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Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-110687DOI: 10.3384/diss.diva-110687ISBN: 978-91-7519-286-4 (print)OAI: oai:DiVA.org:liu-110687DiVA: diva2:748435
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
List of papers
1. The effect of gluten-free diet on Th1--Th2--Th3-associated intestinal immune responses in celiac disease
Open this publication in new window or tab >>The effect of gluten-free diet on Th1--Th2--Th3-associated intestinal immune responses in celiac disease
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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
Keyword
Arrays, biopsies, celiac disease, children, gene expression, gluten-free diet, PBMC, Th1, Th2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67826 (URN)10.3109/00365521.2011.551888 (DOI)000289437200005 ()
Available from: 2011-04-29 Created: 2011-04-29 Last updated: 2014-11-11
2. Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes
Open this publication in new window or tab >>Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-74185 (URN)10.1111/j.1365-2249.2011.04510.x (DOI)
Available from: 2012-01-20 Created: 2012-01-20 Last updated: 2017-12-08
3. Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease
Open this publication in new window or tab >>Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease
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2014 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 49, no 2, 145-156 p.Article in journal (Refereed) Published
Abstract [en]

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

Place, publisher, year, edition, pages
Informa Healthcare, 2014
Keyword
arrays; celiac disease; children; gene expression; gluten-free diet; IL-17; mucosa; Th17
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104288 (URN)10.3109/00365521.2013.863966 (DOI)000329874800003 ()
Available from: 2014-02-17 Created: 2014-02-14 Last updated: 2017-12-06
4. Probiotics and innate immune response in infants
Open this publication in new window or tab >>Probiotics and innate immune response in infants
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We studied the effects of probiotic treatment on the innate immune system during infancy. The study included a subgroup of infants recruited to the pilot study testing the feasibility of probiotics intervention in infants with genetic risk of type 1 diabetes (T1D). A mixture of Lactobacillus rhamnosus GG (5 x 109 cfu), Lactobacillus rhamnosus LC705 (5 x 109 cfu), Bifidobacterium breve Bbi99 (2 x 108 cfu) and Propionibacterium freudenreichii ssp. Shermani JS (2 x 109 cfu) was given to the infants beginning one to three weeks after birth until the age of 6 months. Blood samples were drawn at the age of 6, 12 and 24 months for the analyses of beta-cell autoantibodies and the phenotype and stimulation response of monocytes with flow-cytometry, including surface markers on circulating CD14+ monocytes and expression of co-stimulatory markers on CD14+ monocytes as response to stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Also gene expression of toll-like receptor (TLR) signalling molecules was studied in the peripheral blood mononuclear cell (PBMC) population.

In the children who received probiotics the number of circulating CD14+ monocytes expressing CD58 was reduced at the age of 6 months, and a tendency for a decreased induction of CCR5, CD80 and CD58 expressing monocytes as response to LTA was seen when compared to the children who received placebo. At the age of 12 months, the number of monocytes expressing CCR5 was decreased in the probiotic group, and a decreased spontaneous expression of TNFRSF1A and an increased spontaneous expression of TLR9 was observed in the PBMC from the children treated with probiotics. In the whole study group, the numbers of circulating monocytes expressing CD80 increased with age as well as the induction of CCR5, CD80 and CD58 on monocytes as response to stimulation. By the age of 24 months one child in both groups developed multiple autoantibodies.

We demonstrated that probiotics modulated the activation stage and stimulation response of monocytes, and that prolonged effects of the treatment were seen at the age of 12 months. The findings suggest that early microbial exposure may program the function of the innate immune system for later life.

Keyword
Probiotics, monocytes, innate immunity, TLR, LTA, LPS
National Category
Clinical Medicine Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-110686 (URN)
Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2014-09-19Bibliographically approved

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