Pathogenesis of Crohn's Disease and Ulcerative Colitis
Pathogenesis of Crohn's Disease and Ulcerative Colitis
Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. These new insights will help develop better diagnostic approaches that identify clinically important subsets of patients for whom the natural history of disease and response to treatment are predictable.
Ulcerative colitis and Crohn's disease are chronic, relapsing, immunologically mediated disorders that are collectively referred to as inflammatory bowel diseases (IBD). The prevalence of IBD rapidly increased in Europe and North America in the second half of the twentieth century and is becoming more common in the rest of the world as different countries adopt a Western lifestyle. Such epidemiologic observations indicate that there are strong environmental influences on IBD: their influence is confirmed by the relatively low concordance rate in identical twins (~50% for Crohn's disease, and ~10% for ulcerative colitis). These twin studies and the increased incidence of IBD in first-degree relatives of probands with either disease indicate that genetic factors are also integrally involved. Even with this knowledge, the etiologies of these diseases remain an enigma. In the past few years, however, work in animal models, human genetics, basic science and clinical trials, have provided new insights into the pathogenesis of these diseases.
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. This complex theory involves four separate components that must intersect in multiple ways for disease to become clinically apparent (Figure 1).
(Enlarge Image)
Figure 1.
Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host. Genetic susceptibility is influenced by the luminal microbiota, which provide antigens and adjuvants that stimulate either pathogenic or protective immune responses. Environmental triggers are necessary to initiate or reactivate disease expression. Abbreviation: IBD, inflammatory bowel diseases.
A convenient approach to understanding the pathogenesis of IBD considers the possible mechanisms by which ulcerative colitis and Crohn's disease might occur (Box 1). This approach addresses the possibility of a specific infectious etiology and the various ways that commensal bacteria can induce chronic, immune-mediated inflammation. In this review, I discuss the evidence underlying the disparate theories and attempt to reconcile them into a coherent hypothesis based on experimental data obtained in the past few years.
Summary
Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. These new insights will help develop better diagnostic approaches that identify clinically important subsets of patients for whom the natural history of disease and response to treatment are predictable.
Introduction
Ulcerative colitis and Crohn's disease are chronic, relapsing, immunologically mediated disorders that are collectively referred to as inflammatory bowel diseases (IBD). The prevalence of IBD rapidly increased in Europe and North America in the second half of the twentieth century and is becoming more common in the rest of the world as different countries adopt a Western lifestyle. Such epidemiologic observations indicate that there are strong environmental influences on IBD: their influence is confirmed by the relatively low concordance rate in identical twins (~50% for Crohn's disease, and ~10% for ulcerative colitis). These twin studies and the increased incidence of IBD in first-degree relatives of probands with either disease indicate that genetic factors are also integrally involved. Even with this knowledge, the etiologies of these diseases remain an enigma. In the past few years, however, work in animal models, human genetics, basic science and clinical trials, have provided new insights into the pathogenesis of these diseases.
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. This complex theory involves four separate components that must intersect in multiple ways for disease to become clinically apparent (Figure 1).
(Enlarge Image)
Figure 1.
Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host. Genetic susceptibility is influenced by the luminal microbiota, which provide antigens and adjuvants that stimulate either pathogenic or protective immune responses. Environmental triggers are necessary to initiate or reactivate disease expression. Abbreviation: IBD, inflammatory bowel diseases.
A convenient approach to understanding the pathogenesis of IBD considers the possible mechanisms by which ulcerative colitis and Crohn's disease might occur (Box 1). This approach addresses the possibility of a specific infectious etiology and the various ways that commensal bacteria can induce chronic, immune-mediated inflammation. In this review, I discuss the evidence underlying the disparate theories and attempt to reconcile them into a coherent hypothesis based on experimental data obtained in the past few years.
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