Pathophysiology
Clinical meaning
Ulcerative colitis is driven by a dysregulated mucosal immune response to commensal gut flora in genetically susceptible individuals. The epithelial barrier dysfunction involves defective tight junction proteins (claudins, occludins) and reduced mucin production by goblet cells, allowing bacterial translocation across the mucosa. This triggers innate immune activation via toll-like receptors (TLR4 recognizing LPS) on dendritic cells and macrophages. The adaptive immune response is Th2-skewed with IL-5 and IL-13 driving mucosal inflammation, NKT cells producing IL-13 that directly damages epithelial cells, and elevated mucosal antibodies (pANCA positive in 65-70% of UC patients). The inflammatory cascade involves TNF-alpha, IL-1beta, and IL-6 activating NF-kB signaling in colonocytes, upregulating adhesion molecules (ICAM-1, VCAM-1) that recruit neutrophils from the vasculature. Neutrophil infiltration into the crypts forms the pathognomonic crypt abscess on histology. Chronic inflammation leads to architectural distortion with crypt branching, goblet cell depletion, and Paneth cell metaplasia. The colorectal cancer pathway involves inflammation-driven dysplasia through p53 mutations, microsatellite instability, and chromosomal instability occurring in a field effect across the inflamed mucosa. JAK-STAT signaling pathway dysregulation has emerged as a therapeutic target (tofacitinib). Sphingosine-1-phosphate receptor...