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  • 1.
    Chassaing, Benoit
    et al.
    University Auvergne.
    Rolhion, Nathalie
    University Auvergne.
    de Vallee, Amelie
    University Auvergne.
    Salim, Sa´ad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Prorok-Hamon, Maelle
    University of Liverpool.
    Neut, Christel
    University Lille 2.
    Campbell, Barry J
    University of Liverpool.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Hugot, Jean-Pierre
    University of Paris Diderot.
    Colombel, Jean-Frederic
    University Lille 2.
    Darfeuille-Michaud, Arlette
    University Auvergne.
    Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyers patches via long polar fimbriae2011Ingår i: JOURNAL OF CLINICAL INVESTIGATION, ISSN 0021-9738, Vol. 121, nr 3, s. 966-975Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Crohn disease (CD) is a multifactorial disease in which an abnormal immune response in the gastrointestinal (GI) tract leads to chronic inflammation. The small intestine, particularly the ileum, of patients with CD is colonized by adherent-invasive E. coil (AIEC) a pathogenic group of E. coil able to adhere to and invade intestinal epithelial cells. As the earliest inflammatory lesions are microscopic erosions of the epithelium lining the Peyers patches (PPs), we investigated the ability of AIEC bacteria to interact with PPs and the virulence factors involved. We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice. In conclusion, we have identified LPF as a key factor for AIEC to target PPs. This could be the missing link between AIEC colonization and the presence of early lesions in the PPs of CD patients.

  • 2. Gullberg, Elisabet
    et al.
    Keita, Åsa
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi.
    Salim, Sa´ad
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi.
    Andersson, Margaretha
    Caldwell, Karin D
    Söderholm, Johan D
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Artursson, Per
    Identification of cell adhesion molecules in the human follicle-associated epithelium that improve nanoparticle uptake into the Peyer's patches2006Ingår i: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 319, nr 2, s. 632-639Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to identify cell adhesion molecules that could serve as targets of the human follicle-associated epithelium (FAE) overlying Peyer's patches and to assess nanoparticle uptake levels across this epithelium. We first studied the expression of the mouse M-cell marker β1- integrin and used a model of human FAE derived from intestinal epithelial Caco-2 cells and Raji B-cells to identify additional potential targets by cDNA array. The protein expression of potential targets in the model FAE and in human ileal FAE tissues was quantified by immunofluorescence. Integrin targeting was studied by investigating the transport of Arg-Gly-Asp (RGD)-coated (integrin-binding), Arg-Gly-Glu (RGE)-coated (nonintegrin-binding), and uncoated nanoparticles across ileal specimens mounted in Ussing chambers. Both β1- integrin and the cell adhesion molecule CD9 were more abundantly expressed in the model and human FAE compared with the Caco-2 control cells or villus epithelium (VE). Uncoated nanoparticles were not taken up across either FAE or VE. General integrin targeting with RGD improved the nanoparticle transport dramatically across the FAE and to a lower extent across the VE. Compared with RGE, RGD improved transport 4-fold across the FAE. There was no difference in the transport of RGD- and RGE-coated nanoparticles across the VE. In conclusion, β1-integrin and CD9 were identified as targets in human FAE. The difference in RGD- and RGE-mediated transport across the FAE, but not the VE, suggests that a specific integrin interaction was the dominating mechanism for improved nanoparticle uptake across the FAE., whereas charge interaction contributed substantially to the improved VE uptake. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

  • 3.
    Keita, Åsa
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Salim, Sa´ad
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi.
    Jiang, T.
    Department of Clinical and Experimental Medicine Linköping University.
    Yang, P-C
    Intestinal Disease Research Program McMaster University, Hamilton, Canada.
    Franzén, Lennart
    Aleris Medilab Täby.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Magnusson, Karl-Eric
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    Söderholm, Johan D
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease2008Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, nr 2, s. 135-144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In Crohn's disease (CD), inflammation is driven by luminal commensal micro-organisms, however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle-associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non-pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr-EDTA, horseradish peroxidase, and non-pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non-exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K-12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr-EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co-localizing with dendritic cells, and augmented tissue release of TNF-α. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 4.
    Keita, Åsa V
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Gullberg, Elisabet
    Department of Pharmacy, Uppsala University, BMC, Uppsala, Sweden.
    Ericson, Ann-Charlott
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Salim, Sa’ad Y
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wallon, Conny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Kald, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Artursson, Per
    Department of Pharmacy, Uppsala University, BMC, Uppsala, Sweden.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum2006Ingår i: Laboratory investigation, ISSN 0023-6837, Vol. 86, nr 5, s. 504-516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The follicle-associated epithelium (FAE), covering Peyer's patches, provides a route of entry for antigens and microorganisms. Animal studies showed enhanced antigen and bacterial uptake in FAE, but no study on barrier function of human FAE has been reported. Our aim was to characterize the normal barrier properties of human FAE. Specimens of normal ileum were taken from 30 patients with noninflammatory colonic disease. Villus epithelium (VE) and FAE were identified and mounted in Ussing chambers. Permeability to 51Cr-EDTA, transmucosal flux of the protein antigen, horseradish peroxidase (HRP), and transport of fluorescent Escherichia coli (chemically killed K-12 and live HB101) were measured. Uptake mechanisms were studied by confocal- and transmission electron microscopy, and by using pharmacological inhibitors in an in vitro coculture model of FAE and in human ileal FAE. HRP flux was substantially higher in FAE than in VE, and was reduced by an amiloride analog. Electron microscopy showed HRP-containing endosomes. Transport of E. coli K-12 and HB101 was also augmented in FAE and was confirmed by confocal microscopy. In vitro coculture experiments and electron microscopy revealed actin-dependent, mainly transcellular, uptake of E. coli K-12 into FAE. 51Cr-EDTA permeability was equal in FAE and VE. Augmented HRP flux and bacterial uptake but similar paracellular permeability, suggest functional variations of transcellular transport in the FAE. We show for the first time that FAE of human ileum is functionally distinct from regular VE, rendering the FAE more prone to bacterial–epithelial cell interactions and delivery of antigens to the mucosal immune system.

  • 5.
    Myrelid, Pär
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Salim, Sa´ad
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Darby, Trevor
    National University of Ireland University of Coll Cork, Ireland.
    Almer, Sven
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Melgar, Silvia
    National University of Ireland University of Coll Cork, Ireland.
    Andersson, Peter
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis2015Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, nr 8, s. 991-1001Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. The aim of this study was to examine the effect of colitis and anti-inflammatory therapies on the healing of colonic anastomoses in mice. Methods. Female C57BL/6 mice were randomized into eight groups; four groups receiving plain tap-water and four groups receiving dextran sulfate sodium. Intra-peritoneal treatment was given therapeutically for 14 days with placebo, prednisolone, azathioprine, or infliximab (IFX). Colonic anastomoses were performed and bursting pressure (BP) measurements were recorded and the inflammation evaluated with histology and zymography. Results. The mice with colitis had a more active inflammation based on histology and bowel weight compared with the tap water group, 8.3 (7.6-9.5) mg/mm and 5.5 (4.8-6.2) mg/mm respectively (p less than 0.0001). Similarly mice with colitis receiving placebo had a more active inflammation, 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms among the colitic mice; prednisolone 8.1 (7.5-9.1) mg/mm (p = 0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p = 0.0046), IFX 6.7 (6.4-7.9) mg/mm (p = 0.0055). BP for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from azathioprine or IFX groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast BP for the prednisolone group was significantly decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p = 0.0004). Conclusions. All therapies had a beneficial effect on the colitis. An impaired BP of colonic anastomoses was noted after preoperative steroids but not after azathioprine or IFX in this model.

  • 6.
    Myrelid, Pär
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Salim, Sa’ad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Melgar, Silvia
    Biosciences Institute, University College Cork, Cork City, Ireland.
    Pruteanu, Mihaela
    Biosciences Institute, University College Cork, Cork City, Ireland.
    Andersson, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Söderholm, Johan D.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Effects of Anti-Inflammatory Therapy on Bursting Pressure of colonic Anastomosis in Dextran Sulfate Sodium Induced Colitis in MiceManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: The aim of this experimental study was to evaluate the effect of colitis and anti inflammatory therapies, respectively, on the healing of colonic anastomoses in mice.

    Methods: Eighty four female C57BL/6 mice where randomized into eight groups; four groups continued receiving plain tap water and four groups receiving dextran sulfate sodium. Intraperitoneal treatment was given for 14 days with placebo, prednisolone (2 mg/kg bodyweight), azathioprine (5 mg/kg bodyweight) or infliximab (5 mg/kg bodyweight) until surgery with transsection of the colon and an end to end colonic anastomosis was performed. All mice were sacrificed on day 2 and bursting pressure measurements were recorded.

    Results: In the DSS group the mice receiving placebo (n=4) had a more active inflammation with a bowel weight of 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms; prednisolone 8.1 (7.5-9.1) mg/mm (p=0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p=0.0046), infliximab 6.7 (6.4-7.9) mg/mm (p=0.0055). Bursting pressure for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from the azathioprine or infliximab groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast bursting pressure for the prednisolone-treated group was decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p=0.0004), as well as compared with azathioprine (p=0.0004) and infliximab (p=0.0015).

    Conclusions: All given therapies had effect on the DSS-induced colitis. A severe decrease in bursting pressure of a colonic anastomosis was seen after preoperative steroids but we found no effect of azathioprine or infliximab. Thus, AZA and IFX may not increase the risk for anastomotic complications per se; the need for these therapies may rather be seen as markers of severe IBD with increased risk of surgical complications.

  • 7.
    Salim, Sa'ad
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Magnusson, Karl-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Perdue, Mary H
    McMaster University.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009Ingår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, nr 1, s. 82-90Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Salim, Sa´ad
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Importance of Disrupted Intestinal Barrier in Inflammatory Bowel Diseases2011Ingår i: INFLAMMATORY BOWEL DISEASES, ISSN 1078-0998, Vol. 17, nr 1, s. 362-381Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The current paradigm of inflammatory bowel diseases (IBD), both Crohns disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness. Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD.

  • 9.
    Salim, Sa'ad Yislam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Mucosal dendritic cells in inflammatory bowel disease2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease
    Öppna denna publikation i ny flik eller fönster >>Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, nr 2, s. 135-144Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In Crohn's disease (CD), inflammation is driven by luminal commensal micro-organisms, however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle-associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non-pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr-EDTA, horseradish peroxidase, and non-pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non-exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K-12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr-EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co-localizing with dendritic cells, and augmented tissue release of TNF-α. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    Nyckelord
    Adult Aged Bacterial Adhesion *Bacterial Translocation Case-Control Studies Colitis, Ulcerative/immunology/microbiology Crohn Disease/genetics/immunology/*microbiology Dendritic Cells/microbiology Escherichia coli/*physiology Female Humans *Ileum Immunoen
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-43367 (URN)10.1002/path.2337 (DOI)73653 (Lokalt ID)73653 (Arkivnummer)73653 (OAI)
    Tillgänglig från: 2009-10-10 Skapad: 2009-10-10 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease
    Öppna denna publikation i ny flik eller fönster >>CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease
    Visa övriga...
    2009 (Engelska)Ingår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, nr 1, s. 82-90Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-16424 (URN)10.2353/ajpath.2009.080273 (DOI)
    Tillgänglig från: 2009-01-23 Skapad: 2009-01-23 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's disease
    Öppna denna publikation i ny flik eller fönster >>T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's disease
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

    Nyckelord
    Blood, E.coli LF82, FACS, IBD, ileum, mixed lymphhocyte reaction
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-52228 (URN)
    Tillgänglig från: 2009-12-11 Skapad: 2009-12-11 Senast uppdaterad: 2009-12-11Bibliografiskt granskad
    4. Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82
    Öppna denna publikation i ny flik eller fönster >>Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    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.

    Nyckelord
    52Cr-EDTA, dentric cells, E.coli, HRP, permeability, Ussing chanbers
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-52233 (URN)
    Tillgänglig från: 2009-12-11 Skapad: 2009-12-11 Senast uppdaterad: 2009-12-11Bibliografiskt granskad
  • 10.
    Salim, Sa'ad Yislam
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Fru Che, Karlhans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
    Söderholm, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland.
    T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's diseaseManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

  • 11.
    Salim, Sa'ad Yislam
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Myrelid, Pär
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland.
    Darfeuille-Michaud, Arlette
    Pathogénie Bactérienne Intestinale Laboratoire de Bactériologie, CBRV, Université d'Auvergne, Clermont-Ferrand, France.
    Pizzaro, Theresa T.
    Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA, USA.
    Söderholm, Johan D.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland.
    Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82Manuskript (preprint) (Övrigt vetenskapligt)
    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.

  • 12.
    Silva, M.A.
    et al.
    Department of Pathology and Molecular Medicine, McMaster University, Health Science Centre 3N5C, 1200 Main St. West, Hamilton, ON L8N 3Z5, Canada.
    Quera, R.
    Internal Medicine Department, University of Chile Clinical Hospital, Clínica Las Condes, Santiago, Chile.
    Valenzuela, J.
    Internal Medicine Department, University of Chile Clinical Hospital, Clínica Las Condes, Santiago, Chile.
    Salim, Sa´ad
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi.
    Söderholm, Johan D
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Perdue, M.H.
    Department of Pathology and Molecular Medicine, McMaster University, Health Science Centre 3N5C, 1200 Main St. West, Hamilton, ON L8N 3Z5, Canada.
    Dendritic cells and toll-like receptors 2 and 4 in the ileum of Crohn's disease patients2008Ingår i: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 53, nr 7, s. 1917-1928Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigated myeloid-dendritic cell (DC) marker and Toll-like receptor (TLR)-2 and 4 distributions in ileal samples from Crohn's disease (CD) patients (n = 14) and controls (n = 13). In controls, no TLR-2+ cells were observed, and higher numbers of TLR-4+ and DC-SIGN+ cells (P < 0.01) were detected in ileal samples when compared versus colonic tissues. In non-inflamed CD ileum, TLR-4+ and DC-SGN+ cells were depleted from superficial areas of the villus, and a significant CD1a+ cell infiltration (P < 0.01) was observed when compared to ileal controls and non-inflamed colonic CD samples. In inflamed CD ileum, DC-SIGN+, CD1a+, TLR-4+ and few TLR-4 +DC-SIGN+ cells were detected as well as CD83 depletion. No correlation between TLR-2 and DC markers was detected in CD samples. A unique distribution of myeloid-DC markers characterized the CD ileum. Also, the presence of significant amounts of ileal CD1a+ cells may provide a relevant DC-mediated mechanism for antigen recognition in the pathogenesis of CD. © 2007 Springer Science+Business Media, LLC.

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