Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
| Autor: | Ruoyi Jiang, Steven J. Burden, Panos Stathopoulos, Damian C. Ekiert, Pablo A Suarez, Ljuvica Kolich, Casey Vieni, Rachel L. Redler, Kazushiro Takata, Miriam L. Fichtner, Kevin C. O’Connor, Richard Nowak |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Immunology Antibody Affinity Autoimmunity Plasma protein binding medicine.disease_cause Autoantigens Article Affinity maturation Immunoglobulin Fab Fragments 03 medical and health sciences 0302 clinical medicine Protein Domains Myasthenia Gravis medicine Humans Immunology and Allergy Receptors Cholinergic Receptor Autoantibodies Chemistry Autoantibody Receptor Protein-Tyrosine Kinases medicine.disease Molecular biology Myasthenia gravis 030104 developmental biology Immunoglobulin G Mutation Monoclonal Tolerance Tyrosine kinase 030217 neurology & neurosurgery Neuroscience Protein Binding |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20200513 |
| Popis: | IgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high-affinity threshold to reach pathogenic capacity. This capacity is dependent on self-antigen driven maturation, which includes the accumulation of indispensable somatic mutations that may alter electrostatic interactions with the antigen. 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. Graphical Abstract |
| Databáze: | OpenAIRE |
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