IgA autoantibodies demonstrate a novel mechanism of MuSK myasthenia gravis pathology
Bibliographic record
Abstract
Patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG) develop muscle weakness due to functionally monovalent immunoglobulin (Ig) G4 autoantibodies (Abs) that target MuSK and disrupt acetylcholine receptor (AChR) clustering. Emerging evidence from other autoimmune conditions suggests that Abs of the IgA class-the archetypal immunoglobulin isotype at mucosal sites-may synergize with IgG Abs, contributing to pathology. In MuSK MG, however, the presence of disease-specific IgA Abs has not yet been recognized, limiting a broader understanding of IgG4-driven autoimmunity. To address this knowledge gap, we leveraged cell-based binding assays, patient-derived recombinant monoclonal autoantibodies (mAbs), high-throughput B-cell receptor sequencing, C2C12 mouse myotube cultures and passive immunization experiments. Among 112 sera collected from 25 patients with MuSK MG (discovery cohort), MuSK-specific IgA Abs were detected in eight samples, corresponding to 3/25 (12%) patients. This finding was validated in a second, independent cohort (validation cohort; n = 14 individuals), wherein one additional patient (1/14; 7.1%) harboured MuSK IgA Abs. Across all cases, MuSK IgA Abs coexisted with MuSK IgG Abs, while domain mapping demonstrated a polyclonal IgA response in 2/4 (50%) patients. Notably, in a paradigmatic case with longitudinal samples spanning over a decade, MuSK IgA seropositivity was persistent, and clonally expanded MuSK IgA B cells showed remarkable resistance to therapeutic B-cell depletion. We generated three patient-derived MuSK-specific IgA mAbs for in-depth molecular profiling. These mAbs were highly hypermutated, bound to distinct MuSK domains and shared target epitopes with MuSK IgG4 mAbs. Two IgA mAbs cross-reacted with murine MuSK, enabling functional studies with C2C12 myotubes. Mechanistically, individual IgA mAbs promoted AChR clustering (indicative of MuSK agonism) and partially antagonized the pathogenic effects of MuSK IgG4 monovalency. When modelling a polyclonal response, however, the combination of the same IgA mAbs significantly impaired cluster formation, demonstrating cooperative pathogenic potential. Consistent with this, passive transfer of both IgA clones into mice induced a myasthenic phenotype characterized by progressive weight loss, muscle weakness and structural disruption of the neuromuscular junction (effects similar to those elicited by a functionally monovalent MuSK IgG4 mAb). These findings uncover a previously unrecognized pathogenic Ab isotype in a subset of patients with MuSK MG and show a mechanism through which bivalent MuSK Abs may synergize to induce pathology. The identification of MuSK-specific IgA B cells could signal a role of mucosal or environmental factors in the pathogenesis of MuSK MG and other IgG4-mediated diseases, offering a worthy avenue for future research.
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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) | 0.000 | 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".