Researchers have identified a distinct immune signature associated with treatment-resistant myasthenia gravis (MG). The study, published in the journal Med, may offer new clues about why some individuals don’t respond to current therapies and potential targets for future treatment.
Although many people living with MG improve with immunosuppressive drugs, some develop refractory myasthenia gravis, meaning their symptoms remain difficult to control despite treatment.
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In the study, researchers analyzed blood samples from people with acetylcholine receptor antibody–positive MG and compared immune cell patterns between individuals with varying treatment responses, including those with refractory disease, and healthy controls. Using detailed immune profiling, researchers looked at how different immune cells and signaling pathways behaved in each group.
The findings showed that people with refractory disease had a markedly different immune profile compared with those whose disease was more manageable. In particular, they had higher levels of memory B cells, a type of immune cell that can produce antibodies and drive autoimmune responses. When stimulated in laboratory experiments, immune cells from these individuals also produced increased amounts of inflammatory signaling molecules, including interleukin-6 and tumor necrosis factor-alpha.
At the same time, regulatory T cells and dendritic cells, both of which help regulate inflammation, were present at lower levels in people with refractory MG. This imbalance may allow the immune response to remain overactive and contribute to persistent disease activity.
The researchers also identified elevated levels of proteins C3, C5 and clusterin, which are involved in the complement system, a part of the immune response that can damage tissue when activated.
Finally, the researchers looked at patients who had received rituximab, a therapy designed to remove B cells from the body. While the drug successfully reduced these cells in many study participants, some still did not see meaningful improvement. The results suggest that other immune cells, including long-lived antibody-producing cells that rituximab does not target, may continue driving the disease in these cases.
Overall, the findings point to a distinct immune signature in refractory MG and may help explain why certain treatments work for some patients but not others.
“Our work suggests that future treatment strategies directed at plasma cells or at promoting immune tolerance mechanisms are likely to be beneficial in refractory disease,” the researchers concluded.
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