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.