气候变化领域集成服务门户(CCPortal): Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

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DOI	10.1073/pnas.2020635118
	Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis
	Vergoossen D.L.E.; Plomp J.J.; Gstöttner C.; Fillié-Grijpma Y.E.; Augustinus R.; Verpalen R.; Wuhrer M.; Parren P.W.H.I.; Dominguez-Vega E.; van der Maarel S.M.; Verschuuren J.J.; Huijbers M.G.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Autoimmunity; IgG4; Monoclonal antibodies; MuSK; Myasthenia gravis
语种	英语
scopus关键词	antibody; immunoglobulin G4 antibody; muscle specific kinase; muscle specific kinase antibody; phosphotransferase; unclassified drug; animal cell; animal experiment; animal model; animal tissue; Article; autoimmunity; C2C12 cell line; controlled study; embryo; female; human; human cell; immunoglobulin class switching; immunopathogenesis; in vitro study; in vivo study; mouse; muscle weakness; myasthenia gravis; neuromuscular junction; nonhuman; pathogenicity; priority journal; signal transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180063
作者单位	Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Center of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Department of Immunology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Lava Therapeutics, Utrecht, 3584 CM, Netherlands
推荐引用方式 GB/T 7714	Vergoossen D.L.E.,Plomp J.J.,Gstöttner C.,et al. Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis[J],2021,118(13).
APA	Vergoossen D.L.E..,Plomp J.J..,Gstöttner C..,Fillié-Grijpma Y.E..,Augustinus R..,...&Huijbers M.G..(2021).Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Vergoossen D.L.E.,et al."Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).