New antibody may explain mystery cases of NMOSD-like disease

An international team of researchers identified a self-reactive antibody that may explain cases of neuromyelitis optica spectrum disorder (NMOSD)-like disease that test negative for known NMOSD-causing antibodies.

Self-reactive antibodies against the protein modulator VRAC current 1 (MLC1) were identified in multiple people with NMOSD-like disease who lacked known disease-causing antibodies. In rodent models, anti-MLC1 antibodies triggered damage to the same brain cells that are damaged in NMOSD.

The findings expand the known number of antibodies that can cause NMOSD-like disease, which may aid in NMOSD diagnosis and help personalize treatment.

“MLC1 antibodies identify a subset of patients with an NMOSD-like [disease], underscoring their potential as a disease marker with [disease-driving] relevance,” the researchers wrote.

The study, “Antibodies against MLC1 found in patients with NMOSD-like disease mediate astrocytopathy in rodent models,” was published in Science Translational Medicine.

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Astrocytes are ‘key target’

NMOSD is caused when the immune system mistakenly attacks healthy parts of the nervous system. It is marked by damaging inflammation of the spinal cord and the optic nerve, which relays signals between the eyes and the brain. Most cases test positive for self-reactive antibodies targeting a protein, aquaporin-4 (AQP4), that is highly present at the surface of astrocytes, the star-shaped brain cells that normally help to support neurological function.

The identification of anti-AQP4 antibodies “indicated that astrocytes are a key target of the autoimmune attack” in NMOSD, Simone Mader, a co-senior author of the study and a professor at Uniklinikum Erlangen, said in a news story from Friedrich-Alexander-Universität Erlangen-Nürnberg, in Germany.

The discovery initially helped distinguish NMOSD from multiple sclerosis (MS) and other related diseases affecting the brain and spinal cord and resulting in similar symptoms.

Some people with NMOSD-like symptoms who tested negative for anti-AQP4 antibodies were found to have self-reactive antibodies targeting a different protein, myelin oligodendrocyte glycoprotein (MOG). This is now considered a separate disease called MOG antibody-associated disease (MOGAD).

In people with NMOSD-like disease who don’t have antibodies against AQP4 or MOG — known as seronegative cases — “it has remained largely unclear which molecular mechanisms are behind the disease,” Mader said. This can make it more difficult to diagnose these cases and develop effective treatments.

Mader and colleagues initially detected a particular antibody staining pattern in brain tissue sections of a seronegative person with NMOSD-like disease after these were exposed to the person’s blood, suggesting an autoimmune reaction.

After comprehensive studies, they were able to identify MLC1, a protein also found on the surface of astrocytes, as a target of the patient’s autoimmune attack. The team then developed a test to screen for anti-MLC1 antibodies in blood samples from nearly 300 people with inflammatory diseases of the brain and spinal cord.

Four patients tested positive for antibodies against this protein. All “exhibited overlapping yet atypical clinical features of MS and NMOSD and tested negative for AQP4 and MOG antibodies,” the researchers wrote.

The scientists then tested the effects of anti-MLC1 antibodies in brain tissue from mice and in a rat model of brain inflammation. In both models, these antibodies were shown to damage or even destroy astrocytes, effects comparable to those of anti-AQP4 antibodies in NMOSD.

The results “suggest that the studied [self-targeting antibodies] are not merely an accompanying phenomenon but are involved in the processes that cause the disease,” Mader said.

“Identifying additional disease-relevant [self-targeting antibodies] could help more precisely distinguish between the different forms of neurological autoimmune diseases,” said Mader. “In the long term, such insights could also provide starting points for more targeted therapies.”