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Disabling gene defuses rheumatoid arthritis in mice

Scientists studying mice have identified a gene that allows immune cells known as neutrophils to protect themselves from the inflammatory chemicals they secrete.

Researchers at Washington University School of Medicine in St. Louis showed that knocking the gene out in mice prevented the development of an arthritis-like disorder by making the neutrophils victims of their own damaging secretions.

The newly identified role for the gene, Foxo3a, may open a new window for treating arthritic conditions caused by immune dysfunction. Currently, most treatments in development for these disorders focus either on preventing wayward immune cells from attacking the joints or on reducing the ability of these cells to open fire. The new results suggest it may be just as helpful to let these cells kill themselves and each other.

"We already know a great deal about Foxo3a from studies of its role in some cancers, and hopefully that puts us in a good position to devise ways to manipulate its activity," says senior author Stanford Peng, M.D., Ph.D., assistant professor of medicine and of pathology and immunology. "If the human version of this gene functions in a similar fashion, modifying its activity may be a useful approach for arthritis therapy even when the disease is already well underway."

Peng and colleagues will publish their results in the June issue of Nature Medicine.

Rheumatoid arthritis, the most prevalent autoimmune form of arthritis, afflicts approximately 2.1 million Americans or about 1 percent of the population. Women are two to three times more likely to develop the disorder than men. Symptoms often occur in episodic bursts and may include morning stiffness, fatigue and joint and muscle pain. In severe cases, rheumatoid arthritis can damage cartilage, tendons, ligaments and bone, leading to joint deformity and instability.

Rheumatoid arthritis has long been recognized as a condition that involves defensive cells from the body's immune system mistakenly attacking healthy joint tissues. Scientists once thought the cells that were most active in these attacks were adaptive immune cells including T cells. Most of these cells are like guided missiles: they get a fix on a specific target, pursue it and attack it.

"Classically, everyone thought that the T cells somehow recognized something specific in the joint like collagen or some other protein and attacked it," Peng explains. "In recent years, though, it's become more accepted that rheumatoid arthritis is also the result of a less specific but still harmful inflammation generated by cells from the other branch of the immune system, the innate immune system."

Innate immune cells such as neutrophils respond rapidly to invaders and normally comprise the body's frontline defenses against bacterial infection.

Peng became interested in Foxo3a because of prior studies his research team had conducted on a related gene, Foxj1. Both genes belong to the forkhead family of genes, which regulates the activity of other genes and has been connected to cancer and longevity. Last year Peng found that knocking out Foxj1 produced a lupus-like condition in mice.

Foxj1 and Foxo3a are thought to play similar roles in immune T cells. To get a better sense for Foxo3a's activities, Peng's group created a line of mice where Foxo3a had been disabled and studied the effects this change had on T cells.

As a follow-up, Peng decided to inject the new line of mice with antibodies that normally induce a condition like rheumatoid arthritis. But the mice remained healthy even after the injections.

"It was a surprise finding," Peng says. "We really didn't expect to see this kind of response."

Further study revealed that neutrophils in the mice were killing themselves through a cellular self-destruct process known as apoptosis. Damaged or highly stressed cells can pull their own plug in this or a similar manner to pr event themselves from becoming cancerous.

"It seems that evolution has somehow provided protective mechanisms for innate immune cells when they go into the hazardous inflammatory environments they create," Peng notes. "They need ways to keep themselves alive, and Foxo3a is one of those ways."

Peng's group is currently trying to discern more details of Foxo3a's activities in neutrophils, including the pathways the gene activates to block apoptosis. They will also be looking for drugs that inhibit Foxo3a and testing them in the mice as potential anti-arthritis drugs.

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Jonsson H, Allen P, Peng SL. "Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis." Nature Medicine, June 2005.


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Source:Washington University School of Medicine


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