Pathophysiology - Aberrant Immunologic Response
Under normal circumstances, the intestine is an immunologically tolerant organ, especially considering the very high microbial constituents residing in its lumen. A viral or bacterial infection is normally cleared by the mucosal immune system. Antigens cross the intestinal epithelial through M cells and are phagocytosed by macrophages which present antigens to the CD4+ T cells. Macrophages become activated by locally secreted factors: bacterial lipopolysaccharides, prostaglandins, cytokines and leukotrienes. Regulatory lymphocytes such as TH3, T regulatory 1 and CD4+/CD25+ T cells manage to limit and stop the temporary inflammation (Brookes et al, 2004).
However, in Crohn's disease the immunoregulatory mechanism of the GI tract is impaired. This results in a failure to suppress the inflammatory response, followed by a highly activated effector cells and an uncontrolled immune response. The antigenic trigger is most likely the presence of common, non-pathogenic microbial agents within the intestine, against which the patient mounts an activated immune response (Figure 4).
The etiology of these changes remains unknown. Genetic, microbial, immunologic, environmental, dietary, vascular, psychosocial factors, smoking, oral contraceptives or non-steroidal anti-inflammatory drugs have been suggested as potential causative agents.
Genetic factors
In Crohn's disease studies have identified an inherited susceptibility for an aberrant immunologic response. However, classic Mendelian inheritance is not seen. Identification of CARD15 or nucleotide-binding oligomerization domain-2 (NOD2) is a strong indicator that innate immunity may play an important role in the pathogenesis of Crohn's disease (Brookes et al, 2004). The disease-associated alleles are highly expressed in innate immune system (macrophages, monocytes, dendritic cells). Genetic variations were also found surrounding the TNF genes, which further supports evidence that TNF-alpha plays an important role in Crohn's disease. Mutations in the ICAM-1 binding domain, IBD-5 gene on chromosome 5q or the IBD-3 gene on chromosome 6 have been also linked with inflammatory bowel disease (Thoreson R, 2007).
Immunologic factors
The antigen-presenting cells in the lamina propria play a very important role in directing what type of immune response ensues. A naive T-cell has two potential directions in which those cells can be driven. One direction would be towards a T-helper2 (Th2) response, an antibody-mediated response, which is typical of allergic diseases such as asthma. That involves a group of cytokines which are not increased in the mucosa in Crohn's disease. Alternatively, this naive T-cell may be driven to become a regulatory T-helper-1 (Th1) cell. It is clear that in Crohn's disease this is the prevailing direction.
The Th1 cells secrete cytokines and growth factors that play an important role in the immunologic response in the intestine: Tumor necrosis factor (TNF)-alpha, interferon (INF)-alpha, interleukine (IL)-12, and IL-18 (Brookes et al, 2004).
TNF-alpha has been shown to play a critical role in the inflammation in this disease. It is primarily produced by activated macrophages, but also lymphocytes and natural killer cells. TNF-alpha has numerous biologic properties involving inflammation, proliferation, and differentiation, by inducing synthesis of proteases, prostaglandins, leukotrienes, eicosanoids. Increased concentration of TNF-alpha have been found in the stool, blood, and mucosa of Crohn's disease patients (Sandborn WJ et al, 2007). TNF-alpha production also leads to activation of macrophages, the priming of neutrophils, and an increase in intestinal epithelial permeability.
The proinflammatory cytokines cause inflammation by upregulating expression of adhesion molecules such as ICAM-1 and VCAM-1. Thus more neutrophis are recruited to the infected tissue, resulting in tissue inflammation.
This constant infiltration of large numbers of macrophages, monocytes, lymphocytes, and plasma cells causes prolonged inflammation and tissue damage.
A central regulator of innate immunity is the granulocyte macrophage colony-stimulating factor (GM-CSF) secreted by the mucosal cells. It contributes to the differentiation of a granulocytic cell population, as well as macrophage monocyte cell populations. On the other hand, GM-CSF is a potent functional stimulant. These cells are much more effective at microbial uptake and eradication
Prostaglandins which are synthesized from arachidonic acid and cyclooxygenase cause edema, vasodilation, and pain, and they are found in elevated levels in the stool, blood, and rectal mucosa of Crohn's patients.
Microbial factors
Infectious agents such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen in Crohn's disease is the result of a dysfunctional response to an infectious source (Thoreson R, 2007).