Pathogenesis of IBD
Discuss the pathogenesis of IBD?
- Crohn’s disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated.
- However, their exact aetiologies remain uncertain.
- The most widely held hypothesis on the pathogenesis of IBD is that overly aggressive acquired (T cell) immune responses to a subset of commensal enteric bacteria develop in genetically susceptible hosts, and environmental factors precipitate the onset or reactivation of disease.
Genetics
To date, four genes have been associated with Crohn’s disease and one with ulcerative colitis. The first gene to be associated with Crohn’s disease was CARD15 (caspase recruitment domain family member 15, formerly known as NOD2). Mutations in CARD15 are associated with distal ileal Crohn’s disease in particular, and have been found in some patients with stricturing disease. The common threads with the genes isolated are that the implicated genes regulate several important biologic functions, including immunoregulation, mucosal barrier integrity and microbial clearance and/or homeostasis.
Immune response
Both Crohn’s disease and ulcerative colitis patients have activated innate (macrophage, neutrophil) and acquired (T and B cell) immune responses and loss of tolerance to enteric commensal bacteria. In contrast to innate immune responses, which are similarly activated in all forms of IBD, T-cell profiles are disparate in Crohn’s disease and ulcerative colitis. Crohn’s disease is a predominantly TH1- and TH17-mediated process, while ulcerative colitis seems to be an atypical TH2 disorder.
Crohn’s disease and ulcerative colitis are characterized by enhanced recruitment and retention of effector macrophages, neutrophils and T cells into the inflamed intestine, where they are activated and release proinflammatory cytokines. Accumulation of effector cells in the inflamed intestine is a result of enhanced recruitment as well as prolonged survival caused by decreased cellular apoptosis.
Commensal Microbial Stimulants
Enteric microflora can stimulate immune responses either by functioning as adjuvants or antigens. As adjuvants they activate innate immune responses, including dendritic cells and other APCs, and as antigens they stimulate the clonal expansion of T cells that selectively recognize the antigen through their T-cell receptor.
Environmental Triggers
Several environmental factors have been implicated in the pathogenesis of IBD. These factors include smoking, which is protective in ulcerative colitis but detrimental in Crohn’s disease, diet, the use of antibiotics and NSAIDs, stress and infection. Unfortunately, the mechanisms by which these factors initiate the onset of disease or reactivate quiescent IBD are not well understood. From a broad perspective, these triggering factors alter mucosal barrier integrity, immune responses, or the luminal microenvironment, each of which have an impact on susceptibility to inflammation
Conclusion
- Chronic intestinal inflammation results from the interactions of genetic, immunologic, microbial and environmental factors.
- IBD results from the failure to appropriately down regulate nonspecific inflammation initiated by an environmental trigger, such as an acute, self-limited infection or NSAID use.
- Normal hosts quickly clear infections of invasive enteric bacteria, down regulate innate immune responses and heal the injured mucosa without stimulating effector T-cell responses.
- By contrast, genetically susceptible hosts who are unable to clear an invading pathogen and/or generate tolerogenic immune response to commensal microbial agents by mounting appropriate innate immunity, down regulating immune responses or healing the mucosal barrier subsequently activate pathogenic T-cell responses to commensal bacteria and proceed to chronic, relapsing intestinal inflammation.
- Resistance to T-cell apoptosis, lack of response to down regulatory signals and continuous exposure to luminal antigens and adjuvants help sustain this inflammatory response.
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