Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis.

Autor:	Vergoossen DLE; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Plomp JJ; Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Gstöttner C; Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Fillié-Grijpma YE; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Augustinus R; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Verpalen R; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Wuhrer M; Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Parren PWHI; Department of Immunology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.; Lava Therapeutics, 3584 CM, Utrecht, The Netherlands., Dominguez-Vega E; Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., van der Maarel SM; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Verschuuren JJ; Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Huijbers MG; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands; m.g.m.huijbers@lumc.nl.; Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 30; Vol. 118 (13).
DOI:	10.1073/pnas.2020635118
Abstrakt:	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. Competing Interests: Competing interest statement: M.G.H, J.J.P., S.M.v.d.M., and J.J.V. are co-inventors on two patent applications on MuSK-related research. Leiden University Medical Center, M.G.H., J.J.P., S.M.v.d.M., and J.J.V. receive license income from these patents. P.W.H.I.P. is a named inventor on DuoBody-related patents and patent application assigned to Genmab. The authors have no additional financial interest. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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