NEW YORK (Reuters Health) - Mutations in the CARD15 gene, which encodes nucleotide-binding oligomerization domain protein 2 (NOD2), are one cause of Crohn disease. Now researchers believe they’ve uncovered the mechanism underlying this association.
According to a report in the August issue of Nature Immunology published online June 27, NOD2, which is mutated in about 15% of patients with Crohn disease, is a negative regulator of toll-like receptor 2 (TLR2)-mediated T helper type 1 (Th1) responses.
TLRs on the surface of cells in the gut recognize pathogenic bacteria and initiate inflammation, Dr. Warren Strober from the National Institutes of Health in Bethesda, Maryland, explained in a telephone interview with Reuters Health.
Using NOD2-deficient mice, a model for Crohn disease, they discovered that intact NOD2 signaling normally inhibits the TLR2-driven Th1 inflammatory response to pathogenic bacteria.
In the absence of NOD2 signaling, such as that occurring in the presence of NOD2 mutations, NOD2-mediated inhibition of TLR2-mediated inflammation is lost and Th1 responses go unchecked.
“In the absence of this negative regulatory gene, you get a bigger response to pathogenic bacteria and this makes you hyperresponsive to your own bacteria,” Dr. Strober said.
This study, he added, “validates the concept that, at least in the 15% of Crohn disease patients with NOD2 mutations, disease is due to an excessive Th1 response.” This study also “connects up this theory of hyperresponsiveness to a particular gene.”
“With the knowledge that there is over responsiveness in Crohn disease and in particular that NOD2 provides negative regulation, the prospect is now open to replacing the defective gene with gene therapy,” Dr. Strober told Reuters Health. His team is already working on this in animal models.
This study also introduces the possibility that patients with Crohn disease and intact NOD2 signaling might be treated by introducing Gram-positive bacteria, which stimulates the NOD2 pathway, into the intestinal flora, the scientists suggest in their report.
Source: Nat Immunol 2004. [ Google search on this article ]
MeSH Headings:CD4-Positive T-Lymphocytes: Th1 CellsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
