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Immune system’s attack dogs kept on genetic leash


Loss of restraint may contribute to lupus, other autoimmune disorders

When they’re not busy battling invaders, some of the cells that act as the attack dogs of the mouse immune system have to be kept on a genetic leash to prevent them from mounting inappropriate attacks on the mouse’s own tissues, researchers from Washington University School of Medicine in St. Louis have found.

The findings, reported in this week’s issue of Science, are the first scientific proof of a theory that could open up a significant new front in the battle to control autoimmune diseases like lupus, multiple sclerosis and diabetes.

"We used to think of mature immune cells like T cells and B cells as metabolically inactive when waiting for infections or other signals that trigger an attack," says Stanford Peng, M.D., Ph.D., assistant professor of internal medicine and of pathology and immunology. "We’re now thinking these resting cells actually are very metabolically active, and they are kept in a quiescent state by genes actively working to shut down activating proteins."

In the new study, Peng and colleagues showed for the first time that a gene, Foxj1, helps keep immune attack cells inactive. If malfunctions in this gene and others contribute to human autoimmune diseases, researchers may be able to develop new treatments that restore the genes’ functions and ease patients’ symptoms.

"Our efforts to develop new treatments have been focused on pathological targets in autoimmune diseases -- genes that are overused or are used inappropriately, leading to immune system attacks on self," Peng explains. "Another concept we should keep in mind is that the loss of one of these regulatory genes that keep the immune system in check also may be a primary contributing factor."

Peng notes, though, that errors in regulatory genes are unlikely to be the sole cause of a particular autoimmune disorder.

"You probably need multiple malfunctions in different genes to cause a severe autoimmune syndrome," he explains.

The Lupus Foundation of America estimates about 1.5 million Americans have lupus, which can cause arthritis, prolonged fatigue, skin rashes, kidney damage, anemia and breathing pain.

Many key symptoms of human lupus spontaneously appeared in lines of mice being bred for other purposes by various scientists in the 1960s and 1970s. Peng and colleagues compared the activity levels of different genes in cells from normal mice and from the mice that develop lupus. They measured how often cells used the genes to make messenger RNA, which is like an order slip for production of a copy of the gene’s protein.

"Although Foxj1 had never previously been shown to have an immune system role, cells of the mice with lupus were clearly making less RNA from this gene, and this is typically reflective of reduced activity on the part of the gene’s protein," Peng says.

When Peng’s group disabled the gene in the immune systems of normal mice, they developed a lupus-like syndrome, with inflammation in the salivary glands, lungs, kidneys and several other organs.

The protein made from the gene already was known to be a transcription factor -- a protein that promotes or suppresses the creation of proteins made from other genes. Peng found that lack of the Foxj1 protein increased activity of another transcription factor, NF-B.

"This protein belongs to a family of transcription factors heavily implicated in various types of inflammation," Peng says. "So our thinking is that without the protein, more NF-B is activated, possibly triggering the inappropriate activation of immune cells."

Peng speculates that other Fox gene family members may play an intrinsic role in keeping immune cells quiet or in preparing them to battle invaders.

"There’s not a lot known yet about the family of Fox genes," Peng says. "One member, Foxp3, has been linked to the development of regulatory T cells that suppress the activation of other immune cells. But that’s an external limit on cell activation. Foxj1 is the first gene to limit activity instrinsically, or from within the cell itself."

Peng continues to investigate the basic biochemistry of the gene, which also has been identified in humans. He hopes to look for signs of malfunction in the gene in humans with lupus and other autoimmune disorders.

"This may be relevant to other diseases beyond lupus," Peng says. "In diabetes, for example, it’s known that T cells, one of the cell types affected by this gene, attack the pancreas. In multiple sclerosis, T cells appear to attack the brain. So this gene may have a much more general role to play."

Lin L, Spoor MS, Gerth AJ, Brody SL, Peng SL. Modulation of Th1 activation and inflammation by the NF-B repressor Foxj1. Science, Feb. 13, 2004.

Funding from the Lupus Research Institute, the Arthritis Foundation, the National Institutes of Health, the Siteman Cancer Center, the Diabetes Research and Training Center and the Digestive Diseases Research Core Center of the Washington University School of Medicine supported this research.

Michael C. Purdy | WUSTL
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