Crohn’s Disease – PATHOGENESIS

Posted by Alex

The absence of an etiologic factor leaves a gap in our understanding of the pathogenesis of IBD. Although a number of potential factors may influence the initiation of the inflammatory response, a popular view is that a defect exists in the “down-regulation”

TABLE 104-1 — EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE

More common in whites than nonwhites

Increased frequency among European stock

More common among Jews (especially Ashkenazic) than non-Jews (3 to 6 times)

Most frequent age of onset: 15 to 30 years

Aggregation in families (25-40%)

Concordance for Crohn’s in twins

Cigarette smokers–Crohn’s disease

Nonsmokers–ulcerative colitis

of immune events (see Part XIX), allowing persistent amplification of the tissue-damaging process. The inflammatory reaction in IBD closely mimics infectious enterocolitis with the exception of the failure to halt progressive tissue destruction. Subtle differences exist between the immunologic findings of UC and CD, such as the production of immunoglobulin heavy-chain allotypes or neutrophil-cytoplasmic antibodies; however, pathognomonic findings to classify these disorders remain elusive. Nosology is currently based on descriptive clinical, endoscopic, and histologic criteria, and misclassification often is recognized as the clinicopathologic process evolves over time. When the diagnosis changes, it is almost always from UC to CD and virtually never the converse.

Potential initiating events in IBD include increased intestinal permeability, aberrant epithelial processing of antigen, improper epithelial utilization of short-chain fatty acids, and molecular mimicry between a luminal antigen and components of intestinal mucosa. There is evidence of increased intestinal permeability to small or medium-sized molecular particles in patients and relatives of patients with IBD, which may be affected by qualitative differences in intestinal mucus glycoprotein. Similar alterations in colonic mucin fraction IV from patients with UC are present in cotton-top tamarins with spontaneous colitis. Cigarette smoking can also influence mucin production and intestinal permeability, and nonsteroidal anti-inflammatory drugs (NSAID’s) damage proximal and distal intestinal epithelium, increase intestinal permeability, and tend to exacerbate IBD.

Intestinal epithelial cells stimulated by interferon express class II major histocompatibility complexes and become antigen-presenting cells. The processing and presentation of antigens to T8 (suppressor T cells) are altered in patients with IBD such that the presentation of antigen is preferentially directed toward the T4 (helper T cell) system. This could be a primary, genetically mediated event that stimulates the gut immune system rather than induces tolerance.

A defect in the ability of the gut epithelium to metabolize short-chain fatty acids derived from the intestinal lumen or injury to the epithelium by an infectious or toxic injury may alter or expose cell proteins that are perceived as foreign by the mucosal immune system. A conclusive target antigen has not been identified for either UC or CD. A variety of antibodies to epithelial cell components, some of which cross-react with enterobacterial antigens, are present but are not specific for IBD. In addition, serum antibodies against enteric bacteria or food-related antigens (e.g., milk protein) are increased nonspecifically. Also, evidence exists of autoimmune lymphocyte-mediated cytotoxicity against epithelial cells, but a consistent abnormality in mucosal or systemic immune regulation has not been identified. Most of the local (mucosal) or systemic immunologic parameters represent secondary rather than primary changes.

Once initiated, many of the pathophysiologic events in IBD are related to amplification of the inflammatory process. When antigens are presented to mucosal macrophages, cytokines and other inflammatory mediators are activated and released. IL-1 is released and induces T-cell activation and proliferation. Activated T cells become cytotoxic and/or release IL-2, which induces clonal expansion of helper T cells, B-cell proliferation, and antibody synthesis. IgG production by B cells activates complement and subsequently the kinin system. The arachidonic acid cascade of inflammatory mediators is shifted toward the proinflammatory, lipoxygenase pathway with enhanced production of leukotriene B₄ , a potent chemotactic agent for neutrophils, and platelet-activating factor (PAF) is produced. When neutrophils accumulate and are stimulated, they further damage tissue by releasing reactive oxygen species, amplifying the inflammatory process by recruiting additional acute inflammatory cells, whether or not the primary initiating sequences have been halted.

The release of inflammatory mediators, including prostaglandins and leukotrienes, histamine from mast cells, and neuropeptides such as substance P or vasoactive intestinal peptide, alters epithelial function and contributes to the intestinal secretory process, including diarrhea. The enteric nervous system helps regulate the local and systemic immune system, linking the association of “stress” and psychological factors with disease flare-ups.