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Research Finds New Clues to Crohn's Disease

Two studies clarify role of specific protein

THURSDAY, Feb. 3, 2005 (HealthDayNews) -- Scientists have filled in a few more details in the complicated picture that makes up Crohn's disease.

Two different research teams detail in the Feb. 3 issue of Science how a particular gene contributes to the inflammation that is characteristic of the illness.

"This is getting maybe four pieces in a 5,000-piece puzzle," said Dr. Gerald Dryden, an assistant professor of medicine at the University of Louisville.

"It's another piece in the puzzle of how the disease works, but at this point in time doesn't bring us any closer to genetic screening or to therapeutic approaches," added Dr. Lloyd Mayer, chairman of immunobiology at Mount Sinai School of Medicine in New York City.

Down the line, however, this and other revelations may lead to new treatments, they said.

"Gene therapy is a distinct long-term possibility," said Dr. Scott Plevy, co-director of the Inflammatory Bowel Disease Center at the University of Pittsburgh. "And by understanding pathways better, we may be able to identify other ways to ratchet down the inflammatory response."

People with Crohn's disease have chronic inflammation, usually of the small intestine, which results in pain and diarrhea. The condition is a complicated one and involves genetic, environmental and immune system responses.

Crohn's seems to flare up when immune system cells release excess amounts of cytokines or molecules that attack the intestinal cells, causing the inflammation. The question has been what causes the immune system to malfunction this way.

In 2001, scientists found an association between Crohn's and mutations on the Nod2 gene, one of a family of genes which sense bacterial proteins when they are inside a cell. When the gene detects the bacteria, it sets off the inflammatory pathway in the cell. "It probably represents susceptibility to Crohn's disease in about 25 percent of people with the disease," Dryden said.

Oddly, however, when scientists examined the mutation in mice, they discovered that it resulted in a loss of immune function response. Experts had thought that an immune system overreaction was responsible for the inflammation.

One of the new studies, by researchers at the University of California, San Diego, seems to settle that paradox. The protein encoded by Nod2 acts as an early warning system, setting off the body's defenses when something foreign such as a bacteria or virus, enters a cell. When there's a mutation, however, this sensing system fails to detect certain bacteria, enabling the invader to cause infection and inflammation. "It's a problem with the signaling," Dryden said. "The early warning alarm is not being sounded so the cell doesn't mount the anti-microbial defense, so an infection sets in."

The second paper, from a team at Yale University, found that the Nod2 mutation also turns on a chemical which leads to inflammation. This study was done in test tubes, however, and not in mice.

The information may set scientists on the path to finding treatments for about a quarter of the people suffering from Crohn's disease. Of course, that still leaves researchers scratching their heads over the remaining 75 percent who don't have the mutation.

"This truly is a multi-factorial disease," Dryden said. "It has many triggers. Many pathways can take you to that ultimate inflammation."

More information

Learn more about Crohn's disease from the National Digestive Diseases Clearinghouse.

SOURCES: Lloyd Mayer, M.D., chairman, immunobiology center, Mount Sinai School of Medicine, New York City; Scott Plevy, M.D., associate professor, medicine and immunology, and co-director, Inflammatory Bowel Disease Center, University of Pittsburgh; Gerald Dryden, M.D., assistant professor, medicine, University of Louisville, Kentucky; Feb. 3, 2005, Science
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