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Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery Östergötland.
Pathogénie Bactérienne Intestinale Laboratoire de Bactériologie, CBRV, Université d'Auvergne, Clermont-Ferrand, France.
Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA, USA.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

SAMP1/YitFc mice are a unique murine model for Crohn’s disease (CD) as they develop spontaneous intestinal inflammation without chemical or genetic manipulations. Inflammation is primarily located in the distal ileum, which is the hallmark location for CD. It is at the distal ileum of CD where small erosions that develop at the follicle-associated epithelium (FAE) and are one of the earliest observable lesions in recurrent ileitis. In the report, we studied the intestinal permeability defect and examined the role of dendritic cells (DCs) in the SAMP1/YitFc mice ileitis. Segments of FAE and VE from 11 and 27 weeks old SAMP1/YitFc mice and AKR control background stains were mounted on Ussing chambers. Electrical conductivity and permeability to 51Cr-EDTA, horseradish peroxidise (HRP) and E.coli HB101 and LF82 were recorded. There was ileal permeability to 51Cr-EDTA and HRP in the 27 weeks old SAMP1/YitFc mice. Both E.coli HB101 and LF82 increased conductance by two-folds in FAE and VE of SAMP1/YitFc mice. Furthermore, both bacterial strains increased tissue conductance and 51Cr-EDTA passage. There was greater passage of E.coli LF82 in the 27 week old DAMP1/YitFc mice than in controls. Confocal microscopy revealed a high number of CD11c+ DCs in the sub-epithelial dome (SED) area, though there was no difference between the SAMP1/YitFc mice than the AKR controls. Immunofluorescence characterisation also did not reveal any phenotypic difference in DCs between the mice strains. These results show that SAMP1/YitFc mice have a barrier defect, which was more pronounced in the FAE of older mice, and demonstrate a mucosal sensitivity bacteria. It also confirms that this model of chronic ileitis is primarily a defect in permeability defect and not DCs.

Keyword [en]
52Cr-EDTA, dentric cells, E.coli, HRP, permeability, Ussing chanbers
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-52233OAI: diva2:280718
Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved
In thesis
1. Mucosal dendritic cells in inflammatory bowel disease
Open this publication in new window or tab >>Mucosal dendritic cells in inflammatory bowel disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crohn's disease, a chronic inflammation of the bowel, is a multi-factorial condition where uncontrolled immune responses to luminal bacteria occur in genetically predisposed individuals. The first observable clinical signs are small ulcers that form at a specialised form of epithelium, follicle-associated epithelium (FAB). The FAB covers immune inductive sites, Peyer's patches, which function primarily as sensory areas that sample the externaI gut environment. Dendritic cells are one of the key cells that are involved in sensing luminal contents and orchestrating the gut immune system.

The main aim of this thesis was to determine whether the barrier of the FAB is breached in Crohn's disease and if dysfunctional immune regulators, namely dendritic cells, playaroIe in initiating and/or maintaining the chronic intestinal inflammation.

Using biopsies and surgical specimens, we were able to show that in Crohn's disease, there was an increased transmucosaI transport of Escherichia coli compared to specimens from ulcerative colitis and non-inflammatory bowel disease (IBD) controIs. Dendritic cells internalised a higher percentage of bacteria that had translocated across the FAB in the Crohn's samples. Furthermore, significantly higher concentrations of TNF-u was released upon bacterial stimulation by tissues from patients with Crohn's disease than in controIs.

We went on to characterise the dendritic cells present in the Peyer's patches of patients with Crohn's disease. We found an accumulation of both immature and mature dendritic cells beneath the FAB, in the sub-epithelial dome (SED). Normally, mature dendritic cells migrate towards T cell-rich areas. However, we observed mature dendritic cells accumulating in the SED because they lacked the CCR7 migratory receptor. Furthermore, they were more prone to take-up bacteria, and produced TNF.

To study the function of mucosal dendritic cells, we performed isolation experiments and mixed Iymphocyte reactions. Dendritic cells from both the ileum and blood of patients with active Crohn's had reduced capacity for inducing T cell proliferation than non-IBD controIs. Blood dendritic cells of patients in remission had normalised function that was similar to dendritic cells from healthy controls.

The SAMPl/YitFc mice, considered an appropriate murine model for Crohn's disease, had an inherent permeability defect that increased with the chronicity of intestinaI inflammation. However unlike in human Crohn's disease, dendritic cells did not seem to playaroIe in murine ileitis.

This thesis highlights the accumulation of the actively surveying dendritic cells that are prone to bacterial internalisation, and points to their possible different functional roles in active versus in-active disease; thereby confirming dendritic cells as one ofthe key components in the pathogenesis ofCrohn's disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 72 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1129
Blood, Crohn's disease, dendritic cells, E. coli, FACS, follicle-associated, epithelium, human, ileum, mixed lymphocyte reaction, permeability, Peyer's patches, SAMP1/YitFc, Ussing chambers, villous epithelium
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-52234 (URN)978-91-7393-625-5 (ISBN)
Public defence
2009-05-19, Berzeliussalen, Hälsouniversitetet, Campus Valla, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved

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Salim, Sa'ad YislamMyrelid, PärSöderholm, Johan D.
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Surgery Faculty of Health SciencesDepartment of Surgery Östergötland
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