Genetic and environmental risk factors

Several genetic mutations have been associated with CD, but no single mutated gene is responsible for its development. Many of the genetic mutations associated with the condition involve defects in innate immunity.4 The NOD2 gene, located on chromosome 16q12, is the most studied site of mutations associated with CD. It encodes a protein that modulates mitogen-activated protein kinase pathways and nuclear factor κB in the presence of bacterial cell wall peptidoglycan components.2 Defects in the NOD2 gene may affect the ability of the immune system to locate and destroy invading bacteria. Some mutations more recently associated with CD include those of the IL23R gene5 and the ATG16L gene.4 The first is related to an inflammation pathway, and the second is involved in the process of cell autophagy. 

In addition to genetic mutations, several environmental triggers have been identified, but evidence points to the absence of a single causative factor. Any break in the mucosal barrier caused by infection, antibiotics, or nonsteroidal anti-inflammatory drugs can serve as a trigger.4 Smoking is also recognized as a risk factor. It is possible that different environmental factors prompt the development of CD in different populations. 

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In the presence of triggers and a genetic predisposition, the interaction between a defective innate or adaptive immune system and enteric bacteria can result in the pathologic process responsible for the chronic inflammation of CD. In the intestine, innate immunity includes the epithelial barrier and the phagocytes of the lamina propria. Some bacteria are able to survive within phagocytes and avoid killing. 

High levels of Escherichia coli have been observed in the small bowel of patients with CD.6 These bacteria have been named adherent-invasive E coli (AIEC) because they can survive and multiply inside macrophages and epithelial cells. They have been found in biopsy specimens of early CD lesions, so they may play a role in the etiopathogenesis of the condition. Although most bacteria cause infected macrophages to undergo apoptosis, AIEC do not. The infected macrophages remain activated and secrete high levels of tumor necrosis factor-alpha (TNF-α). The pathogens may in this way promote chronic antigenic stimulation that results in chronic inflammation. AIEC are thought to take advantage of defects in bacterial recognition related to the NOD2 mutation and in the autophagy pathway related to the ATG16L mutation in affected individuals, and this may be one of the factors leading to CD.

The adaptive immune system, T lymphocytes in particular, has been more definitively linked to the pathogenesis of CD. Inflammation is thought to be triggered by the release of interferon-gamma (IFN-γ) from T helper type 1 (Th1) cells, which are usually activated by intracellular pathogens.1 Usually, a Th1 cell is activated by an antigen-presenting cell (APC) in the presence of interleukin 12 (IL-12), which is secreted by the APC.4 In CD, this pathway is thought to be dysfunctional. High levels of IL-12 in the intestinal mucosa lead to increased Th1 production of IFN-γ, which then upregulates macrophages in a cycle of uncontrolled inflammation.1 Several other subsets of T helper cells have been described, such as the Th17 and Th2 cells. Evidence does not conclusively point to a single cell subpopulation as the cause of CD.4 It is rare for only one cell type to be activated during an immune response, and plasticity is usually a characteristic of the reaction.4 After T cells are activated, their cytokines act on the local environment to attract other inflammatory cells. The migrating inflammatory cells are regulated differently from those of the gut and may be more easily activated to secrete destructive and proinflammatory factors. 

Defective immune regulation may also play a role in CD. The immune system of the gastrointestinal tract, in comparison with the systemic immune system, is suppressed in normal individuals. Regulatory cells prevent immune responses against commensal flora or dietary antigens. It has been proposed that defective T regulatory cells allow active inflammation to be maintained.4 

Dysfunction at any of these levels may lead to IBD. What one sees as the disease progresses is the result of multiple factors coming into play, including collagenase, elastase, matrix metalloproteinases, and superoxides, among others, which produce tissue damage.4 The histologic findings of CD include transmural inflammation anywhere along the gastrointestinal tract and the formation of lymphoid aggregates across the layers of the bowel wall.1 Neutrophils infiltrate the epithelial layer overlying lymphoid aggregates. They infiltrate the crypts, form abscesses, and eventually destroy the crypts, leading to atrophy of the colon. Aphthous ulcers are a gross feature of CD. They may enlarge or become stellate, and they may combine to form longitudinal ulcerations. A network of ulcerations surrounding inflamed mucosa may lead to a cobblestone appearance.1