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Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
National Institute for Health and Welfare, Finland.
National Institute for Health and Welfare, Finland.
National Institute for Health and Welfare, Finland.
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2012 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 167, no 2, 226-234 p.Article in journal (Refereed) Published
Abstract [en]

Up-regulation of interleukin (IL)-17 in small intestinal mucosa has been reported in coeliac disease (CD) and in peripheral blood in type 1 diabetes (T1D). We explored mucosal IL-17 immunity in different stages of CD, including transglutaminase antibody (TGA)-positive children with potential CD, children with untreated and gluten-free diet-treated CD and in children with T1D. Immunohistochemistry was used for identification of IL-17 and forkhead box protein 3 (FoxP3)-positive cells and quantitative polymerase chain reaction (qPCR) for IL-17, FoxP3, retinoic acid-related orphan receptor (ROR)c and interferon (IFN)-γ transcripts. IL-1β, IL-6 and IL-17 were studied in supernatants from biopsy cultures. Expression of the apoptotic markers BAX and bcl-2 was evaluated in IL-17-stimulated CaCo-2 cells. The mucosal expression of IL-17 and FoxP3 transcripts were elevated in individuals with untreated CD when compared with the TGA-negative reference children, children with potential CD or gluten-free diet-treated children with CD (P andlt; 0·005 for all IL-17 comparisons and P andlt; 0·01 for all FoxP3 comparisons). The numbers of IL-17-positive cells were higher in lamina propria in children with CD than in children with T1D (P andlt; 0·05). In biopsy specimens from patients with untreated CD, enhanced spontaneous secretion of IL-1β, IL-6 and IL-17 was seen. Activation of anti-apoptotic bcl-2 in IL-17-treated CaCo-2 epithelial cells suggests that IL-17 might be involved in mucosal protection. Up-regulation of IL-17 could, however, serve as a biomarker for the development of villous atrophy and active CD.

Place, publisher, year, edition, pages
John Wiley & Sons, 2012. Vol. 167, no 2, 226-234 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-74185DOI: 10.1111/j.1365-2249.2011.04510.xOAI: diva2:481171
Available from: 2012-01-20 Created: 2012-01-20 Last updated: 2014-09-19
In thesis
1. Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes
Open this publication in new window or tab >>Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Celiac disease (CD) and type 1 diabetes (T1D) are two chronic autoimmune diseases with increasing incidence worldwide. A combination of genetic, environmental and immunological factors is considered to be involved in development of the diseases, even though the exact disease mechanisms still are unknown. CD and T1D are both believed to be associated with type 1 like immune responses. However, there is limited knowledge about the complex network of intestinal and peripheral immune responses associated with the diseases.

Aims: The aim of this thesis was to explore intestinal and peripheral immune responses in children at different stages of CD and in children with T1D. Further, we studied peripheral immune responses in children at risk for T1D supplemented with probiotics during their first 6 months of life (PRODIA study).

Results & Discussion: Children with untreated CD had up-regulated T-helper (Th)1, T-cytotoxic (Tc)1, Th17 and T-regulatory (Treg) responses, but down-regulated Th2 and Th3 responses in the small intestine. The type 1 response (Th1 and Tc1) seemed to remain elevated in CD children under gluten free diet (GFD)-treatment and thus seemed to be related to the disease itself rather than the gluten intake. The Th2, Th3, Th17 and Treg responses seemed to be gluten dependent, since they normalized upon GFD-treatment. The alterations in the intestinal biopsies did not seem to correlate with the alterations seen in the blood Children with potential CD had diminished levels of the Th17 cytokine IL-17, whereas children with untreated CD had elevated levels of IL-17, indicating that IL-17 immunity develops in the late phase of CD when villous atrophy has developed. Furthermore, stimulation of intestinal epithelial cells with IL-17 induced anti-apoptotic mechanisms. The low intestinal expression of Th1, Th17 and Treg markers was normal in children with T1D, whereas children with T1D and CD had the same pattern as children with untreated CD: high intestinal secretion of pro-inflammatory and Th17 cytokines. The immune responses in children with T1D were generally influenced by the degree of villous atrophy.

As expected, the number of children in the PRODIA study developing T1D related autoantibodies during their first two years of life was low. No difference in the autoantibody emergence was seen between infants given probiotics compared to placebo. In the probiotic group, the number of circulating CD58+ monocytes was lower at 6 months of age. At 12 months of age the number of circulating CCR5+ monocytes was lower in the probiotic group, whereas the spontaneous expression of TLR9 on PBMCs was higher.

Conclusion: Most of the intestinal T-cell associated immune alterations were generally gluten dependent, since they normalized on a GFD treatment, but the type 1 response seemed to be related to the disease itself, since it was still seen in GFD treated individuals. IL-17 immunity seemed to be induced in the late stage of CD, when villous atrophy has developed and it seemed to be involved in protection from tissue damage in the inflamed intestinal mucosa. The intestinal immune responses were generally not reflected in peripheral blood.

Probiotic supplementation in infancy modulated the activation stage and stimulation response of monocytes. Thus, early exposure to microbes seemed to influence the function of the innate immune system in later life.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 129 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1410
National Category
Clinical Medicine Immunology
urn:nbn:se:liu:diva-110687 (URN)10.3384/diss.diva-110687 (DOI)978-91-7519-286-4 (print) (ISBN)
Public defence
2014-10-10, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2014-09-19Bibliographically approved

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Lahdenperä, AnnaFälth-Magnusson, KarinHögberg, LottaLudvigsson, Johnny
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PediatricsFaculty of Health SciencesDepartment of Paediatrics in LinköpingDepartment of Paediatrics in Norrköping
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Clinical and Experimental Immunology
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