The idiopathic inflammatory bowel diseases comprise two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. Accumulating evidence suggests that inflammatory bowel disease results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Genetic studies highlight the importance of host–microbe interactions in the pathogenesis of these diseases.1-13 Prominent among these genetic findings are genomic regions containing nucleotide oligomerization domain 2 (NOD2),14 autophagy genes,4,7,8,10 and components of the interleukin-23–type 17 helper T-cell (Th17) pathway.2 The NOD2 protein is an intracellular sensor of bacterial peptidoglycan, and autophagy enables cells to regulate and degrade diverse intracellular components, including pathogens.15 The autophagy gene, ATG16L1, has been associated with Crohn’s disease but not, thus far, with ulcerative colitis. The interleukin-23–Th17 pathway mediates microbial defense and intestinal inflammation.16,17 Multiple genes regulating this pathway have been associated with both Crohn’s disease and ulcerative colitis. This review summarizes recent progress in studies of intestinal immunity and genetics in inflammatory bowel disease.
Inflammatory bowel disease affects approximately 1.4 million Americans, and its peak onset is in persons 15 to 30 years of age.18 Crohn’s disease generally involves the ileum and colon, but it can affect any region of the intestine, often discontinuously. Ulcerative colitis involves the rectum and may affect part of the colon or the entire colon (pancolitis) in an uninterrupted pattern. In Crohn’s disease the inflammation is often transmural, whereas in ulcerative colitis the inflammation is typically confined to the mucosa. Crohn’s disease can be associated with intestinal granulomas, strictures, and fistulas, but these are not typical findings in ulcerative colitis. Cigarette smoking affects these two diseases differently: smokers are at increased risk for Crohn’s disease and tend to have more severe disease, whereas former smokers and nonsmokers are at greater risk for ulcerative colitis. Patients with inflammatory bowel disease are at risk for primary sclerosing cholangitis, ankylosing spondylitis, and psoriasis.19
Familial clustering of cases and twin studies have established a role for genetic factors, which are likely to play a more prominent role in Crohn’s disease than in ulcerative colitis.14 The observation that cases of both these diseases can occur within the same family suggests that some of the genes may be common to both disorders. As with other complex genetic disorders, inflammatory bowel disease entails the interaction of genetic and nongenetic factors. Changes in diet, antibiotic use, and intestinal colonization (e.g., the eradication of intestinal helminths) have probably contributed to the increased prevalence of inflammatory bowel disease during the past century.20,21
Our current knowledge of inflammatory bowel disease is based on a combination of gene association studies, clinical investigations, and laboratory experiments in mice. In this review, we first describe homeostasis of the intestinal immune system in health and then focus on advances in our understanding of how genetic alterations in this system contribute to the development of inflammatory bowel disease.