Protein may key lupus’ attack on neurons

Researchers studying the autoimmune disease lupus have identified a protein on the surface of brain cells that enables rogue antibodies to attach to and kill these neurons.

Although lupus is more commonly marked by joint pain, rashes, and kidney problems, patients also fare worse on tests revealing subtle changes in memory and learning than healthy individuals do. Neuron damage traceable to the vulnerable surface protein, called NR2, could account for these mental lapses, says study coauthor Betty Diamond, a rheumatologist at the Albert Einstein College of Medicine in New York. If so, blocking NR2 might provide means for scientists to waylay antibodies that attack a person’s own brain cells, she says.

Diamond and her team searched a library of proteins for ones that bind to a specific antibody that attaches to DNA in laboratory animals and causes autoimmune symptoms. “It knocked our socks off” to find that NR2 binds to this antibody, Diamond says, because NR2 is plentiful on neuron surfaces. There, NR2 is part of a receptor that serves as a docking port for glutamate, a chemical that carries signals between brain cells. It turns out that NR2 structurally resembles a DNA sequence targeted by the antibody.

Many lupus patients harbor anti-DNA antibodies in their blood. When Diamond and her colleagues exposed lab-grown neurons to such antibodies from the blood of four lupus patients with neurological problems, the brain cells promptly died.

Next, the scientists injected some of the anti-DNA antibodies into the brains of live mice. That caused neuron loss in the animals. However, mice primed with a drug that blocks NR2 were protected, so the team suggests that these lupus patients’ autoimmune antibodies act through NR2.

The scientists also discovered anti-DNA antibodies in the spinal fluid of one lupus patient whose mental capacity is declining. Antibodies aren’t made in the nervous system and rarely penetrate the brain or spinal cord. How the lupus antibodies might gain access to neurons is still a mystery, Diamond says. The work appears in the November Nature Medicine.

Finding a potential role for NR2 in lupus “is a striking observation,” says immunologist Michael C. Carroll of Harvard Medical School in Boston. The connection between lupus and the nervous system has been difficult to pin down because patients don’t link subtle cognitive problems to the disease, he says.

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