Crohn's disease: an immune deficiency state

Abstract

Crohn's disease is a chronic inflammatory disorder primarily affecting the gastrointestinal tract. Its clinical manifestations arise from a substantial infiltration of the intestinal mucosa by activated leukocytes and the downstream consequences of chronic inflammation. The underlying cause driving this immunological reaction remains poorly understood. A number of hypotheses have been proposed, most of which postulate a primary over-activation of the immune response, based on the pathological appearances of active Crohn's lesions. Interestingly, none of these theories have been mechanistically proven. It is possible that the immunological events responsible for disease initiation are quite different from those contributing to its persistence and propagation. A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative immunodeficiency. This review considers the evidence for such a phenomenon in contrast to alternative prevailing hypotheses and attempts to address some of the potential paradoxes that it generates.

Fig. 1

Schematic representation of the proposed mechanisms involved in the pathogenesis of Crohn’s disease. Damage to the mucosa allows penetration of gut contents including bacteria (brown ovals) into the bowel wall. The outcome depends upon the subsequent inflammatory response. A vigorous response leads to the secretion of high levels of IL-8 and TNF-α attracting large numbers of neutrophils, which phagocytose and digest the bacteria and foreign material. A weak inflammatory response predisposes to Crohn’s lesions because the foreign material is taken up by macrophages to form granulomata and foci of chronic inflammation. A naturally weak response can be boosted in the small bowel by MDP signaling through the CARD15 pathway of macrophages to induce them to produce IL-8. In the large bowel a similar role might be performed by Toll-like receptor-4 (TLR4). The predisposition to Crohn’s disease is greatly increased by a combination of a low innate inflammatory response coupled to failure of one of the compensatory mechanisms