Crohn's disease as an immunodeficiency

Abstract

The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools.

Figure 1. Three-stage hypothesis for the development of Crohn’s disease

In a healthy individual (resistant to the development of Crohn’s disease (CD); right-hand side of the image), bacterial entry/invasion occurring despite the action of antimicrobial peptides and maintenance of tight-junction (TJ) stability elicits an acute inflammatory response. Stimulated macrophages secrete TNF-α (and other proinflammatory cytokines) to facilitate neutrophil influx and bacterial clearance – promoting resolution of inflammation. In a patient susceptible to CD (left-hand side of the image), bacteria may invade as a consequence of a failure of barrier function or an intrinsic capability of the microorganisms themselves (A). Macrophages encountering these bacteria produce less proinflammatory cytokines and neutrophil influx is impaired (B). Bacterial persistence and chronic macrophage activation result in granulomatous chronic inflammation (C). Known disease-associated polymorphisms are shown in italics with the relevant cell type. AIEC: Adherent-invasive Escherichia coli; TLR: Toll-like receptor. Redrawn with permission from original artwork by Bu’Hussain Hayee.

Figure 2. Relationship between the acute inflammatory response and disease development

The acute inflammatory response is considered to follow a normal distribution across a population. As the lower end of the spectrum is approached, individuals are increasingly likely to develop CD. At the lowest extreme, patients with inherited diseases of immune function are also predisposed to systemic microbial infection. CD: Crohn’s disease.