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Immunity. 2006 Sep;25(3):473-85. Epub 2006 Aug 31.

Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis.

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Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC, Room 5W3940, 10 Center Drive, Bethesda, Maryland 20892, USA.


In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4+ T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4+ T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4+ T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.

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