By Lisa Seachrist

Washington Editor

BETHESDA, MD.--It's simply an immunological misstep: The immune system no longer tolerates the very proteins found in the body it is supposed to be protecting. But that misstep starts a pathway that can lead to the joint and organ destruction that characterize arthritis and lupus.

Finding a way to circumvent this pathway has been extraordinarily difficult because it is a complex set of interactions that induces this "break in tolerance" and ultimately forces the body to damage its own tissues.

Nevertheless, researchers from the University of Florida, Gainesville, have found encoded in the mouse genome at least two genes that can suppress that pathway and allow mice destined to die of lupus nephritis to remain disease free.

"These genes could potentially be very valuable should their human versions prove to suppress lupus as well," said Edward K. Wakeland, who presented this work last week during the Arthritis Research Meeting at the National Institutes of Health. "Understanding their function could ultimately lead to new drug therapies."

Wakeland and his colleagues began their search for genes that cause lupus in mice by crossing an inbred strain of lupus-prone mice called NZM2410 with normal mice. In this fashion, they identified four genes associated with the development of the disease. One, SLE 1, found on mouse chromosome 1, appears to have a human counterpart found on human chromosome 1.

From those experiments, the researchers found that SLE 1 alone could cause only a minor form of lupus. To elucidate the pathways that lead to lupus, the researchers crossed the 1 mouse with a mouse strain known as NZW, which has two copies of the SLE 1 gene but doesn't succumb to lupus.

The resulting mice not only got lupus, but became very ill. "These mice got sick, and they got sick very fast," Wakeland said. "So we had to assume that there was some sort of suppressor gene acting in the NZW mice in order for them to remain well."

Wakeland envisioned a scenario where the genes that lead to autoimmunity behaved very much like those in a cancer cascade: one gene may spur cell growth and a different gene may quell the activity of the first gene. If the suppressor gene fails to work, a cell may grow out of control and begin its journey toward becoming a cancer. For autoimmunity, one gene may set the body against itself and another may hold that gene in check.

"I predict a lot of diseases like obesity and heart disease will have such pathways," Wakeland told BioWorld Today. "You see these sorts interactions all the time in developmental genetics studies: As soon as you find a gene that makes one phenotype you find another that suppresses the action of that gene. It's a classic genetic approach."

Through their investigations, the researchers discovered several regions on the mouse chromosome that contained genes capable of deactivating SLE 1. The two most important reside on chromosome 17 in the major histocompatability complex -- a region previously implicated in autoimmune disease -- and one on chromosome 9.

The researchers found that if a mouse has one good copy of one of these genes and one faulty copy, SLE 1 can lead to lupus. However, that finding doesn't explain why the mice became so sick when SLE 1 was associated with only moderate disease. Wakeland postulates that because NZW mice also harbor two other genes associated with lupus, the failure to suppress SLE 1 may allow those genes to worsen lupus symptoms.

"We simply don't know what SLE 1 and these suppressors are doing," Wakeland said. "But we have the means to find out."

Wakeland and his colleagues already suspect that SLE 1 may actually allow the body to break its tolerance for chromatin, allowing the body to trigger antibodies to chromatin.

"Ultimately, if we can figure out what these genes are doing and how they are doing it, we could identify people who are susceptible to lupus and possibly prevent the disease from ever occurring," Wakeland said. "That is the most optimistic view of the value of genetic information."

Wakeland's work on SLE 1 is supported by Millennium Pharmaceuticals Inc., of Cambridge, Mass. *