Duke Researchers Discover Candidate Susceptibility Gene For Autoimmune Disease

May 14, 1996

DURHAM, N.C. -- Researchers at Duke University Medical Center have identified a gene in mice that, when malfunctioning, causes a joint-destroying, arthritis-like disease in the animals. The discovery may provide a clue to the underlying genetic defects that can lead some people's immune systems to attack their own bodies, the Duke researchers say.

Led by Dr. Perry Blackshear of the Howard Hughes Medical Institute at Duke University, the research team published their results in the May issue of the journal Immunity. Gregory Taylor and Ester Carballo of Blackshear's lab were the lead authors of the paper. Blackshear also is a professor of biochemistry and medicine at Duke medical center.

To date, doctors have not identified any specific genes for autoimmune diseases such as rheumatoid arthritis, although many researchers believe there may be several genes that, when defective, predispose people to develop autoimmune disorders.

The Duke researchers made the discovery while trying to understand the role of a gene of unknown function that seemed to be involved in the action of insulin, a hormone involved in diabetes. Instead, they found they had actually located what may be a key gene involved in autoimmune diseases such as arthritis and dermatitis.

"This research is a perfect example of how research in one area can often lead to an understanding in an apparently unrelated field," Blackshear said. "We were studying factors in the body that are influenced by insulin, which regulates sugar levels in the bloodstream, and instead, discovered a gene that appears to regulate the inflammatory response."

Working with Duke University Arthritis Center researchers Dr. Bart Haynes and Dr. Dhavalkumar Patel, and with Dr. Gary Gilkeson, Blackshear's team determined that the animals had characteristic antibodies against their own tissues that represent an inflammatory autoimmune response. By comparing their mice with other animals that had similar clinical signs, the researchers hypothesized the animals were producing too much of a potent inflammatory protein called tumor necrosis factor alpha (TNFa).
To test their idea, the researchers injected the TTP-deficient animals with an antibody that neutralizes TNFa. In a dramatic and almost complete reversal, all signs of disease completely disappeared.

The findings support preliminary results of human clinical trials being conducted at Duke and other research institutions of an experimental treatment for rheumatoid arthritis (RA) that also uses antibodies to TNFa, Blackshear said. Such studies have shown antibodies to TNFa can significantly reduce the symptoms of RA in patients.

"We know that TNFa is involved in many human inflammatory diseases including autoimmune disorders and septic shock," Blackshear said. "This finding provides insight into a new gene that appears to regulate TNFa. It is possible that defects in this gene may cause people to be susceptible to developing autoimmune diseases."

The corresponding gene has been identified in people, and Blackshear's group will soon begin a study to see if mutations in the gene correlate with autoimmune disease in people.

"The TTP-deficient mouse is an exciting new model of arthritis," said Haynes, chairman of medicine at Duke and director of the Duke University Arthritis Center. "It also provides important new information about the types of genes that can cause arthritis."

In addition to using the animal model to understand the autoimmune response, Blackshear will continue studies to determine how TTP is involved in the insulin response.

"Right now we really don't have a good handle on what TTP is doing, although there are hints it is involved in gene regulation," Blackshear said. "Our next step will be to determine if it is involved in synthesis or degradation of TNF_ and then move forward to our original question of how TTP is involved in insulin's actions. This may turn out to be a gene with many different functions."

David Lee, Wi Lai, and Michael Thompson of Duke and Hal Broxmeyer of Indiana University School of Medicine also contributed to the research.
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Duke University

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