Neurotoxic Autoantibodies Impair Brains of Offspring in Maternal Lupus

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Betty Diamond, MD, and her colleagues at The Feinstein Institute for Medical Research have shown that anti-DNA antibodies can circulate in maternal serum and pass through the fetus during development in models of systemic lupus erythematosus (SLE).

Betty Diamond, MD, and her colleagues at The Feinstein Institute for Medical Research have shown that anti-DNA antibodies can circulate in maternal serum and pass through the fetus during development in models of systemic lupus erythematosus (SLE). Lupus is an autoimmune disease that can cause any number of symptoms. It remains a challenging condition to control, and the work that has been going on in the Diamond laboratory for decades is defining the disease process and identifying ways to treat it.

In the latest study, published this week in Nature Medicine, Dr. Diamond’s team found that high levels of autoantibodies in the maternal circulation of pregnant SLE mice crossed into the developing fetal brain and triggered abnormalities. When the offspring grew up, there was evidence of cognitive impairment.

This is very important because children of mothers with lupus have a four-fold increase in learning disabilities. The question is whether these circulating autoantibodies damage neurons in the developing human fetus and could be responsible for the increased risk for learning problems years later. No one knows yet.

Dr. Diamond and her colleagues are currently conducting a clinical study in patients to identify pregnant or young mothers with high antibody levels, and follow their children over time to see if they are at higher risk for learning problems.

In lupus, as in other auto-immune diseases, the immune system creates antibodies against its own tissue. These anti-DNA antibodies are present in about 70 percent of lupus patients. The presence of these anti-DNA antibodies is used to diagnose the condition. It is known that these antibodies contribute to tissue and kidney damage.

In a series of papers, the Feinstein scientists found that anti-DNA antibodies cross-react with a molecule on neurons – a receptor for a neurotransmitter called glutamate. If these anti-DNA antibodies get into the brain, patients can experience memory impairment or behavior problems.

They purified anti-DNA antibodies from the blood of lupus patients and used laboratory models to test how the antibodies get into the brain. They found that infection or stress can trigger a cascade of events that allows the anti-DNA antibodies to get into the brain. Stress induced the anti-DNA antibodies to take up residence in the amygdala, which triggered behavior problems. By contrast, exposure to an infection caused antibodies to move into the brain region called the hippocampus – the so-called seat of memory. And as one might expect, memory problems took hold.

Patients with lupus have a number of neurologic and psychiatric symptoms and brain scans have shown that there are abnormalities in the amygdala and hippocampus. The Feinstein scientists are now trying to see whether patients with these abnormal brain scans also have the presence of anti-DNA antibodies in their blood.

Dr. Diamond and her colleagues are also collaborating with Yousef Al-Abed, PhD, a medicinal chemist at the Feinstein, to develop and test small molecules that block anti-DNA antibodies from binding to the glutamate receptor in the brain. Having such a treatment could stave off the many cognitive and behavior problems patients with lupus experience and might protect their children in utero.

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