Researchers Identify Roles of Gene Mutations Causing Lupus in Mice

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Newswise | Researchers Identify Roles of Gene Mutations Causing Lupus

in Mice

Newswise — 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. 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.

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;

Mobley, senior flow cystometry specialist; Nguyen,

graduate student in UT Southwestern’s Medical Scientist Training

Program; Jill Mooney, graduate student in immunology; and Dr.

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; Wang, graduate

student, Medical Scientist Training Program; Guy Bartov, research

technician in pathology; Dr. Mc, assistant professor of

pathology; Dr. Xin Zhou, associate professor of pathology; and Dr.

Schultz, associate professor of pathology. The study was

supported by the NIH, the Lupus Research Institute and the Alliance

for Lupus Research.

Dr. Chandra Mohan's bio -

http://www.utsouthwestern.edu/findfac/professional/0,2356,38207,00.html

Dr. Wakeland's bio - http://www.utsouthwestern.edu/findfac/

professional/0,2356,36900,00.html

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