A defect in epithelial barrier integrity is not required for a systemic response to bacterial antigens or intestinal injury in T cell receptor-alpha gene-deficient mice.
OBJECTIVE
Genetically induced disruption of the intestinal epithelial barrier leads to development of intestinal inflammation. In the interleukin-10 gene-deficient inflammatory bowel disease (IBD) mouse model, for instance, a primary defect in intestinal epithelial integrity occurs before the development of enterocolitis. In humans, a causal role for epithelial barrier disruption is still controversial. Although studies with first-degree relatives of IBD patients suggests an underlying role of impaired barrier function, a primary epithelial barrier defect in IBD patients has not been confirmed. The purpose of this article is to examine whether a primary epithelial barrier disruption is a prerequisite for the development of intestinal inflammation or whether intestinal inflammation can develop in the absence of epithelial disruption. We examined the intestinal epithelial integrity of the T cell receptor (TCR)-alpha gene-deficient mouse model of IBD.


METHODS
In vivo colonic permeability, determined by mannitol transmural flux, was assessed in 6-week-, 12-week-, and 25-week-old TCR-alpha gene-deficient and wild-type control mice using a single-pass perfusion technique. Mice were scored for intestinal histological injury and intestinal cytokine levels measured in organ cultures. Systemic responses to bacterial antigens were determined through 48-h spleen cell cultures stimulated with sonicate derived from endogenous bacterial strains.


RESULTS
In contrast with previous findings in the interleukin-10 gene-deficient IBD model, TCR-alpha gene-deficient mice did not demonstrate evidence of primary intestinal epithelial barrier disruption at any age, despite developing a moderate to severe colitis within 12 weeks. A rise in intestinal interferon (IFN)-gamma levels preceded the onset of mucosal inflammation and then correlated closely with the degree of intestinal inflammation and injury. Spleen cells from TCR-alpha gene-deficient mice released IFN-gamma in response to stimulation with endogenous luminal bacterial antigens, a finding that suggests that the systemic response to bacterial antigens occurred independently of epithelial barrier disruption.


CONCLUSIONS
Intestinal inflammation and a systemic response to bacterial antigens can develop in the absence of a measurable disruption of intestinal permeability.
Sydora
Beate C
BC
Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Tavernini
Michele M
MM
Doyle
Jason
J
Fedorak
Richard N
RN
D000367:Age Factors; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001419:Bacteria / Q000276:immunology; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism*; D019673:Genes, T-Cell Receptor alpha; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008353:Mannitol / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism
D000942:Antigens, Bacterial; D008353:Mannitol; D007371:Interferon-gamma