Innate immunity in inflammatory bowel disease: a disease hypothesis

Abstract

Crohn's disease arises from a defective interaction between the highly concentrated mass of bacteria in the gastrointestinal tract and the underlying tissues. It has generally been believed to result from an excessively exuberant inflammatory response or from 'autoimmunity'. Recent evidence has emerged that the problem is instead a failure of the way in which the body responds to the penetration of bacteria and other bowel contents through the intestinal mucosal barrier. Rather than Crohn's disease being caused by excessive inflammation, the primary mechanism is actually that of an immunodeficiency. Failure of inflammatory mediator production leads to insufficient recruitment of neutrophils, resulting in inadequate removal of bacteria and other debris. This impairment of acute inflammation can be compensated in some circumstances by signalling through NOD2. If not cleared, the foreign material in the bowel wall is taken up within macrophages, eliciting a granulomatous reaction and the local and systemic sequelae so characteristic of Crohn's disease.

Figure 1

It is proposed that the extent of the acute inflammatory response follows a Normal Gaussian distribution in the population and that those individuals at the extreme lower end of the response are susceptible to Crohn's disease. Inflammation can be enhanced, and the curve shifted to the right, taking those liable to Crohn's disease into a resistant phenotype, by secondary compensatory systems that react to stimulation by agonists from the gut content. These include MDP, signalling through NOD2

Figure 2

Schematic representation of mechanisms outlined in the legend to Figure 1