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INTRODUCTION

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Inflammatory bowel disease (IBD) is a spectrum of chronic, idiopathic, inflammatory intestinal conditions. IBD causes significant gastrointestinal (GI) symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD conventionally is divided into 2 major subtypes: ulcerative colitis and Crohn disease. Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent (e.g., proctitis, left-sided colitis, or pancolitis). Crohn disease, by contrast, is characterized by transmural inflammation of any part of the GI tract but most commonly the area adjacent to the ileocecal valve. The inflammation in Crohn disease is not necessarily confluent, frequently leaving "skip areas" of relatively normal mucosa. The transmural nature of the inflammation may lead to fibrosis and strictures or fistula formation.

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PATHOGENESIS OF IBD. Crohn disease and ulcerative colitis are chronic idiopathic inflammatory disorders of the GI tract; a summary of proposed pathogenic events and potential sites of therapeutic intervention is shown in Figure 47–1. Crohn disease and ulcerative colitis result from distinct pathogenetic mechanisms. Histologically, the transmural lesions in Crohn disease exhibit marked infiltration of lymphocytes and macrophages, granuloma formation, and submucosal fibrosis, whereas the superficial lesions in ulcerative colitis have lymphocytic and neutrophilic infiltrates. Within the diseased bowel in Crohn disease, the cytokine profile includes increased levels of interleukin (IL)-12, IL-23, interferon-γ, and tumor necrosis factor-α (TNFα), findings characteristic of T-helper 1 (TH1)–mediated inflammatory processes. In contrast, the inflammatory response in ulcerative colitis resembles aspects of that mediated by the TH2 pathway. Understanding of the inflammatory processes has evolved with the description of regulatory T cells and pro-inflammatory TH17 cells, a novel T-cell population that expresses IL-23 receptor as a surface marker and produces, among others, the pro-inflammatory cytokines IL-17, IL-21, IL-22, and IL-26. TH17 cells seem to play a prominent role in intestinal inflammation, particularly in Crohn disease.

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Figure 47–1

Proposed pathogenesis of inflammatory bowel disease and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired, bacterial antigens can gain access to antigen-presenting cells (APC) such as dendritic cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete cytokines such interleukin (IL)-12 and IL-18, thereby inducing the differentiation of TH1 cells in Crohn's disease (or, under the control of IL-4, type 2 helper T cells [TH2] in ulcerative colitis). The balance of pro-inflammatory and anti-inflammatory events is also governed by regulatory TH17 and TReg cells, both of which serve to limit immune and inflammatory responses in the GI tract. Transforming growth factor (TGF)β and IL-6 are important cytokines that drive the expansion of the regulatory T cell subsets. The TH1 cells produce a characteristic array of cytokines, including interferon (IFN)γ ...

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