Up to 75 percent of patients with systemic lupus erythematosus — an incurable autoimmune disease commonly known as “lupus” —  experience neuropsychiatric symptoms.  But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” says Allison Bialas, PhD, a research fellow working in the lab of Michael Carroll, PhD, of 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.”

Perhaps, Bialas thought, changes in the immune systems of lupus patients were directly causing these symptoms from a pathological standpoint. Working with Carroll and other members of his lab, Bialas started out with a simple question, and soon, made a surprising finding – one that points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other diseases. The team has published its findings in Nature.

“How does lupus’s chronic inflammation affect the brain?”

Lupus, which affects at least 1.5 million Americans, causes the immune system to attack the body’s tissues and organs. This causes the body’s 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,” says Carroll, senior author on the study and a senior investigator in the Program of Cellular and Molecular Medicine at Boston Children’s.

So, working with a mouse model of lupus, it was quite unexpected when Carroll’s team discovered 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.

Interferon-alpha could be detected within the brain (red) and active interferon-alpha receptor signaling (IFNAR) was also observed (green), which is responsible for triggering microglia attack on synapses. Credit: Carroll lab / Boston Children’s Hospital

 

“We’ve found a mechanism that directly links inflammation to mental illness,” says Carroll, who is also professor of pediatrics at Harvard Medical School. “This discovery has huge implications for a range of central nervous system diseases.”

Blocking inflammation’s effects on the brain

The team decided to see if they could reduce synapse loss by administering a drug that blocks interferon-alpha’s receptor, called an anti-IFNAR.

Remarkably, they found that anti-IFNAR did seem to have neuro-protective 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.

Although further study is needed to determine exactly how interferon-alpha is crossing the blood brain barrier, the team’s 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,” says Bialas, first author on the new paper. “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 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 suggests. His team plans to find out.

This research was supported by the Alliance for Lupus Research (ALR – 332527); the NIH (AI039246, AI42269, AI74549); MedImmune LLC; and the Jeffrey Modell Foundation. In addition to Bialas and Carroll, other authors on the paper included: Jessy Presumey, Abhishek Das, Cornelis van der Poel, Peter H. Lapchak, Luka Mesin, Gabriel Victora, George C. Tsokos, Christian Mawrin and Ronald Herbst.