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INFLAMMATORY BOWEL DISEASE |
1 Department of Surgery and Clinical Research Centre, University Hospital, Linköping, Sweden, and Intestinal Disease Research Programme, McMaster University, Hamilton, Canada
2 Intestinal Disease Research Programme, McMaster University, Hamilton, Canada, and Department of Laboratory Medicine and Pathology, St. Michael’s Hospital and the University of Toronto, Toronto, Ontario, Canada
3 Intestinal Disease Research Programme, McMaster University, Hamilton, Canada
4 Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Correspondence to:
Correspondence to:
Dr J D Söderholm
Department of Surgery, University Hospital, SE-581 85 Linköping, Sweden; johda{at}ibk.liu.se
Background and aims: The exact nature of the epithelial barrier defect in Crohn’s disease remains to be elucidated. Previously we showed increased permeability to proteins in ileal Crohn’s disease. Our aims were to study if this barrier defect (a) involves endocytotic uptake of antigens and (b) is related to low grade inflammation not detectable by histology.
Methods: Macroscopically normal segments of distal ileum of Crohn’s disease patients (n = 10) were subgrouped into non-inflamed (histologically unaffected) and slightly inflamed tissues and studied in Ussing chambers, with normal ileal specimens from colon cancer patients (n = 9) as controls. Endocytotic uptake into enterocytes of the protein antigen horseradish peroxidase was assessed by measuring the area of horseradish peroxidase containing endosomes in electron photomicrographs. Mucosal tumour necrosis factor 
(TNF-) mRNA was quantified using real time polymerase chain reaction. For comparison, the effects of low doses of TNF- on endosomal uptake of horseradish peroxidase were studied in cultured T84 cells grown on filter supports.
Results: The area of horseradish peroxidase containing endosomes was increased (p<0.001) in enterocytes of non-inflamed ileum of Crohn’s disease (2.8 (0.7) µm2/300 µm2) compared with control ileum (0.6 (0.06)). In non-inflamed mucosa, a significant association between endosomal uptake and mucosal expression of TNF- mRNA (p = 0.03) was found. Low concentrations of TNF- (0.25–1.0 ng/ml) enhanced the endosomal uptake of horseradish peroxidase in polarised T84 cells, without affecting transepithelial electrical resistance.
Conclusions: Our findings suggest increased endosomal uptake of antigens in ileal Crohn’s disease that may be mediated by TNF-. These data highlight the transcellular route of antigen uptake in barrier dysfunction and implicate the interaction between epithelial cells and the innate immune system in the development of mucosal inflammation.
Abbreviations: CD, Crohn’s disease; Isc, short circuit current; HRP, horseradish peroxidase; RT-PCR, reverse transcripion-polymerase chain reaction; PD, potential difference; TER, transepithelial electrical resistance; TNF-, tumour necrosis factor ; GAPDH, glyceraldehyde-3-phosphate dehydrogenase
Keywords: electron microscopy; Crohn’s disease; endocytosis; tumour necrosis factor ; permeability; T84 cell line
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