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Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis

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 autoantibo...

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Autores principales: Fichtner, Miriam L., Vieni, Casey, Redler, Rachel L., Kolich, Ljuvica, Jiang, Ruoyi, Takata, Kazushiro, Stathopoulos, Panos, Suarez, Pablo A., Nowak, Richard J., Burden, Steven J., Ekiert, Damian C., O’Connor, Kevin C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953735/
https://www.ncbi.nlm.nih.gov/pubmed/32820331
http://dx.doi.org/10.1084/jem.20200513
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author Fichtner, Miriam L.
Vieni, Casey
Redler, Rachel L.
Kolich, Ljuvica
Jiang, Ruoyi
Takata, Kazushiro
Stathopoulos, Panos
Suarez, Pablo A.
Nowak, Richard J.
Burden, Steven J.
Ekiert, Damian C.
O’Connor, Kevin C.
author_facet Fichtner, Miriam L.
Vieni, Casey
Redler, Rachel L.
Kolich, Ljuvica
Jiang, Ruoyi
Takata, Kazushiro
Stathopoulos, Panos
Suarez, Pablo A.
Nowak, Richard J.
Burden, Steven J.
Ekiert, Damian C.
O’Connor, Kevin C.
author_sort Fichtner, Miriam L.
collection PubMed
description 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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spelling pubmed-79537352021-06-07 Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis Fichtner, Miriam L. Vieni, Casey Redler, Rachel L. Kolich, Ljuvica Jiang, Ruoyi Takata, Kazushiro Stathopoulos, Panos Suarez, Pablo A. Nowak, Richard J. Burden, Steven J. Ekiert, Damian C. O’Connor, Kevin C. J Exp Med Article 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. Rockefeller University Press 2020-08-20 /pmc/articles/PMC7953735/ /pubmed/32820331 http://dx.doi.org/10.1084/jem.20200513 Text en © 2020 Fichtner et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Fichtner, Miriam L.
Vieni, Casey
Redler, Rachel L.
Kolich, Ljuvica
Jiang, Ruoyi
Takata, Kazushiro
Stathopoulos, Panos
Suarez, Pablo A.
Nowak, Richard J.
Burden, Steven J.
Ekiert, Damian C.
O’Connor, Kevin C.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title_full Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title_fullStr Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title_full_unstemmed Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title_short Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
title_sort affinity maturation is required for pathogenic monovalent igg4 autoantibody development in myasthenia gravis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953735/
https://www.ncbi.nlm.nih.gov/pubmed/32820331
http://dx.doi.org/10.1084/jem.20200513
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