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Role of gene mutations causing lupus in mice identified


In two related studies, researchers at the University of Texas ( 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 Chandra Mohan 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.

The study is published in 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 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," Mohan said.

Kirthi Raman Kumar, the paper's lead author 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 in the Proceedings of the National Academy of Sciences ( PNAS ), other researchers of UT Southwestern 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 Edward Wakeland 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 Wakeland, who is also a contributing author to the Science paper.

The faulty gene mechanism described by 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, 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, 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.

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.

Source: UT Southwestern Medical Center, 2006


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