Immune profiles in myasthenia gravis

In auto-immune diseases such as MG the immune system produces antibodies that attack an individual’s own body. We looked closely at the immune system in people with MG with different treatment requirements to understand what is different in those who do not respond to standard therapy (refractory disease). Blood samples were studies from 58 participants with MG and positive antibodies against acetylcholine-receptor and compared them to 20 healthy volunteer samples. Patients were divided into groups based on how severe their disease was and how well they responded to standard treatment.
Several striking immune system differences were found in those with “refractory disease”:
  • Overactive B cells: These immune cells make antibodies, including the harmful ones involved in MG. In refractory patients, there were more “memory” B cells, which are better at fuelling long-term immune responses. These cells were also more ready to release inflammatory signals.
  • Reduced immune regulation: Regulatory T cells normally help keep the immune system balanced and prevent excessive inflammation. This set of cells were much lower in refractory patients and were linked with worse symptoms and poorer quality of life.
  • Changes in innate immunity: Dendritic cells, important for controlling T cell activity and promoting tolerance in the immune system, were reduced in refractory MG, and monocytes, which can promote inflammation, were increased.
  • Higher complement system activity: The complement system is a part of the immune system that can damage the neuromuscular junction in MG. We found increased levels of complement proteins (C3, C5, and clusterin) and higher expression of complement receptors on T cells in refractory patients — pointing to ongoing immune attack even during treatment.
A small group of refractory patients treated with the B-cell-removing drug rituximab were followed up after treatment. Everyone showed a drop in circulating B cells, but only some showed a good improvement in symptoms. Patients who did not improve tended to have very few B cells before treatment, suggesting that their disease may be driven by longer-lived cells not removed by rituximab. These individuals also had particularly high complement activity, implying they might benefit more from treatments that target the complement pathway.
Overall, the findings reveal a clear pattern of immune imbalance in refractory MG — too much inflammation and too little regulation. The results point toward potential biomarkers that could help predict which patients will respond to current therapies, and they suggest future treatment strategies should focus on:
  • Reducing long-lived antibody-producing plasma cells
  • Blocking IL-6-mediated inflammation
  • Inhibiting complement-driven damage
  • Boosting regulatory T cell function to restore immune balance
By better understanding the unique immune features of refractory MG, this research brings us closer to more personalised and effective treatment for patients whose disease is currently difficult to control.
The findings have been written as a paper entitled “lymphocyte alterations and elevated complement signalling are key distinguishing features of refractory Myasthenia Gravis”. This has been accepted for publication in the journal “Med” entitled “Lymphocyte alterations and elevated complement signalling are key features of refractory myasthenia gravis”.
To read more about this project, click here.
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