Oct. 5, 2007 In a series of mouse experiments, researchers at the Harvard School of Public Health (HSPH) have pinpointed a specific immune deficiency as the likely fundamental cause of ulcerative colitis, a chronic, sometimes severe inflammatory disease of the colon or large intestine that afflicts half a million Americans.
Remarkably, the researchers also found that once the disease was established in mice, it could be passed from mother to offspring and even between adult animals, with potential implications for public health and prevention.
The researchers have linked ulcerative colitis in mice to a deficiency of a molecular "peacekeeper" in the immune system, allowing harmful bacteria in the large intestine to breach the bowel's protective lining and trigger damaging inflammation.
In a paper being posted online on October 4, 2007, by the journal Cell, a team led by Laurie Glimcher, Irene Heinz Given Professor of Immunology at HSPH, details a series of immunological events by which a shortage of a regulatory protein called T-bet opens the way to a bacterial attack on the intestinal wall.
The resulting inflammation, in turn, causes the characteristic colitis marked by open sores, or ulcerations, throughout the colon. The first co-authors of the paper are Wendy Garrett, a research fellow in the laboratory of Glimcher and a clinical fellow at Dana-Farber Cancer Institute, and Graham Lord, formerly at HSPH and now a Professor of Medicine at King's College, London.
The key abnormality is a deficiency of the T-bet protein in "dendritic" cells - white blood cells that capture identifying antigens of foreign microbes and activate the immune defenses. T-bet, discovered in 2000 in Glimcher's laboratory, is a "master regulator gene," a transcription factor that orchestrates a pro-inflammatory response of the immune system. T-bet had been found to play a role in the body's handling of infectious microbes and cancer cells and has been implicated in rheumatoid arthritis and asthma, but the discovery of its pivotal part in the innate immune system in inflammatory bowel disease came as a total surprise.
"We have identified a new molecular player, T-bet, and when it's missing, there is spontaneous onset of the disease in the mice," said Glimcher. "The importance of this study is that we now have a novel model for ulcerative colitis: The disease appears in 100 percent of the animals and looks just like the human disease."
If some people develop ulcerative colitis because of T-bet DNA variation or polymorphisms, it may be because of an inherited variation in the DNA affecting the T-bet gene. The researchers are following up this lead.
With its close mimicry of human ulcerative colitis, the animal model will have unprecedented value for testing new therapies and preventive measures, said Glimcher, who is also a professor of medicine at Harvard Medical School.
Ulcerative colitis and a related disorder, Crohn's disease, are known collectively as inflammatory bowel disease: they affect an estimated one million people in the United States. Crohn's disease tends to involve the small intestine as well as the colon. Ulcerative colitis usually appears between ages 15 and 30 but also can begin in the 50s and 60s, especially in men. The disease is somewhat more common among men than women, whites than non-whites, and Ashkenazi Jewish individuals than non-Jewish individuals.
Since about 20 percent of patients with ulcerative colitis have a close relative with the disease or with Crohn's disease, scientists have hunted specific genes that may be involved. Studies of the pathology of the inflamed intestine have suggested that an abnormal immune reaction and injury by bacterial residents of the colon are to blame. The T-bet shortage described in the Glimcher paper links these two mechanisms.
Beneficial bacteria in the colon aid in digestion and extraction of nutrients from food. However, harmful microbes also reside in the intestine, so animals that harbor bacteria have evolved a boundary, or barrier, in the form of the intestinal lining to keep the dangerous bacteria from injuring the colon wall.
The key to maintaining this mucosal barrier, the scientists discovered, is the "peacekeeper" activity of T-bet in the dendritic cells of the intestine's immune system. When T-bet is at normal levels, the boundary - a kind of demilitarized zone - remains intact and prevents trouble from pathogenic bacteria. But if T-bet is insufficient, the dendritic cells overproduce a powerful chemical called TNF-alpha (tumor necrosis factor-alpha) that triggers inflammation and causes normal cells to die. In ulcerative colitis, the T-bet-related excess of TNF-alpha leads to the death of cells making up the epithelial barrier of the colon, enabling harmful bacteria to chronically inflame the intestinal wall.
The scientists bred strains of mice that lacked T-bet and showed that the resulting disease was virtually identical to human ulcerative colitis.
Moreover, the investigators demonstrated that female mice with the disease could transmit it to baby mice that had adequate levels of T-bet. (The scientists placed genetically normal infant mice with the sick foster mother on their day of birth.) Presumably, the flourishing colonies of colitis-causing bacteria were passed down from the sick mother to the fostered mice. The disease was even "horizontally" transmissible from T-bet-deficient adult mice with ulcerative colitis to other adults with normal T-bet, through fecal-oral and skin-to-skin contact.
Inflammatory bowel disease can be treated with antibody drugs that block TNF-alpha activity, though their toxicity limits their use. The researchers showed that such antibody drugs cured and also prevented ulcerative colitis in T-bet-deficient mice. However, they are pursuing other potential therapies, such as increasing T-bet levels in the immune cells, administering natural immunity-dampening cells called T-regulatory cells, or giving "probiotics" - healthful bacteria that can keep the harmful microbes under control.
The research was supported by grants from the National Institutes of Health and by an Ellison Scholar Award to Glimcher.
Reference: Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System. Wendy S. Garrett, Graham M. Lord, Shivesh Punit, Geanncarlo Lugo-Villarino, Sarkis K. Mazmanian, Susumu Ito, Jonathan N. Glickman, and Laurie H. Glimcher. Cell 131, 1-13, October 5, 2007.
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