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Gastroenterol Clin North Am. 1995 Sep;24(3):475-507.


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University of North Carolina at Chapel Hill, USA.


Although the causes, events initiating and triggering inflammation, and the precise immunoregulatory defects of IBD are still not known, investigations have provided a better understanding of the mechanisms of perpetuation of inflammation, genetic susceptibility, tissue injury, and symptoms. Ulcerative colitis and Crohn's disease are related disorders that probably share susceptibility genes and have similar nonspecific inflammatory mediator profiles. These diseases, however, almost certainly have different causes and respond to different antigenic stimuli. It is probable that both ulcerative colitis and Crohn's disease represent heterogenic groups of diseases that share similar mechanisms of tissue damage but have different initiating events and immunoregulatory abnormalities. Rodent models demonstrate that a wide variety of initial injuries or perturbations of immunoregulatory pathways can lead to similar phenotypes of intestinal injury, and human studies show evidence of genetic heterogeneity. It is equally apparent from these models that initiating and perpetuating mechanisms are entirely distinct and that the intestine has a remarkable ability to heal. Chronicity of disease depends on continued exposure to toxic luminal components, most commonly of bacterial origin, and genetically determined host susceptibility. Precise mechanisms of differential genetic susceptibility remain unclear, but defective down-regulation of inflammation is consistent with clinical and experimental observations. The author proposes the following sequence of events (Fig. 9). Nonspecific intestinal inflammation can be induced by a wide variety of enteric infections or ingested toxins. Resultant increased mucosal permeability leads to enhanced uptake of toxic luminal bacterial products, which potentiate local injury. The vast majority of hosts respond to these injurious events by promptly down-regulating the inflammatory response and rapidly healing the mucosal damage without residual scarring. The genetically susceptible host, however, who lacks the ability to suppress the inflammatory response efficiently, has inappropriate amplification of the immune cascade. In response to constant exposure to phlogistic luminal constituents, these patients develop an unrestrained inflammatory response, leading to tissue destruction, chronic inflammation, and fibrosis. Thus, IBD is caused by a genetically determined defective down-regulation of inflammation driven by ubiquitous antigens. Luminal anaerobic bacterial antigens are the stimuli in Crohn's disease, but ulcerative colitis may be caused by functionally abnormal aerobic bacteria or primary defects in epithelial cell physiology. Spontaneous or therapy-induced remissions can be achieved, but the risk of reactivation of inflammation is high because of the frequent exposure to triggering episodes that can reignite the inflammatory cascade. [formula: see text] This theory suggests that the intestine is in a constant state of controlled inflammation, mediated by a balance between aggressive luminal forces and host protective mechanisms (Fig. 10). This delicate balance can be deranged by any number of environmental triggering events and is in dysequilibrium in IBD. Amplification of the inflammatory response activates effector cells and cascades of soluble inflammatory molecules, which mediate tissue injury and physiologic responses leading to symptoms of IBD. These relatively nonspecific events are the target of most current therapeutic agents, which can inhibit but not completely block intestinal inflammation because of the overwhelming number of parallel pathways involved. Specific inhibition of selected effector molecules is intellectually intriguing but is less likely to paralyze the inflammatory response during clinically apparent inflammation than is blockade of key immunoregulatory cells and molecules. Better understanding of initiating, perpetuating, and immunoregulatory mechanisms should provide more.

[Indexed for MEDLINE]

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