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Annals of Neurology

Researchers from Osaka University find that treatment with an antibody to a particular protein prevents disease-associated signaling processes and reduces symptoms of neuromyelitis optica in rats

Figure. Anti-RGMa antibody treatment ameliorates NMO pathophysiology

Autoimmune diseases are the molecular equivalent of “friendly fire”: the body attacks itself instead of harmful invaders. Now, researchers from Japan have found that interrupting the complex interplay between different immune cell types can help prevent the damage that this friendly fire causes in one type of autoimmune disease.

In a study published in this month in Annals of Neurology, researchers from Osaka University have revealed that treatment with an antibody to a protein called repulsive guidance molecule-a (RGMa) dramatically improves symptoms of neuromyelitis optica, a devastating autoimmune disorder, in an experimental rat model.

Neuromyelitis optica (NMO) is an inflammatory disorder that can cause pain, paralysis, and even death. In most cases, NMO is caused by antibodies that the body develops to a protein called aquaporin-4 (AQP4). These anti-AQP4 antibodies leak into the tissue at sites of nerve damage that also show massive accumulation of neutrophils. This neutrophil build-up is associated with the death of cells called astrocytes, which ultimately causes NMO symptoms.

“We recently found that injecting rats with an antibody to RGMa can decrease the severity of NMO symptoms,” says lead author of the study Shosuke Iwamoto. “However, it was still unclear how this treatment works mechanistically, whether by affecting AQP4, astrocytes, or some other factor.”

To address this, the researchers used a clinically relevant rat model of NMO to test the effects of the anti-RGMa antibody on disease symptoms, as well as gene and protein expression.

“Our findings revealed a new molecular mechanism of NMO pathophysiology in which RGMa stimulates macrophages to attract neutrophils to the lesions, where they kill off astrocytes,” explains Toshihide Yamashita, senior author.

Importantly, treating rats with an antibody to RGMa prevented these effects, resulting in fewer neutrophils around nerve lesions, less astrocyte killing, and a decrease in symptoms like movement problems and pain.

“Our findings suggest that anti-RGMa antibodies may represent an effective therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO,” says Iwamoto.

Given that the severity of acute NMO attacks greatly affects patients’ long-term outcomes, treatments targeting RGMa that help reduce the severity of the attack or enhance the recovery process are crucial for improving their quality of life. Treatment with an anti-RGMa antibody could potentially even be helpful in preventing NMO relapses in the chronic stage of the disease.

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The article, “RGMa signal in macrophages induces neutrophil-related astrocytopathy in NMO,” was published in Annals of Neurology at DOI: https://doi.org/10.1002/ana.26327

Summary: Researchers from Osaka University have found that repulsive guidance molecule-a (RGMa) induces macrophages to recruit neutrophils to nerve lesions in neuromyelitis optica, where they kill off astrocytes, causing pain and paralysis. Treating rats with an anti-RGMa antibody interrupted this signaling process, resulting in decreased neutrophil recruitment, increased astrocyte survival, and improvement in disease-associated symptoms.

Tweet: Bring (down) the pain: treatment with an anti-RGMa antibody reduces neuropathic pain in a rat model of neuromyelitis optica 

Tweet 2:Fighting friendly fire with fire: an antibody-based treatment decreases autoimmune symptoms in a rat model of neuromyelitis optica

Primary Keyword: Health and medicine
Additional Keywords:Clinical medicine, Diseases and disorders, Human health, Autoimmune disorders, Autoimmunity

Method of Research: Experimental study

Subject of Research: Animals and Human tissue samples (Immunohistochemistry)

Title: “RGMa signal in macrophages induces neutrophil-related astrocytopathy in NMO”
Journal: Annals of Neurology
Authors: Shosuke Iwamoto, Takahide Itokazu, Atsushi Sasaki, Hirotoshi Kataoka, Shinji Tanaka, Takeshi Hirata, Keiko Miwa, Toshihiko Suenaga, Yoshiki Takai, Tatsuro Misu, Kazuo Fujihara, Toshihide Yamashita
DOI: 10.1002/ana.26327

Funded by: Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development