Immune Signature Predicts Treatment Resistance in Myasthenia Gravis

Myasthenia gravis (MG) is a rare autoimmune disorder where the immune system mistakenly attacks the connections between nerves and muscles, leading to muscle weakness that can affect vital functions like vision, movement, speech, swallowing, and breathing. While many individuals with MG respond well to treatment, a significant subset develops a severe, treatment-resistant form known as refractory MG. Currently, clinicians lack reliable biomarkers to predict which patients will benefit from specific therapies, creating a challenge in personalized treatment strategies.

A new study published in With by researchers at the University of Manchester sheds light on the underlying immune mechanisms driving treatment resistance in MG. The research team analyzed blood samples from individuals living with MG, comparing them to those of healthy volunteers, to pinpoint the cellular differences that contribute to therapy failure.

A Pattern of Immune Imbalance

The study revealed distinct immune system abnormalities in patients with refractory MG. Researchers observed an overactive adaptive immune response, characterized by increased numbers of memory B cells. These cells are responsible for long-term immunity and can contribute to the persistent autoimmune attack in MG.

Simultaneously, the study found a significant reduction in regulatory T cells (Tregs). Tregs normally function as a “braking system,” suppressing excessive inflammation and maintaining immune balance. The combination of an amplified immune attack and a weakened regulatory mechanism contributes to substantial immune dysregulation in refractory MG.

Further investigation revealed changes within the innate immune system as well. The researchers noted reduced numbers of dendritic cells and increased levels of monocytes, alongside heightened activity of the complement system. These findings suggest ongoing immune-mediated damage at the neuromuscular junction, the site where nerves communicate with muscles.

Predicting Treatment Response and Tailoring Therapies

The research team also examined a small group of patients with refractory MG who were treated with rituximab, a medication designed to deplete B cells. While rituximab successfully reduced B cell numbers in all patients, only a subset experienced meaningful clinical improvement.

Interestingly, the study found that patients who did not respond to rituximab exhibited a disease profile driven by long-lived plasma cells and particularly high complement activity. This suggests that these patients might benefit more from therapies specifically targeting the complement pathway, rather than solely focusing on B cell depletion.

“For patients whose symptoms do not improve with existing treatments, the lack of clear answers can be incredibly frustrating,” said Dr. Katy Dodd, neurology consultant at Manchester Center for Clinical Neuroscience. “Our findings help explain why some therapies work for certain patients but not others, and point toward more personalized approaches that could improve outcomes in the future.”

“Our study identifies a distinct immune signature associated with treatment-resistant myasthenia gravis,” explained Dr. Madhvi Menon, UKRI Future Leaders Fellow at the Lydia Becker Institute of Immunology and Inflammation and lead author of the paper. “Understanding these immune differences brings us closer to predicting how patients will respond to therapy and to developing more targeted, personalized treatment approaches.”

The identification of this immune signature represents a significant step forward in understanding the complexities of refractory MG. While further research is needed to validate these findings and translate them into clinical practice, this study offers hope for improved diagnostic and therapeutic strategies for individuals living with this challenging autoimmune condition.

Publication details: Katherine C. Dodd et al, Lymphocyte alterations and elevated complement signaling are key features of refractory myasthenia gravis, With (2026). DOI: 10.1016/j.medj.2025.100987

Journal information: With