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  • Review Article
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The immunological and genetic basis of inflammatory bowel disease

Nature Reviews Immunology volume 3, pages 521–533 (2003)Cite this article

Key Points

  • Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Although clinically there are some similarities between the two diseases, there are also marked differences.

  • The aetiology of both forms has not been entirely elucidated however, marked progress has been made recently in understanding the immunopathogenesis and genetic susceptibility of these diseases.

  • Through the study of patients and mouse models, it seems that disease occurs as the consequence of a dysregulated immune response to normal constituents of the intestinal flora in a genetically predisposed host. Such mucosal inflammation can be attributed to either increased effector-cell function or decreased regulatory-cell function.

  • Crohn's disease seems to be driven by interleukin-12 (IL-12) and interferon-γ (IFN-γ), whereas a mouse model of ulcerative colitis has been shown to be driven by natural killer T (NKT) cells that produce IL-13.

  • Mutations in the gene encoding the NOD2 (nucleotide-binding oligomerization domain) protein have been identified in a subgroup of patients with Crohn's disease. This opens up the possibility that Crohn's disease is due, at least in some instances, to defects in innate immunity.

  • Recent findings will facilitate the development of new and specific therapies for patients with these diseases.

Abstract

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-γ (IFN-γ), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

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Figure 1: Pathways to mucosal inflammation.
Figure 2: TH1- and TH2-mediated colitis.
Figure 3: NKT cells and IL-13 in oxazalone-induced colitis.
Figure 4: Possible mechanisms of Crohn's disease caused by NOD2 mutations.
Figure 5: Anatomy of mucosal inflammation and points of therapeutic attack.

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Acknowledgements

G. Bouma is a fellow of the Royal Netherlands Academy of Arts and Sciences and is supported by funding from the Crohn's and Colitis Foundation of America.

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Authors and Affiliations

  1. The Mucosal Immunity Section, National Institutes of Health, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Allergy and Infectious Diseases, 10 Center Drive, Room 11N238, Bethesda, 20892, Maryland, USA

    Gerd Bouma & Warren Strober

  2. The Laboratory of Immunogenetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Gerd Bouma

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  1. Gerd Bouma
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  2. Warren Strober
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Correspondence to Warren Strober.

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DATABASE LINKS

LocusLink

CD25

IFN-γ

IL-1β

IL-2

IL-4

IL-5

IL-6

IL-10

IL-12

IL-12Rβ2

IL-13

IL-15

IL-16

IL-18

IL-23p19

IL-12p35

IL-12p40

NF-κB

NOD2

Rag1

RICK

SMAD7

Stat4

Stat3

TGF-β

TNF

Omin

Crohn's disease

ulcerative colitis

FURTHER INFORMATION

Mouse genome database

Crohn's and colitis foundation of America

Glossary

HAPTENATING AGENT

Small organic molecules that do not provoke an immune response by themselves, but do so when covalently attached to a carrier protein.

TOLL-LIKE RECEPTORS

(TLRs). A family of receptors that recognize conserved products that are unique to microorganisms, such as lipopolysaccharide. TLR-mediated events signal to the host that a microbial pathogen is present.

MICROSATELLITE MARKERS

A class of polymorphic markers (di-, tri- or tetra-nucleotide repeats) that are scattered throughout the genome. Individuals differ in the number of repeats, which can be used in determining the position of disease-susceptibility genes in the genome by studying the co-segregation of these markers with disease in families.

RELATIVE RISK

The probability of an event in the active group divided by the probability of the event in the control group. In this case, the risk of developing Crohn's disease in homozygous or heterozygous carriers of the NOD2 mutation divided by the risk in non-carriers of the mutation.

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Bouma, G., Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3, 521–533 (2003). https://doi.org/10.1038/nri1132

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