Researchers in the U.K. have identified a distinct immune profile in adults with myasthenia gravis (MG) whose disease does not respond to standard therapies.
“Understanding these immune differences brings us closer to predicting how patients will respond to therapy and to developing more targeted, personalised treatment approaches,” Madhvi Menon, PhD, the study’s senior author at the University of Manchester’s Lydia Becker Institute of Immunology and Inflammation in the U.K., said in a university press release.
“These findings identify potential biomarkers of treatment resistance and highlight promising therapeutic targets,” the researchers wrote.
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Study explores immune signatures in refractory MG
The results were described in the study “Lymphocyte alterations and elevated complement signaling are key features of refractory myasthenia gravis,” published in Med.
MG is driven by self-reactive antibodies that attack proteins involved in nerve-muscle communication, leading to symptoms such as muscle weakness and fatigue. In most cases, these antibodies target acetylcholine receptors (AChRs), proteins on muscle cells that help receive nerve signals and trigger muscle contraction.
“A significant proportion of patients with myasthenia gravis (MG) remain refractory [resistant] to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking,” the researchers wrote. “Identifying biomarkers that predict treatment resistance is of increasing clinical importance.”
With this in mind, Menon and colleagues sought to define immune cell profiles in people with refractory MG to help guide more personalized treatment strategies and identify novel therapeutic targets.
The researchers analyzed levels of immune cells and related proteins in blood samples from 58 adults with AChR-related MG and 20 age- and sex-matched healthy individuals. Patients were classified as either refractory (10 people), treatment-responsive (40 people), or treatment-naïve (eight people). Among the treatment-responsive group, 17 were stable on low-dose symptom-relieving medication alone, while 23 were stable on standard immunosuppressive therapy.
Memory B-cells and complement proteins elevated
According to the analysis, people with MG had significantly higher numbers of memory B-cells — long-lived immune cells involved in antibody responses — than healthy controls.
The highest numbers were found among refractory MG patients. Higher memory B-cell counts were associated with worse disease severity, as measured by the MG Composite scale.
When immune cells were stimulated in the lab, cells from MG patients produced significantly more of the inflammatory signaling proteins interleukin-6 and TNF-alpha. The highest levels were seen in people with refractory MG.
A significant proportion of patients with myasthenia gravis (MG) remain refractory [resistant] to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. Identifying biomarkers that predict treatment resistance is of increasing clinical importance.
Among MG patients, those with refractory disease also had higher levels of C3, C5, and clusterin — proteins involved in the complement system, a part of the immune response that has been linked to MG.
Higher levels of these complement proteins were associated with greater disease severity and poorer quality of life, based on standard MG quality-of-life measures. The team also noted increased levels of complement receptors on T-cells, immune cells that help regulate immune responses.
These immune changes in the refractory MG group were accompanied by a marked reduction in regulatory T-cells (Tregs), immune cells that help suppress excessive immune activity and limit autoimmune responses.
Low Treg counts were linked to worse disease severity and poorer quality of life, “suggesting a potential role in ameliorating disease,” the researchers wrote.
Rituximab response varies among refractory patients
The team also found that treatment-resistant patients had changes in other immune-regulating cells, including lower counts of dendritic cells, which were also associated with greater disease severity and reduced quality of life.
When all immune data were analyzed together, refractory MG patients displayed a clearly distinct immune profile compared with treatment-responsive and treatment-naïve patients, revealing a unique immune “signature” linked to treatment resistance.
The combination of elevated memory B-cell counts and reduced regulatory T-cell (Treg) and dendritic cell levels may contribute to broader immune imbalance associated with treatment resistance.
All but two patients with refractory MG were treated with rituximab, sold under the brand name Rituxan and others, which works by depleting B-cells and is sometimes used off-label in refractory cases.
Rituximab removed B-cells from the blood in all treated patients, but not all patients experienced clinical improvement. Those who did not respond tended to have very low B-cell counts before treatment and had lived with MG longer than patients who responded. Even after treatment, some self-reactive antibody-producing cells remained in circulation.
Complement activity may drive persistent disease
While some helpful immune-regulating cells increased after rituximab, other parts of the immune system remained largely unchanged, with signs of ongoing complement activity in some non-responders. Levels of complement proteins C3, C5, and clusterin also remained unchanged after treatment.
Together, these findings indicate that refractory MG may be associated with long-lived B cells, fewer immune-regulating cells, and high complement activity. This suggests that treatments targeting the complement system may offer greater benefit in refractory MG than therapies focused solely on B-cell depletion.
“For patients whose symptoms do not improve with existing treatments, the lack of clear answers can be incredibly frustrating,” said Katy Dodd, PhD, the study’s first author and a neurology consultant at Manchester Centre for Clinical Neuroscience. “Our findings help explain why some therapies work for certain patients but not others, and point toward more personalised approaches that could improve outcomes in the future.”
“Frequency of memory B cells or Tregs or circulating C3, C5, or clusterin levels are potential prognostic markers that are worth further … evaluation,” the team concluded.
