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Immunopathology of childhood celiac disease: Key role of intestinal epithelial cells
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. (Marie-Louise Hammarström)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. (Marie-Louise Hammarström)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. (Marie-Louise Hammarström)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. (Marie-Louise Hammarström)
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, e0185025Article in journal (Refereed) Published
Abstract [en]

BACKGROUND & AIMS: Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.

METHODS: Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.

RESULTS: More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.

CONCLUSION: A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.

Place, publisher, year, edition, pages
2017. Vol. 12, no 9, e0185025
National Category
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-139860DOI: 10.1371/journal.pone.0185025ISI: 000411339900076PubMedID: 28934294OAI: oai:DiVA.org:umu-139860DiVA: diva2:1144053
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2017-11-16Bibliographically approved
In thesis
1. Innate immunity of human intestinal epithelium in childhood celiac disease: influences from celiac disease associated bacteria and dietary oats
Open this publication in new window or tab >>Innate immunity of human intestinal epithelium in childhood celiac disease: influences from celiac disease associated bacteria and dietary oats
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background & Aims: Celiac disease (CD) is a chronic inflammatory small-bowel enteropathy caused by permanent intolerance to gliadin in wheat gluten, and related proteins in ray and barley. It is disputed whether CD patients tolerate oats. The only treatment of CD is lifelong gluten-free diet (GFD). Only individuals that carry the HLA-DQ2 and/or DQ8 alleles, and eat gluten can develop CD. Dysbiosis in the gut microbiota is a suggested risk factor for CD. T cells in small intestinal mucosa, including intraepithelial lymphocytes (IELs), are known to be important in the pathogenesis of CD. In contrast, the role of intestinal epithelial cells (IECs) is poorly understood. In this thesis we investigated the role of IECs in the immune pathology of CD from duodenal mucosa of children with CD, clinical controls and treated CD. We also investigated the role of CD associated bacteria and oats supplemented GFD on the mucosal immune system.

Results: A new CD-associated bacterium, Prevotella jejuni, was isolated and characterized. It is a saccharolytic and proteolytic anaerobe. More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were upregulated in IECs in active CD. In two in vitro models for intestinal epithelium, small intestine enteroids and T84 polarized tight monolayers, we showed that 70% of these genes were upregulated by interferon (IFN)-γ via the IRF1 pathway. IRF1 was also upregulated by the CD-associated bacteria P. jejuni and Actinomyces gravenitzii. IECs expressed the NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin (IL)-18, which induces IFN-γ in IELs. P. jejuni bound the intestinal epithelial cell lines T84, Caco2, HT29, and INT407, while Lachnoanaerobaculum umeaense preferentially bound Caco2. P. jejuni caused decreased transepithelial resistance over tight monolayers, while L. umeaense caused an increase. P. jejuni upregulated mRNAs for the detoxification molecules CYP1A1, CYP1A2, CYP1B1, and TIPARP, the chemokines CX3CL1, CXCL1, and CXCL10, the sialyltranserase ST3GAL4, and the inflammation promoting protein S100A3 in tight monolayers. L. umeaense upregulated the chemokines CCL20 and CXCL10, and down-regulated TLR2. In a randomized, double-blinded intervention trial comparing two study-groups, standard GFD and oat-containing GFD, we found that mRNAs for several immune effector molecules and tight junction proteins were only reduced in patients receiving GFD, but not in a substantial fraction of patients on GFD with oats. The down-regulatory cytokines IL-10 and TGF-β1, the cytotoxicity-activating NK-receptors NKG2C and NKG2E, and the tight junction protein claudin-4 remained elevated in the study group on GFD with oats.

Conclusions: IECs are far from inactive in CD. A key factor in the epithelial reaction in CD appears to be over-expression of IRF1 in IECs. Dual activation of IRF1 and IRF1-regulated genes, both directly by P. jejuni and indirectly by IFN-γ via the IL-18-inflammasome, would drastically enhance the inflammatory response and lead to the pathological situation seen in active CD. P. jejuni harms the intestinal epithelium, i.e., it is a likely risk factor for CD, while L. umeaense strengthen barrier function and local immunity, possibly acting as a protective. A fraction of CD patients should avoid oats in the diet.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2017. 75 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1924
Keyword
Celiac disease, dietary oats, gut microbiota, intestinal epithelium, IEL, IFN-γ, IRF1, IL-18, CXC3L1, inflammasome, permeability, Prevotella jejuni, Lachnoanaerobaculum umeaense
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-140691 (URN)978-91-7601-768-5 (ISBN)
Public defence
2017-11-23, A5_R0, Analysvägen 3, Umeå, 09:00 (English)
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Available from: 2017-11-02 Created: 2017-10-25 Last updated: 2017-10-31Bibliographically approved

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