Inflammatory Bowel Disease: Pathobiology
The current theory on the etiology of inflammatory bowel disease involves the interaction between a triggering environmental factor, possibly in the microbiome, and an individual susceptible to the disease due to genetic defects in immune function and reg
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Key Concepts • The current theory on the etiology of inflammatory bowel disease is an exposure to an environmental factor of host or foreign origin in the individual with a genetic predisposition to dysregulated immunity. • Over 150 genes and several hundred polymorphisms have been associated with the disease through genome-wide association studies (GWAS). Some are associated with CD, others with UC, and some with both diseases suggesting distinct but overlapping pathobiologies. • The NOD2 gene, which is involved in bacterial recognition and response, was the first gene to be associated with the disease and is the most commonly associated gene. • Defects in both innate and adaptive immunity have been demonstrated in murine models and human tissue from patients with the disease. • Innate immunological processes involved in disease pathobiology include epithelial barrier function including tight junction integrity, autophagy, and pathogen recognition. • Adaptive immunological processes involved in disease pathobiology include T cell activation, differentiation, and function. • All major innate and adaptive immunological processes involved in both UC and CD have at least one associated gene known to be correlated with IBD through GWAS.
Introduction Ulcerative colitis (UC) and Crohn’s disease (CD) are the two broad subcategories of idiopathic, inflammatory bowel disease (IBD) first officially described in 1859 and 1932, respectively [1, 2]. They are relapsing, inflammatory conditions of the gastrointestinal tract with distinct yet overlapping clinical and pathological features due to the shared and yet disparate pathobiologies of each (Table 44-1). Their
common characteristics are so pronounced particularly in Crohn’s colitis and UC that prior to the hallmark paper formally differentiating the diseases written by Charles Wells in 1952, the two diagnoses were frequently but incorrectly thought to be a single illness [1]. Although the precise etiology of these two inflammatory bowel diseases is unknown, the current research model suggests that an environmental trigger causes disease in a host predisposed due to intrinsically impaired immunity [3–5]. Environmental factors suggested to play a role in either the cause or course of IBD include external agents (e.g., cigarette smoking, nonsteroidal anti-inflammatory drugs) or agents that are present within the host itself, namely, the commensal and pathogenic organisms comprising the intestinal microbiome. Some environmental factors such as prior appendectomy play a greater or lesser role in disease pathogenesis while others, such as smoking, have an opposite effect in the two diseases. Recently, using genetic techniques developed over the course of the Human Genome Project, significant genetic (allele) associations have been identified in both CD and UC. Although the majority of such IBD alleles are associated with both CD and UC, others are exclusive to one or the other disease. The combination of these host genetic factors with some environmental stimulus ultimately leads to an im
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