Advanced imaging reveals mechanisms that cause autoimmune disease

Researchers have known that the disease is caused by miscommunication between nerves and muscles. The body's immune system mistakenly produces "autoantibodies," or antibodies that attack its own tissues and proteins. In the case of myasthenia gravis, the body produces autoantibodies that target acetylcholine receptors (AChRs), which are essential triggers for normal muscle contraction functions.

Medications prescribed to boost acetylcholine and suppress the immune system have varying levels of success, leading researchers to believe that myasthenia gravis may be caused by varying underlying mechanisms for different people.

Researchers at UC San Diego's School of Biological Sciences used a cutting-edge imaging technique called cryo-electron microscopy (cryo-EM) to probe details of human muscle AChRs at high resolution. As described in the journal Cell, the researchers analyzed the autoantibodies of six different myasthenia gravis patients. They discovered that these antibodies can disrupt the normal receptor functioning in a variety of ways.

Certain antibodies block the regular acetylcholine binding process, the researchers found, while others activate the immune system's complement pathway, leading to receptor destruction. Significantly, all of the autoantibodies directly disrupted the receptor's function as an ion channel. The findings challenge previous assumptions about how myasthenia gravis antibodies disrupt receptor activity.

"By mapping antibody binding sites on the receptor, we revealed a surprising diversity in how autoantibodies contribute to myasthenia gravis," said Neurobiology Professor Ryan Hibbs, the study's senior author. "This knowledge helps explain why some patients respond differently to treatments and provides a foundation for developing more personalized therapies." The researchers believe future myasthenia gravis treatments could target specific antibody interactions rather than relying on more general immunosuppression treatments.

"This study not only advances our understanding of myasthenia gravis but also sheds light on other autoimmune diseases in which antibodies attack ion channels, offering hope for more precise and effective treatment strategies," said Hibbs.

The research was the result of a close collaboration between UC San Diego and Yale University. Professor Kevin O'Connor and Minh Pham at Yale collected blood samples from patients and carried out cell-based functional assays to characterize the pathological properties of their autoantibodies. The UC San Diego team -- Postdoctoral Scholar Huanhuan Li, Research Data Analyst Jinfeng Teng, Project Scientist Colleen Noviello and Hibbs -- conducted the high-resolution structural studies and electrophysiological experiments to define how these antibodies interact with and disrupt the function of AChRs.

"This work exemplifies the power of team science," said Noviello, co-senior author of the study. "By combining patient samples and functional insights from Yale with the molecular resolution of cryo-EM and biophysics from UC San Diego, we were able to visualize, for the first time, how individual myasthenia gravis antibodies engage the receptor and interfere with its function. These insights offer a new path forward for designing treatments that can precisely target the disease-causing mechanisms in each patient."

The collaborative approach used in this study underscores a growing emphasis on personalized medicine and highlights how partnerships between institutions can accelerate discoveries with direct clinical relevance.