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Antibody Destroys Neurons in Lupus

5 November 2001 7:00 pm
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Attacked. Stained nerve cells (left) vanish after anti-DNA antibodies are injected into mouse brains (right).

In patients with lupus, the immune system turns traitor and breaks down the body as if it were an infectious agent. What's not clear is how lupus triggers the cognitive problems that up to 80% of patients suffer. Now, researchers have found that antibodies found at high levels almost exclusively in lupus patients attach to a well-known protein on nerve cells, forcing them to self-destruct.

The misguided immune response in lupus incites skin rashes, kidney damage, seizures, and cognitive trouble such as psychosis and problems with memory and learning. Some of this damage is caused by antibodies that erroneously target the patient's own DNA and wreak havoc in the kidneys. But it wasn't clear how anti-DNA antibodies meddled with the central nervous system. In previous work, immunologist Betty Diamond at the Albert Einstein College of Medicine in New York City discovered that R4A, an antibody developed as a tool to mimic lupus in mice and that closely resembles human anti-DNA antibodies, also binds to a protein shaped like DNA. The same amino acid sequence is found in a protein, NR2, that pokes out from nerve cells as a dock for the neurotransmitter glutamate.

To determine whether R4A interacts with nerve cells, Diamond's team injected the antibody into regions of mice brains with many glutamate receptors, the cortex and hippocampus. This killed considerable numbers of nerve cells compared to mice that were injected with a control antibody, the researchers report in the 1 November issue of Nature Medicine. They then tested the effects of R4A antibody on cultured human nerve cells. Again, the nerve cells died; biochemical tests showed that the antibody ordered them to commit suicide. Finally, Diamond's group injected cerebrospinal fluid from four lupus patients into mice and saw the same damage to nerve cells as with the antibody alone.

"It's among the most important pieces of information to come [out] about lupus in a long time," says rheumatologist David Wofsy at the University of California, San Francisco. "It provides a mechanism to understand one of the most dreaded manifestations of the disease."

Related sites

Betty Diamond's home page
Lupus information from NIH
Lupus Foundation of America

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