Genes tied to abnormal immune response in mice with lupus

Scientists have uncovered a link between a family of genes and abnormalities of the immune system that are associated with systemic lupus erythematosus (SLE), a devastating disease that affects over 1 million Americans. The research, published in the December issue of Immunity, significantly advances the understanding of the pathology of lupus-like autoimmunity in mice and may facilitate the design of future therapies for lupus in humans.

A normal immune system protects the body against viruses, bacteria and other potentially harmful foreign invaders. In an autoimmune disease, like SLE, the immune system loses its ability to tell the difference between foreign substances that pose a threat and the cells of the body. In SLE, the immune system attacks and damages the body’s own tissues and organs, including the joints, kidneys, heart, lungs, brain, blood and skin. Dr. Edward K. Wakeland from the University of Texas Southwestern Medical Center and colleagues used a lupus-prone mouse model of SLE to characterize genes directly involved with SLE susceptibility.

The researchers report that variations in the structure and expression of a subset of genes belonging to the SLAM/CD2 family may contribute to autoimmunity in mice with lupus. Scientists have known for some time that SLAM/CD2 genes play a critical role in controlling immune cells and responses. Evidence presented here suggests that the altered SLAM/CD2 members may be responsible for abnormal lymphocyte responses. The Ly108 gene, which is expressed at elevated levels in lymphocytes from lupus susceptible mice, has emerged as a likely contributor to abnormal immune activation. However, Ly108 and other SLAM/CD2 genes are thought to act in combination with additional genes and signaling molecules in these mice and further research is needed to identify the specific interactions that lead to an overzealous immune response.

The researchers conclude that sequence and expression level differences in a subset of SLAM/CD2 genes are associated with the autoimmune response observed in SLE mice. “Given our association of variations in the SLAM/CD2 cluster with lupus susceptibility in mice, further work on the relationship of polymorphisms in the SLAM/CD2 cluster to SLE in humans is clearly warranted,” says Dr. Wakeland.