Summary: A new study considers whether immune system changes in people with lupus contribute to neuropsychiatric symptoms associated with the disease.
Source: Boston Children’s Hospital.
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.
“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.
Funding: 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.
Source: Michael Carroll – Boston Children’s Hospital
Image Source: NeuroscienceNews.com image is credited to Carroll lab / Boston Children’s Hospital.
Original Research: Abstract for “Microglia-dependent synapse loss in type I interferon-mediated lupus” by Allison R. Bialas, Jessy Presumey, Abhishek Das, Cees E. van der Poel, Peter H. Lapchak, Luka Mesin, Gabriel Victora, George C. Tsokos, Christian Mawrin, Ronald Herbst & Michael C. Carroll in Nature. Published online June 14 2017 doi:10.1038/nature22821
[cbtabs][cbtab title=”MLA”]Boston Children’s Hospital “Surprising New Link Between Inflammation and Mental Illness.” NeuroscienceNews. NeuroscienceNews, 15 June 2017.
<https://neurosciencenews.com/inflammation-mental-illness-6917/>.[/cbtab][cbtab title=”APA”]Boston Children’s Hospital (2017, June 15). Surprising New Link Between Inflammation and Mental Illness. NeuroscienceNew. Retrieved June 15, 2017 from https://neurosciencenews.com/inflammation-mental-illness-6917/[/cbtab][cbtab title=”Chicago”]Boston Children’s Hospital “Surprising New Link Between Inflammation and Mental Illness.” https://neurosciencenews.com/inflammation-mental-illness-6917/ (accessed June 15, 2017).[/cbtab][/cbtabs]
Microglia-dependent synapse loss in type I interferon-mediated lupus
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis—collectively this is referred to as central nervous system (CNS) lupus1, 2, 3, 4. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies5, 6, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab7, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
“Microglia-dependent synapse loss in type I interferon-mediated lupus” by Allison R. Bialas, Jessy Presumey, Abhishek Das, Cees E. van der Poel, Peter H. Lapchak, Luka Mesin, Gabriel Victora, George C. Tsokos, Christian Mawrin, Ronald Herbst & Michael C. Carroll in Nature. Published online June 14 2017 doi:10.1038/nature22821