In a study supported in part by the Alliance for Lupus Research (ALR), researchers have found that a family of genes known to play an important role in regulating immune system responses is involved in determining susceptibility to systemic lupus erythematosus (SLE, or lupus). A research team led by ALR-funded investigator Edward K. Wakeland, PhD, of the University of Texas Southwestern Medical Center at Dallas, found that a cluster of closely related genes on chromosome 1, known as the SLAM/CD2 gene family, plays a crucial role in the development of lupus-like autoimmunity in a mouse strain that is prone to the disease.
“Ten years ago we became interested in that region of chromosome 1 in the mouse because it came up as the strongest region associated with susceptibility to disease in our animal model of SLE,” says Dr. Wakeland. “We became especially interested in this region when other investigators discovered that the corresponding region in the human genome appeared likely to be associated with susceptibility to SLE in humans.”
As they describe in the December 2004 issue of the journal Immunity, the researchers found that susceptibility to disease in their lupus-prone mouse strain was associated with extensive variations in several members of the SLAM/CD2 gene family. The proteins produced by this gene family, which are found on many types of immune cells, influence the way the immune system responds to normal stimulation-for example, to an infection. And, Dr. Wakeland notes, variation in this gene family by itself does not necessarily lead to autoimmune disease. “It's only when you add this gene family to several other possible genes that the mice develop severe, fatal lupus,” he says. Furthermore, other researchers have shown that natural variations in the SLAM/CD2 gene family are associated with resistance to viral diseases in humans and other species.
“Our findings indicate that the genes that are causing lupus are not necessarily 'bad' genes or 'defective' genes,” says Dr. Wakeland. “They are simply naturally occurring genetic variations, and when you have the wrong combination of these variations it tilts the immune system too far out of balance, where you become prone to autoimmune disease.”
What it means for people with lupus: “Evidence is accumulating that these same [SLAM/CD2] genes are associated with susceptibility to lupus in humans,” says Dr. Wakeland. In addition, his research team has found that a gene called Sles1 can suppress the autoimmune activity associated with the SLAM/CD2 gene family in lupus-prone mice, and he recently received a new grant from the ALR to further investigate this gene. As researchers learn more about how various genes affect the delicate balance of the immune system and contribute to the development of autoimmune diseases such as lupus, Dr. Wakeland says, they may ultimately be able to devise therapies that can restore that balance without completely suppressing the immune system, which is a serious drawback of many current treatments for the disease.
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