The genetics and immunopathogenesis of inflammatory bowel disease

• Published in: Nature reviews. Immunology Vol. 8; no. 6; pp. 458 - 466
• Main Author: Cho, Judy H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2008; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Colitis, Ulcerative - genetics; Colitis, Ulcerative - immunology; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Crohn Disease - genetics; Crohn Disease - immunology; Crohn Disease - metabolism; Crohn Disease - pathology; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetics; Health aspects; Humans; Immune response; Immunology; Inflammatory bowel diseases; Inflammatory Bowel Diseases - epidemiology; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - pathology; review-article; Risk factors; Single nucleotide polymorphisms; United States
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/nri2340

Key Points
The central challenge of the intestinal immune system is balancing the need to respond to pathogens while co-existing with commensal bacteria and food antigens. Data from genome-wide association (GWA) studies support the concept that dysregulation of the normally controlled immune responses to commensal gut bacteria in a genetically susceptible individual drives the development of inflammatory bowel disease.
GWA studies provide a broad view of the relative contributions of various genomic loci to common human diseases and involve genotyping a large number of single-nucleotide polymorphisms (SNPs) that sample human genetic variation throughout the genome.
Crohn's disease, but not ulcerative colitis, is associated with functional polymorphisms in the
NOD2
(nucleotide-binding oligomerization domain protein 2),
ATG16L1
(autophagy related 16-like protein 1) and
IRGM
(immunity-related GTPase family, M) gene regions. These genes have been implicated in the innate immune system and intracellular processing of bacterial components.
Crohn's disease-associated polymorphisms in
NOD2
are associated with a decreased ability of the NOD2 protein to appropriately sense bacterial peptidoglycan and activate nuclear factor-κB and mitogen-activated protein kinase pathways. Further studies assessing the altered function of
ATG16L1
and
IRGM
polymorphisms associated with Crohn's disease will be important in establishing the extent to which Crohn's disease occurs as a result of a primary defect in bacterial sensing by the innate immune system.
Consistent with previous epidemiological observations, several genes are associated with both Crohn's disease and ulcerative colitis, notably
IL23R
(encoding interleukin-13 receptor),
IL12B
(encoding the p40 subunit for IL-12 and IL-23) and
STAT3
(encoding signal transducer and activator of transcription 3), all of which are involved in IL-23R signalling. The homeodomain-containing transcription factor NKX2-3 (NK2 transcription factor related, locus 3), which is involved in lymphocyte development, differentiation and organization, is also associated with both Crohn's disease and ulcerative colitis.
Within the
IL23R
gene region, there are multiple independent signals showing association with inflammatory bowel disease and similar patterns of association have been observed in psoriasis and ankylosing spondylitis. The contributions of the
IL23R
region polymorphisms to intestinal inflammation are complex, reflecting contributions from both the innate and adaptive immune systems.
Great progress has been made recently in the identification of genes or genetic loci that are associated with inflammatory bowel diseases. This knowledge is now providing insight into the pathogenesis of these diseases, highlighting roles for genes involved in bacterial sensing and cytokine signalling.
Genome-wide association studies efficiently and powerfully assay common genetic variation. The application of these studies to Crohn's disease has provided insight into the immunopathogenesis of this disease, implicating a role for genes of the innate and adaptive immune systems. In this Review, I discuss our current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis. Crohn's disease, but not ulcerative colitis, is associated with genetic variation in
NOD2
and an autophagy gene,
ATG16L1
, both of which affect the intracellular processing of bacterial components. By contrast, variation in the gene encoding the interleukin-23 (IL-23) receptor subunit, as well as in the
IL12B
,
STAT3
and
NKX2-3
gene regions, is associated with both Crohn's disease and ulcerative colitis. Comparative analyses of gene associations between these two inflammatory bowel diseases reveal common and unique mechanisms of their immunopathogenesis.