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The effect of gluten-free diet on Th1--Th2--Th3-associated intestinal immune responses in celiac disease
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
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2011 (English)In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 46, no 5, 538-549 p.Article in journal (Refereed) Published
Abstract [en]

Objective. To study T-helper (Th)1--Th2--Th3 gene activation profile in the small intestine and peripheral blood of children with celiac disease (CD) with special interest in the response to the gluten-free diet (GFD) treatment in order to elucidate an immune dysregulation not triggered by gluten. Material and methods. Small intestinal biopsies and venous blood were taken from seven children with CD (mean age: 8 years, four girls) at presentation and after 1 year of strict GFD. The Th1--Th2--Th3 gene expression profile was examined by real-time PCR arrays. The findings were compared with the corresponding expressions in peripheral blood and small intestinal biopsies from six reference children without CD (mean age: 6 years, four girls). Results. The Th1 gene expression profile including interferon (IFN)-gamma gamma, signal transducer and activator of transcription (STAT) 1 and interferon regulatory factor (IRF) 1 together with reduced interleukin (IL)-2 expression was pronounced in small intestinal biopsies from children with untreated CD. A downregulation of IFN-gamma gamma transcripts was seen after 1 year of GFD, but there was still increased expression of STAT1 and IRF1 in association with low IL-2 expression in spite of eliminated exposure to wheat gluten. By contrast, the decreased intestinal expression of Th2 gene markers observed at presentation was normalized with GFD. The alterations in the mucosal gene expression profile were not reflected in peripheral blood. Conclusion. The GFD did not correct the increased activation of the IFN-gamma gamma signaling pathway related markers and reduced IL-2 expression, suggesting that they represent an immune dysregulation not dependent on gluten exposure.

Place, publisher, year, edition, pages
Informa Healthcare , 2011. Vol. 46, no 5, 538-549 p.
Keyword [en]
Arrays, biopsies, celiac disease, children, gene expression, gluten-free diet, PBMC, Th1, Th2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-67826DOI: 10.3109/00365521.2011.551888ISI: 000289437200005OAI: oai:DiVA.org:liu-67826DiVA: diva2:413607
Available from: 2011-04-29 Created: 2011-04-29 Last updated: 2014-11-11
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1410
National Category
Clinical Medicine Immunology
Identifiers
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)
Opponent
Supervisors
Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2014-09-19Bibliographically approved

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Lahdenperä, AnneLudvigsson, JohnnyFälth-Magnusson, KarinHögberg, LottaVaarala, Outi
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PediatricsFaculty of Health SciencesDepartment of Paediatrics in LinköpingDepartment of Paediatrics in Norrköping
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