The immunopathogenesis of Crohn's disease: a three-stage model

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The pathogenesis of Crohn's disease (CD) has remained an enigma for at least a century. There was considerable optimism that genetic linkage and genome-wide association (GWA) studies had identified genes causally responsible. However, the realisation that these genes make a relatively minor contribution to the development of CD has led to the acceptance of a ‘missing heritability’. In contrast to the weak genetic effects, patients with CD almost without exception exhibit a gross phenotype, namely a profound systemic failure of the acute inflammatory response. This results in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes, as well as constitutional symptoms.

Introduction

‘Inflammatory bowel disease’ encompasses several distinct clinical entities, the most common being Crohn's disease (CD) and ulcerative colitis (UC). CD is a chronic, relapsing–remitting inflammatory condition predominantly affecting the terminal ileum and colon, associated with distinctive pathological features [1]. Unsuccessful attempts have been made to identify its cause since it first entered the literature at the turn of the 20th century.

Putative ‘causes’ have included infections with a variety of organisms such as mycobacteria, L-form bacteria, E. coli and measles virus. A host of other mechanisms have also been postulated, including auto-immunity and disordered T cell function [2].

The advent of molecular biological and gene sequencing technologies spawned studies relating disease phenotypes to particular regions of the genome and then to specific genes. This search appeared particularly fruitful in relation to CD where a number of statistically significant associations were identified.

Furthermore, gene targeting technologies produced mouse models of relevance to CD, either because the targeted gene corresponded to one of the associated genes described above, or its disruption predisposed to bowel inflammation interpreted as having some similarity to human ‘inflammatory bowel disease’.

This review discusses the concept that the development of CD occurs in three stages. The first of these is ingress of bacteria and antigenic material into the bowel wall. In stage 2, a weak acute inflammatory response results in impaired clearance of this material. Chronic granulomatous inflammation and adaptive immune responses are subsequently provoked in stage 3, culminating in the development of CD. The potential relevance of recently identified susceptibility genes and the relationship of animal models to this pathogenic scheme will be evaluated.

Section snippets

Genetic studies and Crohn's disease

Twin and family studies confirmed a strong genetic influence on the acquisition of CD. For example, approximately 50% of monozygotic twins and 30% of offspring of two affected parents develop disease [3]. Linkage analysis and positional cloning strategies, together with subsequent genome-wide association (GWA) studies, have identified over 30 distinct genetic loci that confer susceptibility. Some of the most strongly associated genes included CARD15, the IBD5 locus, the autophagy genes ATG16L1

Animal models and Crohn's disease

Numerous animal models of inflammatory bowel disease have been described, including chemically induced colitides, inbred animal strains, knockout or transgenic animals and adoptive transfer models [11, 12]. These have been useful tools to investigate the physiology of bowel inflammation, highlighting roles for immune–microflora interactions. However, the direct applicability of most to human CD is unclear. Firstly, there are striking differences in pathological features, with few models

Stage 1: penetration of luminal contents into the bowel wall

The development of CD is dependent on bowel contents. Diversion of the faecal stream in such patients is associated with the induction of remission [16, 17], and experimental re-introduction of ileostomy effluent into the excluded ileum results in recurrence [18]. To produce CD lesions, components of the faecal stream must penetrate the intestinal barrier and gain access to the underlying bowel tissues.

The gastrointestinal epithelial cells normally form a relatively impermeable physical barrier

Stage 2: impaired clearance of foreign material from the bowel wall

It was realised over three decades ago that the consequences of the penetration of faecal contents into the underlying tissues would depend upon the adequacy of the acute inflammatory response. In CD this response is defective as the result of a primary failure of acute inflammation [35••]. Neutrophil accumulation to ‘skin windows’, as well as traumatised bowel mucosa, is impaired in CD patients, as a consequence of diminished concentrations of acute inflammatory mediators such as IL-8 and

Stage 3: compensatory adaptive immune responses

In the absence of adequate neutrophil recruitment, the remaining uncleared debris will be phagocytosed by macrophages. These cells subsequently form granulomata, in an attempt to contain this material. Macrophage activation will then result in a ‘second wave’ of secretion of pro-inflammatory cytokines and chemokines that will drive recruitment of T cells to the site, as well as their polarisation to the characteristic Th1 phenotype. This phase of chronic inflammation is temporally distinct

Conclusion

In conclusion, we propose a model for the pathogenesis of CD that involves three temporally distinct stages: penetration of faecal contents into the underlying tissues (stage 1), which is followed by a weak acute inflammatory response to this material that arises from a generalised defect in pro-inflammatory cytokine secretion by macrophages. The diminished neutrophil recruitment that occurs as a consequence of this defect results in impaired clearance of antigenic material (stage 2).

Conflict of interest statement

None of the authors have any conflicts of interest to declare.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The described recent work investigating cytokine secretion from CD macrophages in response to E. coli, and bacterial clearance, is derived from a paper in press from our laboratory by Andrew M Smith et al. [67••]. We would like to acknowledge the Wellcome Trust for funding this study, and thank Tracy Hankey for help with construction of the figure.

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