Mucosal integrity and barrier function in the pathogenesis of early lesions in Crohn's disease.
Crohn's disease aetiology is multifactorial and remains enigmatic. However, animal models show that disease heterogeneity is probable, in that more than one defective mucosal mechanism can produce the same clinical phenotype. For example, Crohn's-like lesions are reported after compromise of mucosal integrity per se in the presence of an intact immune system, through altered expression of mucosal adhesion molecules, such as cadherins and tight junction proteins, highlighting the importance of the mucosal barrier in the disease process. Key to mucosal damage is the trigger of an inflammatory cascade after luminal antigen processing, a role classically ascribed to M cells in the surface follicle associated epithelium. Direct luminal antigen sampling has recently been proposed, however, by extension of dendritic cell (DC) processes through the intact gut epithelium, and it follows that early mucosal damage could result from de novo lymphoid recruitment. Cytokines, such as tumour necrosis factor alpha (TNFalpha), are known to drive inflammation, but emerging data suggest additional important roles for TNFalpha influencing mucosal barrier efficacy by altering adhesion molecule expression, influencing epithelial apoptosis, and affecting tight junction functionality.
Sanders
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scott.sanders@swh.nhs.uk
D015820:Cadherins / Q000502:physiology; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D018928:Immunity, Mucosal; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008221:Lymphoid Tissue / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein
D015820:Cadherins; C502403:FAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein