Around 75 percent of people with systemic lupus erythematosus — an incurable autoimmune disease commonly known as lupus — experience neuropsychiatric symptoms, such as anxiety, depression and seizures. But until now, the mechanism behind this link has remained unclear.
Now, in a new study using a mouse model of lupus, researchers from Boston Children’s Hospital discovered a mechanism that directly links inflammation to mental illness.
The findings, published in the journal Nature, shed light on the link between lupus and mental illness and may point to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other central nervous system (CNS) diseases.
“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” said first author Allison Bialas, Ph.D. “But their cause has not been clear — for a long time it wasn’t even appreciated that these were symptoms of the disease.”
Lupus causes the immune system to attack the body’s tissues and organs. This signals the body’s white blood cells to release type 1 interferon-alpha, a small cytokine protein that acts as an alarm, resulting in an avalanche of additional immune activity as it binds with receptors in different tissues.
Until now, however, these circulating cytokines were thought to be unable 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 first author Michael Carroll, Ph.D., senior author on the study and a professor of pediatrics at Harvard Medical School. He and research fellow Bialas are part of the Boston Children’s Program in Cellular and Molecular Medicine.
While working with a mouse model of lupus, the research team was quite surprised to discover that enough interferon-alpha did indeed appear to permeate the blood brain barrier to cause changes in the brain. Once across the barrier, it 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 set out to see if they could reduce synapse loss by administering a drug that blocks interferon-alpha’s receptor, called an anti-IFNAR.
Indeed, they discovered 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. In addition, they noticed that mice treated with anti-IFNAR had a reduction in behavioral signs associated with mental illnesses such as anxiety and cognitive defects.
Although more research is needed to determine exactly how interferon-alpha is crossing the blood brain barrier, the new findings establish a basis for future clinical trials to investigate the effects of anti-IFNAR drugs on CNS lupus and other CNS diseases. One such anti-IFNAR, anifrolumab, is currently being evaluated in a phase 3 human clinical trial for treating other aspects of lupus.
“We’ve seen microglia dysfunction in other diseases like schizophrenia, and so now this allows us to connect lupus to other CNS diseases,” Bialas said. “CNS lupus is not just an undefined cluster of neuropsychiatric symptoms, it’s a real disease of the brain — and it’s something that we can potentially treat.”
The implications go well beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection to chronic stress.
“Are we all losing synapses, to some varying degree?” Carroll suggested. His team plans to find out.
Source: Boston Children’s Hospital
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