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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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    Author
    Serena, G.
    Yan, S.
    Camhi, S.
    Date
    2017
    Journal
    Clinical and Experimental Immunology
    Publisher
    Blackwell Publishing Ltd
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.1111/cei.12911
    Abstract
    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 (Treg) 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 Treg 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. Copyright 2017 British Society for Immunology
    Keyword
    autoimmunity
    celiac disease
    microbiome
    Treg
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85009767244&doi=10.1111%2fcei.12911&partnerID=40&md5=5a7e825ee2a2295b2fb668bbdc323cc8; http://hdl.handle.net/10713/10063
    ae974a485f413a2113503eed53cd6c53
    10.1111/cei.12911
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    UMB Open Access Articles 2017

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