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Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis
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 h...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020787/ https://www.ncbi.nlm.nih.gov/pubmed/33753489 http://dx.doi.org/10.1073/pnas.2020635118 |
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author | Vergoossen, Dana L. E. Plomp, Jaap J. Gstöttner, Christoph Fillié-Grijpma, Yvonne E. Augustinus, Roy Verpalen, Robyn Wuhrer, Manfred Parren, Paul W. H. I. Dominguez-Vega, Elena van der Maarel, Silvère M. Verschuuren, Jan J. Huijbers, Maartje G. |
author_facet | Vergoossen, Dana L. E. Plomp, Jaap J. Gstöttner, Christoph Fillié-Grijpma, Yvonne E. Augustinus, Roy Verpalen, Robyn Wuhrer, Manfred Parren, Paul W. H. I. Dominguez-Vega, Elena van der Maarel, Silvère M. Verschuuren, Jan J. Huijbers, Maartje G. |
author_sort | Vergoossen, Dana L. E. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8020787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-80207872021-04-13 Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis Vergoossen, Dana L. E. Plomp, Jaap J. Gstöttner, Christoph Fillié-Grijpma, Yvonne E. Augustinus, Roy Verpalen, Robyn Wuhrer, Manfred Parren, Paul W. H. I. Dominguez-Vega, Elena van der Maarel, Silvère M. Verschuuren, Jan J. Huijbers, Maartje G. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2021-03-30 2021-03-22 /pmc/articles/PMC8020787/ /pubmed/33753489 http://dx.doi.org/10.1073/pnas.2020635118 Text en Copyright © 2021 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Vergoossen, Dana L. E. Plomp, Jaap J. Gstöttner, Christoph Fillié-Grijpma, Yvonne E. Augustinus, Roy Verpalen, Robyn Wuhrer, Manfred Parren, Paul W. H. I. Dominguez-Vega, Elena van der Maarel, Silvère M. Verschuuren, Jan J. Huijbers, Maartje G. Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title | Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title_full | Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title_fullStr | Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title_full_unstemmed | Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title_short | Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis |
title_sort | functional monovalency amplifies the pathogenicity of anti-musk igg4 in myasthenia gravis |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020787/ https://www.ncbi.nlm.nih.gov/pubmed/33753489 http://dx.doi.org/10.1073/pnas.2020635118 |
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