Up to 75 percent of patients with systemic lupus erythematosus experience neuropsychiatric symptoms. But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky.

In general, lupus patients have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures and even psychosis, said Allison Bialas, a Harvard Medical School research fellow in pediatrics at Boston Children’s Hospital. “But their cause has not been clear – for a long time, it wasn’t even appreciated that these were symptoms of the disease,” she said.

Perhaps, Bialas thought, changes in the immune system in lupus patients were directly causing these symptoms from a pathological standpoint.

Working with Michael Carroll, HMS professor of pediatrics at Boston Children’s, and other members of his lab, Bialas started out with a simple question. She soon made a remarkable discovery – one that points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other diseases.

The team’s findings were published June 14 in the journal Nature.

Lupus, which affects at least 1.5 million Americans, causes the immune systems to attack tissues and organs. This causes white blood cells to release type 1 interferon–alpha, a small cytokine protein that acts as a systemic alarm, triggering a cascade of additional immune activity as it binds with receptors in different tissues.

Until now, however, these circulating cytokines were not thought to be able to cross the blood–brain barrier, the highly selective membrane that controls the transfer of materials between circulating blood and the central nervous system (CNS) fluids.

“There had not been any indication that type 1 interferon could get into the brain and set off immune responses there,” said Carroll, senior author on the paper.

So, it was quite unexpected when Carroll’s team discovered in a mouse model of lupus that interferon–alpha did indeed appear to permeate the blood–brain barrier and cause changes in the brain. Once across the barrier, interferon–alpha launched microglia, the immune defense cells of the CNS, into attack mode on the brain’s neuronal synapses. This caused synapses to be lost in the frontal cortex.

“We’ve found a mechanism that directly links inflammation to mental illness,” said Carroll. “This discovery has huge implications for a range of central nervous system diseases.”

The researchers found that anti–IFNAR did seem to have neuroprotective effects in mice with lupus, preventing synapse loss when compared with mice who were not given the drug. What’s more, they noticed that mice treated with anti–IFNAR had a reduction in behavioral signs associated with mental illnesses, such as anxiety and cognitive defects.