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Abstract
The cause of Crohn's disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients' inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease.
Highlights
The cause of Crohn’s disease (CD) has posed a conundrum for at least a century
When a single nucleotide polymorphisms (SNPs) is found to be statistically significantly associated with a disease by genome-wide association studies (GWAS), it can be because the polymorphism is itself pathogenic or, more commonly that it is tagging a closely located genetic variant whose genotype correlates with that of the tagging polymorphism
Studies in patients have clearly demonstrated that there is a defect in the acute inflammatory response resulting in an impaired recruitment of neutrophils to inflammatory sites and a consequent delay in the clearance of bacteria from them
Summary
After almost a century of concerted effort in clinical investigations combined with recent technological developments in genomic medicine, a consensus view is developing as to the causes of CD. Studies in patients have clearly demonstrated that there is a defect in the acute inflammatory response resulting in an impaired recruitment of neutrophils to inflammatory sites and a consequent delay in the clearance of bacteria from them. This results from an initial blunted response by monocytes and macrophages leading to deficient secretion of proinflammatory cytokines. It might reflect the multifactorial extreme end of a normal distribution, or the critical loss of one or more important molecules Molecules contributing to the former will be very difficult to identify whereas some of those playing a more singular role have been highlighted by linkage, GWAS and DNA sequencing studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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