Human in vitro neuromuscular junction model to functionally dissect the pathogenic mechanism of anti-AChR autoantibody-positive myasthenia gravis
Bibliographic record
Abstract
BACKGROUND: Myasthenia gravis is a rare autoimmune disease mediated by autoantibodies directed against acetylcholine receptors (AChRs) at the neuromuscular junction. These autoantibodies cause dysfunction through AChR blockade, AChR degradation due to crosslinking and internalisation, and complement activation. METHODS: platform enabled the connection of human induced pluripotent stem-cell-derived motor neuron spheroids with three-dimensional cultures of skeletal muscle fibres, forming functional neuromuscular junctions. Functional connectivity was assessed by glutamate stimulation of motor neuron spheroids and monitoring of calcium transients in genetically encoded calcium indicator protein 6 (GCaMP6)-transduced muscle fibres. RESULTS: Incubation of in vitro neuromuscular junction tissues with sera from patients with anti-AChR autoantibody-positive myasthenia gravis, in contrast to healthy controls, induced a significant increase in membrane attack complex (MAC) deposition and complement split products, accompanied by a notable reduction in calcium transients. Treatment with zilucoplan, a complement component 5 (C5) inhibitor, prevented complement activation and preserved neuromuscular junction functional integrity. The model demonstrated that complement-mediated damage is a major driver of neuromuscular junction functional impairment in the myasthenia gravis patient sera tested in this study. Furthermore, the study explored the reversibility of neuromuscular junction damage, revealing that shortening the delay before initiating complement inhibitor treatment in the in vitro neuromuscular junction tissues enhances the reversibility of neuromuscular transmission. CONCLUSIONS: These findings offer a mechanistic rationale for the observed clinical response in patients with anti-AChR autoantibody-positive myasthenia gravis treated with C5 inhibitors. The in vitro neuromuscular junction model provides a robust platform for studying the mechanistic pathways of complement-mediated damage and evaluating therapeutic interventions for myasthenia gravis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".