Immune Profiles in Myasthenia Gravis
Research type
Research Study
Full title
Comparison of lymphocyte subset, cytokine, and complement profiles in myasthenia gravis of different severity, disease time-points, and treatment history
IRAS ID
280091
Contact name
Katherine Dodd
Contact email
Sponsor organisation
University of Manchester
Duration of Study in the UK
2 years, 6 months, 0 days
Research summary
Summary of Research
We aim to better describe the immune profile in myasthenia gravis (MG), including lymphocyte subset, cytokine and complement profiles; how they differ between patients of different severity, at times of disease exacerbation, and with different immunosuppressive treatments. Flow cytometry for lymphocyte subset and cytokine analysis will be performed at the University of Manchester, and complement analysis at Cardiff University. We aim to take into account the heterogeneity of MG by taking into account age of onset of MG (early vs late onset) and focussing on acetylcholine receptor antibody (AChR) positive, non-thymomatous MG aged 18-80.
This research project will consist of three work streams:
1. A one-off observational comparison of the immune profile of patients with different MG severity and in comparison to healthy controls. Stable immunosuppressed, stable non-immunosuppressed, and refractory AChR MG patients will be recruited from specialist MG clinics in England. Demographics, medical history, and immune measures will be compared between the groups, along with healthy controls to look for markers of disease severity.
2. A prospective observational study examining changes in lymphocyte subset, cytokine and complement profiles associated with clinical exacerbation of myasthenia gravis. MG patients previously stable at baseline will be reviewed if and when they experience an exacerbation of symptoms, for medical review and repeat immune profile, and again on regain of symptom control to look for markers of disease activity of effective immunosuppression.
3. A prospective cohort study comparing lymphocyte subset, cytokine and complement profile with disease activity following B cell depletion for refractory myasthenia gravis. Participants will be reviewed 4 weeks after rituximab, and at 6 and 12 months following confirmation of B cell depletion.
We hope that these three overlapping projects will build a clearer picture of how the immune profile varies in MG, helping clinicians to optimise an individual’s treatment.Summary of Results
The research study “Immune profiles in myasthenia gravis” aimed to examine circulating immune markers in those with myasthenia gravis (MG) of different treatment requirements.
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.
We also followed a small group of refractory patients treated with the B-cell-removing drug rituximab. 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 promising new treatment strategies focused 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”.REC name
North West - Greater Manchester East Research Ethics Committee
REC reference
21/NW/0188
Date of REC Opinion
23 Jul 2021
REC opinion
Further Information Favourable Opinion