Nedjat-Shokouhi, Bahman;
(2018)
Pathogenesis of Ulcerative Colitis: the role of Claudin-8 in epithelial barrier function and inflammation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Ulcerative colitis is a relapsing and remitting inflammatory bowel disease involving the large bowel. The current hypothesis on the pathogenesis of UC is that an abnormal innate immune response in genetically susceptible individuals, combined with environmental factors, result in excessive activation of the adaptive immune system within lamina propria. The role of abnormal barrier function is widely accepted. Using transcriptomic analysis of punch biopsies of patients with quiescent UC, CLDN8 was identified as grossly downregulated in the intestine. In this thesis, loss of Cldn8, a tight junction (TJ) molecule, was shown to result in reduced susceptibility of mice to DSS-induced colitis. Cldn8 knock out (Cldn98-KO) mice, had smaller increase in intestinal permeability to 3H-mannitol, reduced neutrophils and macrophages in inflammatory cell infiltrate in lamina propria during the early phase of inflammation. The inner layer of mucous is sterile in naïve Cldn8-KO and WT mice, and remains sterile after the animals have been exposed to DSS-water for 12 hours. Transcriptomic analysis between Cldn8-KO and WT mice did not reveal any significant differences between the two groups at different time points. After correction for multiple-testing, no differentially-expressed genes remained. These results suggest that downregulation of CLDN8 in patients with UC is a physiologic response by the intestine to increase local defences against luminal pathogens.
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