ArticleProceedings of the National Academy of Sciences of the United States of America2021
Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
- Muscle-Specific Kinase Signaling and Its Therapeutic Potential.Muscle & nerve · 2026Review
- IgA autoantibodies demonstrate a novel mechanism of MuSK myasthenia gravis pathology.Brain : a journal of neurology · 2026Article
- Monoclonal antibody passive experimental autoimmune myasthenia gravis: current progress and future directions.Cell & bioscience · 2026Review
- Dissecting NMOSD pathogenesis through animal models: a mechanism-oriented systems perspective.Frontiers in immunology · 2026Review
- MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis.The Journal of clinical investigation · 2025Article
- Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models.iScience · 2025Article
- Agonist antibody to MuSK protects mice from MuSK myasthenia gravis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Myasthenia gravis: the future is here.The Journal of clinical investigation · 2024Review
- MuSK Myasthenia Gravis-Potential Pathomechanisms and Treatment Directed against Specific Targets.Cells · 2024Review
- The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling.Skeletal muscle · 2024Article
- Clinical Features and Prognostic Analysis of MuSK-Antibody-Positive Myasthenia Gravis versus Double-Seropositive Myasthenia Gravis: A Single-Center Study from Central South China.Neuropsychiatric disease and treatment · 2024Article
- Exploring the depths of IgG4: insights into autoimmunity and novel treatments.Frontiers in immunology · 2024Review
- A clinical perspective on muscle specific kinase antibody positive myasthenia gravis.Frontiers in immunology · 2024Review
- IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation.Neurology(R) neuroimmunology & neuroinflammation · 2023Article
- Myasthenia Gravis: Novel Findings and Perspectives on Traditional to Regenerative Therapeutic Interventions.Aging and disease · 2023Article
- Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK.Scientific reports · 2023Article
- Impact of structural modifications of IgG antibodies on effector functions.Frontiers in immunology · 2023Review
- Ocular Myasthenia Gravis: A Current Overview.Eye and brain · 2023Review
- Effect of monovalency on anti-contactin-1 IgG4.Frontiers in immunology · 2023Article
- Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed "Fab-arm exchange" in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.
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