Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures, 2025, Li et al.

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Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures
Huanhuan Li; Minh C. Pham; Jinfeng Teng; Kevin C. O’Connor; Colleen M. Noviello; Ryan E. Hibbs

Skeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. While treatments exist, variable patient responses suggest pathogenic heterogeneity. Progress in understanding the molecular basis of MG has been limited by the absence of structures of intact human muscle AChRs.

Here, we present high-resolution cryoelectron microscopy (cryo-EM) structures of the human adult AChR in different functional states. Using six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays revealed how these autoantibodies directly inhibit AChR channel activation.

These findings provide critical insights into MG immunopathogenesis, uncovering unrecognized antibody epitope diversity and modes of receptor inhibition, and provide a framework for developing personalized therapies targeting antibody-mediated autoimmune disorders.


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From introduction —

Current approved MG treatments are focused on increasing ACh availability at the NMJ, broad immunosuppression, and recently, complement inhibition and reduction of circulating immunoglobulin.

However, the responses to these therapies are variable. Approximately 40% of patients respond poorly to complement inhibitors, and in some patients, the disease worsens as a result of treatment. This variability suggests that the underlying pathogenic mechanisms differ among patients.

Conclusions —

Our study provides key insights into the diverse pathological mechanisms underlying MG by examining the structure and function of the human muscle AChR bound to diverse MG autoantibodies. We defined distinct binding positions and mapped an epitope landscape across the muscle receptor, highlighting the complexity and heterogeneity of MG autoantibodies.

findings enhance our understanding of the mechanisms by which autoantibodies interfere with ion channel function and trigger indirect pathogenic processes, such as complement activation and receptor internalization.

From results (linespace added) —

To refine our understanding of MG pathology, we propose expanding the concept of ‘‘blocking ACh binding’’ to ‘‘interfering with channel activity.’’ Using structural analysis and electrophysiology, we identified at least four distinct ways by which antibodies can directly disrupt normal channel function:

(1) direct competition with ACh binding. For example, Fab3 inserts its CDR3 loop in a way that physically blocks ACh access.

(2) Destabilizing ACh binding. Fab1b and Fab2 prevent loop C closure, destabilizing ACh’s interaction with the receptor.

(3) Neutralizing the receptor’s cation-concentrating potential. Fab6 and Fab7 alter surface electrostatics by forming salt bridges in the receptor vestibule, which influences cation influx.

(4) Preventing receptor conformational transitions. Both Fab6 and Fab9 bind in a way that allosterically limits the receptor’s conformational changes required for ACh binding and channel activation. These mechanisms are closely linked to the spatial binding positions of the autoantibodies and do not require the Fc or bivalent binding to exert their effects.