Northwestern Medicine Uncovers Hidden Immune Environment in Myasthenia Gravis, Offering New Hope for Patients
CHICAGO, IL – Scientists at Northwestern Medicine have made a significant breakthrough in understanding myasthenia gravis (MG), a chronic autoimmune disease characterized by debilitating muscle weakness and fatigue. A new study, published in Science Advances, reveals a previously undetected immune environment within the thymus that may play a crucial role in sustaining the disease, opening promising new avenues for future research and treatment development.
Myasthenia gravis, which disproportionately affects women under 40 and men over 60, occurs when the body’s immune system erroneously attacks the communication points between nerves and muscles. This autoimmune assault leads to symptoms that worsen with activity and improve with rest, primarily impacting eye movements, facial expressions, speech, swallowing, and chewing. In severe cases, respiratory muscles can become dangerously compromised, posing a life-threatening risk.
While the role of harmful antibodies in MG has long been established, their presence alone doesn’t fully explain the wide variation in symptom severity among patients or why some individuals continue to experience disease activity even after standard treatments, including the surgical removal of the thymus (thymectomy).
"During childhood, the thymus is responsible for training the body’s immune cells. However, in adulthood, the thymus can shrink and begin to malfunction, potentially contributing to myasthenia gravis," explained Dr. Ankit Bharat, chief of Thoracic Surgery in the Department of Surgery and executive director of the Northwestern Medicine Canning Thoracic Institute, and senior author of the study. "Our research suggests that myasthenia gravis involves more than just antibodies. We’ve discovered evidence that the thymus may foster an abnormal immune environment, supporting the survival and persistence of certain B-cells, even after thymectomy. Understanding this environment provides a completely new framework for studying and potentially treating the disease."
Hope for Patients Like Marissa Humayun
For patients like 30-year-old Marissa Humayun of Chicago, these findings offer a renewed sense of hope after years of battling the disease. In early 2023, at just 26, Humayun experienced sudden stroke-like symptoms, including a drooping eyelid and double vision. Initially, blood tests for common MG antibodies were negative. Dr. Neena Cherayil, assistant professor of Neurology and a Northwestern Medicine neuro-ophthalmologist, diagnosed Humayun with ocular myasthenia gravis (OMG) and seronegative myasthenia, a rare form where patients exhibit symptoms despite lacking the typical antibody markers.
Three months after her diagnosis, Humayun underwent robotic thymectomy performed by Dr. Bharat. Despite the successful surgery, her symptoms recurred, a challenge faced by some MG patients. Humayun now manages her condition with regular infusion therapy at Northwestern Memorial Hospital, under the care of Dr. Arjun Seth, assistant professor of Neurology and a Northwestern Medicine neuromuscular medicine specialist.
"When I’m symptomatic, I experience droopy eyelids, fatigue, and double vision – especially if I’ve overexerted myself or didn’t get enough rest," Humayun shared. "Myasthenia gravis is an incredibly discouraging disease, but I’ve learned to appreciate what my body can do each day. Dr. Bharat is an inspiring surgeon and scientist, and Northwestern Medicine has been incredibly supportive throughout my diagnosis and treatment. I’m optimistic for the future, knowing that scientists here in Chicago are actively working to find solutions for the myasthenia gravis community."
Dr. Bharat emphasized the potential impact of their discoveries: "Our hope is to identify patients, like Marissa, who are at risk of symptom recurrence after thymectomy and other treatments. This study also provides clues as to why some patients do not respond to conventional medical treatments. We aim to pinpoint these at-risk patients and ultimately develop clinical interventions that can eliminate these persistent cells and prevent future relapses."
A Surprising Discovery: The "Tolerance Checkpoint Swap"
To delve deeper into the complex environment of the thymus, Northwestern Medicine scientists analyzed 23 thymus samples from 16 patients. They employed a combination of advanced technologies, including single-cell RNA sequencing, immune receptor analysis, and spatial transcriptomics, allowing them to identify individual cell types and their precise locations within the tissue.
By integrating their data with previously published datasets, the team constructed an unprecedented atlas containing nearly 347,000 cells – the most comprehensive map of the MG thymus ever assembled. While scientists initially expected to identify a single dominant immune-cell population driving the disease, their findings revealed something far more intricate.
The study uncovered a diverse population of class-switched B-cells clustered within and around abnormal germinal centers in the MG tissue. Intriguingly, these cells did not exhibit the characteristics of traditional immune regulation. Instead, they appeared to rely on an alternative survival pathway involving molecules known as BAFF and BCMA.
The scientists refer to this phenomenon as a potential "tolerance checkpoint swap," where B-cells deviate from normal immune-control mechanisms and become supported by survival signals from their surrounding tissue environment.
"We didn’t find one dominant B-cell clone taking over," Dr. Bharat noted. "Instead, we discovered a diverse population of B-cells thriving within an abnormal immune ‘neighborhood.’ This neighborhood itself may be instrumental in helping these cells survive."
Next Steps: A Roadmap for Future Research
These groundbreaking findings may help to explain several long-standing mysteries surrounding myasthenia gravis, including why antibody levels don’t always correlate with disease severity and why the efficacy of thymectomy can vary significantly among patients. However, the scientists caution that this study did not directly investigate these specific questions.
"This study is not a treatment announcement and does not alter current recommendations for myasthenia gravis patients," Dr. Bharat clarified. "Thymectomy remains an evidence-based treatment for appropriately selected patients, and further research will be necessary to determine whether these newly identified pathways directly contribute to disease progression."
Instead, the research provides a detailed and invaluable roadmap for future investigations. "This study gives us a map," Dr. Bharat stated. "The next crucial step is to determine if these pathways actively drive the disease and if they can be targeted to restore immune tolerance. That is the immense promise of this research."
Northwestern Memorial Hospital’s pulmonology and lung surgery program has consistently ranked among the best in the nation, holding the top spot in Illinois for 15 consecutive years and ranking No. 4 in the U.S. according to U.S. News & World Report‘s 2026 – 2027 rankings. For more information, visit nm.org.
