei.12911
          5290237
          27936497
          © 2017 British Society for Immunology
          Page count
          Figures: 10, Tables: 0, Pages: 18, Words: 9930
          Funding
          Funded by: The National Institutes of Health (NIH)
          Award ID: DK048373
          Award ID: DK104344
          Categories
          Original Article
          Original Articles
          Translational
          Inflammation
          Custom metadata
          2.0
          cei12911
          March 2017
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.4 mode:remove_FC converted:03.02.2017

          Treg , microbiome, celiac disease, autoimmunity

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