ArticleThe Journal of experimental medicine2020
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis.
Article in The Journal of experimental medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- IgA autoantibodies demonstrate a novel mechanism of MuSK myasthenia gravis pathology.Brain : a journal of neurology · 2026Article
- Article
- Clinical utility of human leukocyte antigen genotyping and immunoglobulin G4 autoantibody testing in autoimmune neurological diseases: A focused minireview.World journal of biological chemistry · 2026Review
- Who Can Safely Discontinue Treatment in Myasthenia Gravis? Insights From a Long-Term Real-World Study.European journal of neurology · 2026Article
- Dysbiosis of gut microbiota and metabolomic alterations in myasthenia gravis: insights from 16S rRNA sequencing and untargeted metabolomics.Frontiers in immunology · 2026Article
- Seq2Bind webserver for binding site prediction from sequences using fine-tuned protein language models.NAR genomics and bioinformatics · 2025Article
- Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis.Science advances · 2025Article
- Serological Markers of Clinical Improvement in MuSK Myasthenia Gravis.Neurology(R) neuroimmunology & neuroinflammation · 2024Article
- Agonist antibody to MuSK protects mice from MuSK myasthenia gravis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Glycosylation: mechanisms, biological functions and clinical implications.Signal transduction and targeted therapy · 2024Review
- The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling.Skeletal muscle · 2024Article
- Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis.Frontiers in immunology · 2024Review
- Exploring the depths of IgG4: insights into autoimmunity and novel treatments.Frontiers in immunology · 2024Review
- Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice.The Journal of experimental medicine · 2023Article
- Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.Frontiers in immunology · 2023Review
- Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy.Acta neuropathologica communications · 2022Article
- Novel pathophysiological insights in autoimmune myasthenia gravis.Current opinion in neurology · 2022Review
- IgG4 Valency Modulates the Pathogenicity of Anti-Neurofascin-155 IgG4 in Autoimmune Nodopathy.Neurology(R) neuroimmunology & neuroinflammation · 2022Article
- Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Pathogenic muscle-specific tyrosine kinase (MuSK)-specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm-exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.