Anti-RGMa antibody treatment ameliorates NMO pathophysiology CREDITTakahide Itokazu

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.

Flares happen. We do everything we can to prevent them and to understand why they occur. But sometimes they just happen. This is true regardless of the inflammatory or autoimmune disease: lupus, arthritis, fibromyalgia, vasculitis and all the others. As frustrating as they can be, there are things you can do to manoeuvre your way through them with care and grace.

Autoimmune diseases are triggered when the immune system malfunctions and attacks the body’s own structures. Although there is not, as yet, any cure for such diseases, their progression can be slowed down by therapeutic measures. Researchers at MedUni Vienna’s Center for Physiology and Pharmacology have now discovered a central signaling pathway in immune cells that may help in the development of a new therapeutic approach. Their study was recently published in the journal Cell Reports.

The immune system protects the body from infections of all kinds and is designed to distinguish between foreign threats and the body’s own tissues. T cells, which are deployed at the command of other immune cells, the dendritic cells, are an important component of the immune system. The dendritic cells are not only responsible for activating the T cells but also for deactivating them – primarily to prevent them from attacking the body’s own tissues. This mechanism, known as immunotolerance, is the key to the current treatments for autoimmune diseases, whereby certain pharmaceutical agents (JAK inhibitors) are used. The aim is to inhibit T-cell activity against endogenous structures, so as to slow down the progression of the autoimmune disease.

JAK inhibitors are used to treat various autoimmune diseases, such as rheumatoid arthritis. The effect of the inhibitors – on all immune cells simultaneously – has been demonstrated in several studies. A research team led by Gernot Schabbauer and Omar Sharif from the Institute of Vascular Biology and Thrombosis Research at MedUni Vienna’s Center for Physiology and Pharmacology has now investigated the specific effect of JAK inhibitors on dendritic cells and, in particular, the role played by the immunotolerance of T cells (peripheral T cell tolerogenesis) in autoimmune diseases.

Targeted cell-based therapy
Working in collaboration with scientists at the Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis at MedUni Vienna and St. Anna Children’s Cancer Research, they discovered a key building block in immune cells that is relevant in the context of autoimmune diseases. “This is the signaling pathway in dendritic cells that promotes T-cell tolerogenesis. This enables the dendritic cells to increase the immunotolerance of the T cells in particular and prevent them from attacking the body’s own structures,” explains the study’s lead author Andrea Vogel from MedUni Vienna’s Institute of Vascular Biology and Thrombosis Research.

The researchers’ findings are a step towards a potential new cell-based therapeutic approach for autoimmune diseases. The aim is to specifically target the signaling pathway in the dendritic cells, so as to “switch off” the misdirected T cells and slow down progression of the autoimmune disease. Further research on this will follow, emphasises Andrea Vogel: “The next thing we want to investigate is whether this signaling pathway in dendritic cells also plays a role in cancer.”