Researchers Identify Roles of Gene Mutations Causing Lupus in Mice

In two related studies, researchers at UT Southwestern Medical Center have pinpointed defective genes in mice responsible for triggering the mysterious autoimmune disease lupus, which prompts the body’s immune system to mistakenly attack healthy organs and tissues.

A research team led by Dr. Chandra Mohan, associate professor of internal medicine, found that a defect in the Ly108 gene causes immune cells called B-cells to attack the body’s healthy cells, resulting in systemic lupus erythematosus, or SLE. Their findings are published in an issue of the journal Science.

Further research based on the study’s findings may lead to better diagnostic tests and therapeutic drugs to help cure human lupus, said Dr. Mohan, the paper’s senior author.

"If we can demonstrate that the same gene defect we described in the mouse model also causes human lupus, it would open ways to block the disease by developing therapeutics targeting pathways activated by the mutated Ly108 gene," Dr. Mohan said.

Kirthi Raman Kumar, the paper’s lead author and a graduate student in immunology, said, "This is the first demonstration of how immature B-cells from lupus-prone mice behave differently from lupus-resistant normal mice and how this difference can lead to autoimmunity."

In a separate lupus study published online in an issue of Proceedings of the National Academy of Sciences, another team of UT Southwestern researchers describe the role of a mutated gene called Tlr7, which interacts with Ly108 in triggering the mechanisms leading to a deadly form of lupus in mice by causing another component of the immune system to malfunction.

The research team led by Dr. Edward Wakeland, professor of immunology and director of UT Southwestern’s Center for Immunology, explained that mice that died of lupus carried twice the normal amount of copies of the mutated receptor gene Tlr7.

"If you put both genes together, you create fatal disease - the mouse dies of the mouse version of SLE," said Dr. Wakeland, who is also a contributing author to the Science paper.

The faulty gene mechanism described by Dr. Wakeland’s lab occurs in the body’s basic or innate immune system, which recognizes an initial infection and responds to very generic forms of single-stranded viral RNA.

In contrast, Dr. Mohan’s group explained a key mechanism in the development of lupus occurring in the adaptive immune system, which consists of cells that constantly adapt themselves to better recognize invading organisms and produce antibodies to fight them.

Both studies could yield promising targets for the development of specific drugs to treat or prevent human lupus, Drs. Mohan and Wakeland said.

Many of the current medications for lupus are drugs that were developed to treat other diseases. Such lupus medications include corticosteroids, chemotherapy drugs and the malaria drug Plaquenil.

"The available treatments are non-specific and can often cause undesirable side effects," Dr. Mohan said.