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Immune response of the small intestinal mucosa in children with celiac disease: impact of two environmental factors, resident microbiota and oats
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Celiac disease (CD) is an immune-mediated enteropathy caused by permanent intolerance to dietary gliadin in wheat gluten and related prolamines in barley and rye. The pathogenesis of CD is still unknown and several different environmental factors have been associated with CD, such as dysbiosis of the microflora. In this translational study we investigated the immune status and the interplay of T-cells and Tregs in the mucosa of children with CD and controls, as well as the immune status in treated CD patients, provoked by either dietary oats, CD associated bacteria or gluten.

The major findings in the studies were: First, indicators of extrathymic T-cells maturation (ETCM), i.e., the RAG1 enzyme required for recombination of the T cell receptor (TCR) genes and the preTα-surrogate chain in the immature TCR, were both expressed at lower levels in CD patients compared to controls. In addition, IELs expressing RAG1 were less abundant in CD patients compared to controls. The levels of these two indicators stayed low in treated CD patients as well, suggesting that impaired capacity of ETCM is an inherent feature of CD patients. Second, IL-17A, a cytokine involved in both inflammation and anti-bacterial responses was increased in active CD. The major cellular source was CD8+IELs. Furthermore, ex vivo challenge of biopsies from treated CD patients with gluten and with CD-associated bacteria induced an IL-17A response. The CD-associated bacteria also influenced the magnitude of the IL-17A response to gluten. Third, we investigated the effect of dietary oats on local immune status in the intestinal mucosa by comparing CD patients receiving GFD with and without oats. 22 different mRNAs for immunity effector molecules and tight junction proteins were analyzed. We found that expression of two down-regulatory cytokines, two activating NK-receptors and the tight-junction protein claudin-4 normalized in patients on a standard GFD while they did not normalize in patients on a GFD with oats. Fourth, we analyzed the expression level of mRNAs for chemokines, cytotoxic effector molecules, NK-receptors and their ligands in IELs and epithelial cells. Expression levels of several of these genes follow disease activity, suggesting massive recruitment of immune cells by both cell types accompanied by increased IEL-mediated cytotoxicity in the epithelium of inflamed mucosa.

In this thesis we have identified three potential risk factors for development of CD: 1) an inherent lower level of ETCM in the small intestinal mucosa than in controls. This could lead to decreased generation of regulatory T cells and less capacity to tolerate gluten and adapt to the local milieu in the mucosa. 2) Dysbiosis of the resident microbiota with increased IL-17A production that could promote local inflammation and immune cell infiltration as well as antibacterial reactions. 3) Dietary oats may provoke a local immune response in a sub-population of CD patients. These patients should probably avoid oats in their GFD but larger studies are needed.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 69 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1576
Keyword [en]
Celiac disease, Oats, Microflora, Immune response
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-71030ISBN: 978-91-7459-663-2 (print)ISBN: 978-91-7459-664-9 (print)OAI: oai:DiVA.org:umu-71030DiVA: diva2:621630
Public defence
2013-06-13, E04, byggnad 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2013-05-23 Created: 2013-05-16 Last updated: 2013-05-23Bibliographically approved
List of papers
1. Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for coeliac disease?
Open this publication in new window or tab >>Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for coeliac disease?
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2009 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 58, no 2, 189-195 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Coeliac disease is a small intestine enteropathy caused by permanent intolerance to wheat gluten. Gluten intake by patients with coeliac disease provokes a strong reaction by intestinal intraepithelial lymphocytes (IELs), which normalises on a gluten-free diet. AIM: To investigate whether impaired extrathymic T cell maturation and/or secondary T cell receptor (TCR) gene recombination in IELs are features of coeliac disease which could contribute to the failure of establishing tolerance to gluten.

METHODS: Expression levels of the four splice-forms of recombination activating gene-1 (RAG1) mRNA and preT alpha-chain (preTalpha) mRNA were determined in IEL-subsets of children with coeliac disease and controls. Frequencies of RAG1 expressing IELs were determined by immunomorphometry.

RESULTS: In controls, the RAG1-1A/2 splice-form selectively expressed outside the thymus, was dominant and expressed in both mature (TCR(+)) and immature (CD2(+)CD7(+)TCR(-)) IELs ( approximately 8 mRNA copies/18S rRNA U). PreTalpha was expressed almost exclusively in CD2(+)CD7(+)TCR(-) IELs ( approximately 40 mRNA copies/18S rRNA U). By contrast, RAG1 and preTalpha mRNA levels were low in patients with coeliac disease compared to controls, both with active disease and with inactive, symptom-free disease on a gluten-free diet (p values <0.01 for mature and <0.05 for immature IELs). Similarly, the frequencies of RAG1+ IELs were significantly lower in patients with coeliac disease compared to controls (p<0.001).

CONCLUSIONS: Patients with coeliac disease appear to have an impaired capacity for extrathymic TCR gene rearrangement. This is an inherent feature, which probably plays a pivotal role in the failure to efficiently downregulate the T cell response to gluten.

National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-21080 (URN)10.1136/gut.2007.125526 (DOI)18299319 (PubMedID)
Available from: 2009-04-06 Created: 2009-04-02 Last updated: 2013-05-23Bibliographically approved
2. Intestinal T-cell responses in celiac disease: impact of celiac disease associated bacteria
Open this publication in new window or tab >>Intestinal T-cell responses in celiac disease: impact of celiac disease associated bacteria
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, e53414- p.Article in journal (Refereed) Published
Abstract [en]

A hallmark of active celiac disease (CD), an inflammatory small-bowel enteropathy caused by permanent intolerance to gluten, is cytokine production by intestinal T lymphocytes. Prerequisites for contracting CD are that the individual carries the MHC class II alleles HLA-DQ2 and/or HLA-DQ8 and is exposed to gluten in the diet. Dysbiosis in the resident microbiota has been suggested to be another risk factor for CD. In fact, rod shaped bacteria adhering to the small intestinal mucosa were frequently seen in patients with CD during the "Swedish CD epidemic" and bacterial candidates could later be isolated from patients born during the epidemic suggesting long-lasting changes in the gut microbiota. Interleukin-17A (IL-17A) plays a role in both inflammation and anti-bacterial responses. In active CD IL-17A was produced by both CD8(+) T cells (Tc17) and CD4(+) T cells (Th17), with intraepithelial Tc17 cells being the dominant producers. Gluten peptides as well as CD associated bacteria induced IL-17A responses in ex vivo challenged biopsies from patients with inactive CD. The IL-17A response was suppressed in patients born during the epidemic when a mixture of CD associated bacteria was added to gluten, while the reverse was the case in patients born after the epidemic. Under these conditions Th17 cells were the dominant producers. Thus Tc17 and Th17 responses to gluten and bacteria seem to pave the way for the chronic disease with interferon-γ-production by intraepithelial Tc1 cells and lamina propria Th1 cells. The CD associated bacteria and the dysbiosis they might cause in the resident microbiota may be a risk factor for CD either by directly influencing the immune responses in the mucosa or by enhancing inflammatory responses to gluten.

Place, publisher, year, edition, pages
PLoS, Public Library of Science, 2013
National Category
Pediatrics Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-64525 (URN)10.1371/journal.pone.0053414 (DOI)23326425 (PubMedID)
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-12-06Bibliographically approved
3. Dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease
Open this publication in new window or tab >>Dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease
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(English)Manuscript (preprint) (Other academic)
Keyword
Oats, Celiac disease, Immune response
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-71026 (URN)
Available from: 2013-05-16 Created: 2013-05-16 Last updated: 2013-05-24
4. Gene expression profile of the epithelial reaction in childhood Celiac disease
Open this publication in new window or tab >>Gene expression profile of the epithelial reaction in childhood Celiac disease
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-71029 (URN)
Available from: 2013-05-16 Created: 2013-05-16 Last updated: 2013-05-23Bibliographically approved

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