Crohn’s disease

David Ziring MD

Jorge Vargas MD

Prevalence and incidence

Crohn’s disease (CrD) is a chronic, immune-mediated gastrointestinal (GI) disease and one of the inflammatory bowel diseases (IBD) (including ulcerative colitis [UC] and indeterminate colitis). IBD currently affects nearly 1 million patients in the United States, 25% of whom are children¹^,²^,³. Nearly 30 patients of every 100,000 in the population are diagnosed each year, and the incidence is increasing⁴^, ⁵. The prevalence of IBD is higher in industrialized nations, especially in northern latitudes⁴. The number of patients affected with CrD outnumbers those with UC nearly two-fold².

Aetiology

This disease entity stems from an abnormal host immune response to normally occurring gut constituents. Three unifying forces underlie the pathogenesis of IBD. First, at risk patients have a genetic predisposition. Next, there is an environmental trigger (or triggers, in the case of antigens borne by intestinal bacteria). Lastly, there is a dysregulation of the normal homeostasis of the intestinal immune system.

Genetics

CrD is a polygenic disease, i.e. several genes contribute to the pathogenic immune phenotype. The role that genetic susceptibility plays in developing IBD is illustrated by its prevalence in monozygotic twins. Between 36 and 58% of affected twins have an identical twin with CrD, while nonidentical siblings have only a 4% concordance rate⁶^,⁷^,⁸.

Many genetic susceptibility loci have been identified in patients, but over the last several years, large genetic consortia have pinpointed distinct genes that are associated with the development of CrD. These include genes for proteins that sense bacterial products, like the NOD2/CARD15 gene. 40% of patients with CrD have a ‘gain of function’ mutation in NOD2⁹^, ¹⁰. These patients are more likely to have ileal disease with stricture formation¹¹.

Similarly, a genetic polymorphism has been identified in the protein encoded by the organic cation transporter gene (OCTN)¹². Most recently, researchers have identified a polymorphism in the interleukin-23 (IL-23) receptor gene. This polymorphism provides protection against the development of CrD ¹³. The IL-23 receptor is expressed by a pathogenic subset of T cells thought to be the effectors responsible for intestinal inflammation.

Environment

The rate of new diagnoses of IBD has increased 10-fold since the 1940s. Many believe that this increase is associated with our improved hygiene⁵. The ‘hygiene hypothesis’ posits that autoimmune disease is on the rise because regulatory cells of the developing immune systems are not educated by the normal complement of environmental bacteria.

Immunology

The intestinal immune system is incredibly complex. Several different cell types protect the mucosa from invasion by neighbouring bacteria. This ‘innate immune system’ is comprised of dendritic cells, macrophages, natural killer (NK) cells, and natural killer T (NKT) cells¹⁴. It is the first line of defence and provides the quickest response to antigen without the need for immune memory. Intestinal epithelial cells have receptors for bacterial products. Paneth cells
reside in the crypts and produce antibacterial proteins. Specialized dendritic cells are able to stick their processes in between intestinal epithelial cells and ‘sample’ gut bacteria¹⁵. The chronic inflammation of IBD is due to a loss of tolerance to these antigens. Defects have been identified in special immune suppressor cells, normally responsible for toning down the inflammatory response¹⁶^, ¹⁷.

The effector cells, those cells responsible for coordinating the damaging inflammation in CrD, are a special set of CD4+ T helper cells. These cells produce large amounts of proinflammatory cytokines such as tumour necrosis factor (TNF), IL-6, and IL-17.

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