UT Southwestern researchers identify roles of gene mutations causing lupus in mice

June 15, 2006

DALLAS- 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 today's 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 this week in the 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.

Lupus is a chronic disease that can cause life-threatening damage to many parts of the body, including the kidneys, lungs, heart, central nervous system, joints, blood vessels and skin. It can be associated with severe fatigue, joint pain, skin rashes, hair loss and neurological problems.

Genetic predisposition, gender and race are major risk factors for lupus, which affects an estimated 270,000 to more than one million people in the United States. Women are five times more likely to die from lupus than men, and African-Americans are three times more like to die from lupus than Caucasians, according to the Alliance for Lupus Research. It is also more common in women of Hispanic, Asian and Native-American descent. Nine out of 10 people with lupus are women.
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Other UT Southwestern researchers involved with the Ly108 study in Science are: Dr. Liunan Li, postdoctoral fellow in immunology; Mei Yan, research assistant; Madhavi Bhaskarabhatla, research assistant; Angela Mobley, senior flow cystometry specialist; Charles Nguyen, graduate student in UT Southwestern's Medical Scientist Training Program; Jill Mooney, graduate student in immunology; and Dr. John Schatzle, associate professor of immunology. The study was funded by the National Institutes of Health and the Lupus Research Institute.

Other UT Southwestern authors of the PNAS paper on Tlr7 are: lead author Dr. Srividya Subramanian, a former postgraduate student in the Center for Immunology, now a postdoctoral researcher at Harvard University; Dr. Katalin Tus, assistant instructor, Dr. Quan Li, assistant professor, Xiang-Hong Tian, research scientist, Jinchun Zhou, senior research associate, and Chaoying Liang, senior research associate, all in Center for Immunology; Andrew Wang, graduate student, Medical Scientist Training Program; Guy Bartov, research technician in pathology; Dr. Lisa McDaniel, assistant professor of pathology; Dr. Xin Zhou, associate professor of pathology; and Dr. Roger Schultz, associate professor of pathology. The study was supported by the NIH, the Lupus Research Institute and the Alliance for Lupus Research.

This news release is available on our World Wide Web home page at http://www.utsouthwestern.edu/home/news/index.html

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Profile of Dr. Chandra Mohan - http://www.utsouthwestern.edu/findfac/professional/0,2356,38207,00.html

Profile of Dr. Edward Wakeland - http://www.utsouthwestern.edu/findfac/professional/0,2356,36900,00.html

UT Southwestern Medical Center

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