By Lisa Seachrist

Washington Editor

Even though scientists have unearthed a vast amount of knowledge about the immune system, the causes of autoimmunity remain a mystery.

Diseases like lupus, multiple sclerosis and rheumatoid arthritis are the result of a complex web of genetic and environmental interactions. Unraveling that web and identifying genes associated with the disease has been a daunting challenge.

But a group of researchers from California found that sitting on the tail end of the long arm of chromosome 1 is a gene that appears to predispose people to lupus.

"The human genome has almost 100,000 genes," said Betty Tsao, an associate professor of rheumatology at the University of California at Los Angeles. "We have narrowed the search down to a region containing 500 genes."

Systemic lupus erythematosus is a very heterogeneous disease that can affect the kidneys, lungs and central nervous system. The one salient feature of lupus is the production of antibodies against various parts of the body itself. As a result, the immune system begins to attack the organs of the body.

With diseases like cystic fibrosis and Huntington's disease, inheriting two copies of mutated genes is enough to cause the disease. Lupus, on the other hand, is a multigenic disease. A person doesn't inherit a set of mutated genes that cause the disease. Several different diseases work in concert with environmental insults, such as infection, to result in lupus.

"One way to look at it is as the genes being the cards you are dealt in life," said Jane Salmon, a lupus researcher at Cornell University Medical College, in New York. "The combination of those cards and the way your opponents, like infection, play determine if you get lupus and how sick you are."

Identifying the multitude of genes that play a role in lupus is the hard part. Last year, researchers identified a region of DNA, also on chromosome 1, that is associated with kidney disease caused by lupus, but the correlation holds only for African-Americans.

In order to locate a lupus gene, Tsao and her colleagues used a clue from mouse models of the disease. A region of mouse chromosome 1 is associated with an increased level of antibodies directed against DNA as well as a lupus-like disease. The region on mouse chromosome 1 is homologous to the far end of the long arm of human chromosome 1.

Using microsatellite DNA markers, the researchers compared variations in the DNA between 52 pairs of siblings with lupus from 43 families. The families studied were Caucasian, African-American and Asian.

"You would assume that siblings would have the same alleles about 50 percent of the time," said Tsao. "If an allele is associated with the disease, you would expect it to show up more than 50 percent of the time."

The researchers reported in the February 15 Journal of Clinical Investigation that the region is linked to lupus regardless of ethnicity and severity of the disease. In addition, the region is also associated with immunoglobulin G (IgG) antibodies against DNA.

"We are hopeful that this means that we have an important clue to the basic cause of lupus," said Tsao. "We are reasonably sure that [the gene] is associated with autoantibody production."

Brian Kotzin, of the National Jewish Medical and Research Center, in Denver, agrees the gene likely will be associated with autoantibody production. He also notes the research needs to be confirmed.

"The study needs to be confirmed with another group of patients," said Kotzin. "But this represents a very important first step toward finding a gene for lupus."

Salmon noted the study was "very important because it supported the mouse model of lupus."

However, both Salmon and Kotzin said there would be a lot of work required to isolate the gene.

"There is no precedence for finding a gene associated with a complex disease, so finding the gene is likely to be very hard work," Tsao agreed. "But we may be very lucky." *