Immune cell traps may worsen NMOSD attacks, study finds
Web-like structures released by cells could play a role
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Acute attacks of neuromyelitis optica spectrum disorder (NMOSD) may be worsened by web-like structures released by immune cells that normally help fight infection, a study suggests.
NMOSD patients experiencing disease attacks had higher blood levels of markers of these web-like structures, called neutrophil extracellular traps (NETs), relative to healthy people.
Data from lab-grown patient cells and an NMOSD mouse model suggested that NET formation disrupts the blood-brain barrier (BBB), a highly selective membrane that prevents large and potentially dangerous molecules in circulation from entering the brain and spinal cord. BBB disruption is linked to inflammatory attacks and disability severity in NMOSD.
“Together, these findings suggest that aberrant [NET formation] may contribute to BBB disruption in acute NMOSD and support further investigation of NET-associated pathways as potential therapeutic targets,” the researchers wrote.
The study, “Neutrophil extracellular traps exacerbate blood-brain barrier disruption in neuromyelitis optica spectrum disorder,” was published in the Journal of Neuroinflammation.
Neutrophils and the blood-brain barrier
NMOSD is an autoimmune disease marked by inflammatory attacks that mainly affect the spinal cord and optic nerves that transmit visual information from the eye to the brain. This can cause NMOSD symptoms such as muscle weakness and vision problems.
Most patients test positive for self-reactive antibodies against AQP4, a protein found mainly in supporting cells in the brain and spinal cord.
Studies suggest that blood-brain barrier disruption is a critical early event in these inflammatory attacks, facilitating the entry of circulating anti-AQP4 antibodies in the brain and spinal cord. Still, the mechanisms that drive and amplify BBB disruption remain incompletely understood.
Neutrophils, the most abundant immune cell in the bloodstream, are thought to contribute to NMOSD development. They can release NETs, web-like structures designed to entrap and kill infectious microbes.
Scientists in China wanted to find out whether NET formation is abnormally boosted during NMOSD attacks, also known as relapses, and whether NETs contribute to BBB disruption.
The study enrolled 25 adults with NMOSD, mostly women (92%), in the attack phase, defined as new or worsening symptoms. The team collected blood samples from them within 30 days of symptom onset and before relapse-directed treatment.
Researchers also sampled 21 NMOSD patients (81% women) who were in remission, defined as the absence of new or worsening symptoms for at least two months before sampling. A group of 50 age- and sex-matched healthy individuals served as controls.
Data showed that patients experiencing attacks had significantly more neutrophils than patients in remission and healthy controls. In the relapse group, higher neutrophil counts were significantly associated with more severe disability, as assessed with the validated the Expanded Disability Status Scale.
An analysis of all proteins in blood samples ranked those associated with the NET formation pathway “as the second most significantly enriched pathway” in patients experiencing an attack over healthy controls, the researchers wrote.
Compared with controls, patients experiencing relapses also had significantly higher levels of several NET-associated markers in both the blood and the fluid surrounding the brain and spinal cord.
Lab-grown neutrophils from relapsing patients also showed significantly higher signals for NET markers relative to healthy people, “supporting an enhanced propensity for spontaneous NET formation in neutrophils from acute NMOSD patients,” the team wrote.
When researchers induced NMOSD-like disease in mice, they detected NET-like structures in lesions in the corpus callosum, a band of nerve fibers connecting the two halves of the brain.
The team then treated the mouse model with therapeutic approaches designed to either kill neutrophils, prevent NET formation, or break down NETs.
All three approaches significantly reduced NET markers and inflammation in corpus callosum lesions, reduced brain damage markers, and improved motor performance and recognition memory.
The treatments also boosted levels of proteins involved in maintaining BBB integrity and reduced antibody leakage into the brain, findings that support “NETs as important mediators of BBB disruption in NMOSD,” the researchers wrote.
The scientists obtained similar findings when they exposed lab-grown mouse cells lining the brain’s blood vessels to NMOSD patient-derived NETs and when the three treatment approaches were administered to this cellular model.
“This study links aberrant NET formation to BBB disruption in acute NMOSD and shows that neutrophil/NET-targeting interventions attenuate BBB damage and lesion [in living organisms],” the team concluded, suggesting that NET-associated pathways may be potential therapeutic targets.
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