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CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
McMaster University.
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
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2009 (English)In: American Journal of Pathology, ISSN 0002-9440, Vol. 174, no 1, 82-90 p.Article in journal (Refereed) Published
Abstract [en]

Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

Place, publisher, year, edition, pages
2009. Vol. 174, no 1, 82-90 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-16424DOI: 10.2353/ajpath.2009.080273OAI: diva2:139587
Available from: 2009-01-23 Created: 2009-01-23 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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