Study IDs possible ‘off switch’ for overactive immune response in MG
Tapping into immune checkpoint proteins may help in controlling disease
Tapping into PD-1/PD-L1 immune checkpoint proteins — which serve as a kind of natural off switch for an overactive immune response — might help keep myasthenia gravis (MG) under control.
That’s according to the findings of a new study from China using immune cells from patients, which suggested that treatment with these proteins may help ease MG symptoms.
“Our findings underscore the potential therapeutic role of PD-1/PD-L1 agonists in the treatment of MG,” the researchers wrote.
The study, “Immune Modulatory Effects of PD-1/PD-L1 in Myasthenia Gravis: Insights From Peripheral Blood Mononuclear Cell Analysis,” was published in The FASEB Journal.
MG occurs when immune B-cells produce antibodies that disrupt the communication between nerves and muscles, causing symptoms of muscle weakness and fatigue. Other immune cells — such as T-cells and dendritic cells, which normally alert the rest of the immune system to threats — also become overactive in MG.
PD-1 is an immune checkpoint protein found on active T-cells. When it binds to PD-L1 on dendritic cells or other immune cells, it signals T-cells not to respond to threats. In an autoimmune disease like MG, that includes the body’s own tissues. Together, PD-1/PD-L1 help keep the immune response under control.
According to the researchers, using PD-1/PD-L1-activating monoclonal antibodies or agonists along with other treatments might help ease the symptoms of MG. An agonist is a molecule that mimics the actions of a signal — in this case, the one set off by PD-1/PD-L1.
Researchers focus on PD-1 agonists – which mimic the actions of a signal
To test this idea, the researchers first measured the levels of PD-1 and PD-L1 on mononuclear cells — T-cells, dendritic cells, and other white blood cells with a single, round nucleus — from the peripheral (circulating) blood of 36 people. Half were diagnosed with MG, while the other half were healthy controls matched for age and sex.
Compared with the healthy controls, the MG patients had significantly higher levels of PD-1 on B-cells and T-cells. They also had significantly higher levels of PD-L1 on dendritic cells and monocytes, which are immune cells that travel through the blood to tissues where they can become dendritic cells or macrophages, another type of immune cells.
In MG, most patients test positive for antibodies that target the acetylcholine receptor (AChR) on the surface of muscle cells. In this study, patients with higher levels of anti-AChR antibodies also had higher levels of PD-1 on CD8-positive T-cells — those that destroy threats and threatened tissues — and of PD-L1 on dendritic cells.
B-cells are immune cells that produce antibodies, including the self-reactive ones that cause MG. Here, they also showed increased levels of PD-1 in patients who had more B-cells and T-cells in circulation. These immune cells “play a crucial role” in MG, the researchers wrote.
We speculate that PD-1 agonists may be effective in the treatment of MG. … If … used alongside existing treatments, they could better alleviate MG symptoms and provide new therapeutic strategies for MG.
To understand how PD-1/PD-L1 tunes the immune response, the researchers added human PD-L1 or a placebo to lab-grown mononuclear cells from patients. Compared with the placebo, human PD-L1 significantly reduced the levels of the inflammatory protein IL-1beta and IL-4, which prompts B-cells to produce antibodies.
While it is still early to understand if this holds true in patients, “we speculate that PD-1 agonists may be effective in the treatment of MG,” the researchers wrote. By contrast, medications that inhibit PD-1/PD-L1 signaling — known as immune checkpoint inhibitors — may trigger MG.
Overall, according to the researchers, these findings suggest a “potential new therapeutic target for MG treatment.”
“If PD-1/PD-L1-activating monoclonal antibodies or agonists are used alongside existing treatments, they could better alleviate MG symptoms and provide new therapeutic strategies for MG,” the team wrote.
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