PMID- 33753489 OWN - NLM STAT- MEDLINE DCOM- 20211020 LR - 20211020 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 13 DP - 2021 Mar 30 TI - Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis. LID - 10.1073/pnas.2020635118 [doi] LID - e2020635118 AB - 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. CI - Copyright (c) 2021 the Author(s). Published by PNAS. FAU - Vergoossen, Dana L E AU - Vergoossen DLE AUID- ORCID: 0000-0002-0814-4995 AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Plomp, Jaap J AU - Plomp JJ AUID- ORCID: 0000-0002-8427-9090 AD - Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Gstottner, Christoph AU - Gstottner C AUID- ORCID: 0000-0003-4033-4024 AD - Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Fillie-Grijpma, Yvonne E AU - Fillie-Grijpma YE AUID- ORCID: 0000-0003-2965-6604 AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Augustinus, Roy AU - Augustinus R AUID- ORCID: 0000-0002-2032-5537 AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Verpalen, Robyn AU - Verpalen R AUID- ORCID: 0000-0003-2538-180X AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Wuhrer, Manfred AU - Wuhrer M AD - Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Parren, Paul W H I AU - Parren PWHI AUID- ORCID: 0000-0002-4365-3859 AD - Department of Immunology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. AD - Lava Therapeutics, 3584 CM, Utrecht, The Netherlands. FAU - Dominguez-Vega, Elena AU - Dominguez-Vega E AUID- ORCID: 0000-0002-6394-0783 AD - Center of Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - van der Maarel, Silvere M AU - van der Maarel SM AUID- ORCID: 0000-0001-8103-711X AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Verschuuren, Jan J AU - Verschuuren JJ AD - Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. FAU - Huijbers, Maartje G AU - Huijbers MG AD - Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands; m.g.m.huijbers@lumc.nl. AD - Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antibodies, Bispecific) RN - 0 (Autoantibodies) RN - 0 (Immunoglobulin G) RN - 0 (Receptors, Cholinergic) RN - 0 (Recombinant Proteins) RN - EC 2.7.10.1 (MUSK protein, human) RN - EC 2.7.10.1 (MuSK protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Animals MH - Antibodies, Bispecific/administration & dosage/genetics/immunology MH - Autoantibodies/administration & dosage/genetics/*immunology MH - Cell Line MH - Disease Models, Animal MH - Female MH - Humans MH - Immunoglobulin G/administration & dosage/genetics/*immunology MH - Male MH - Mice MH - Myasthenia Gravis/*immunology/pathology MH - Myoblasts MH - Neuromuscular Junction/immunology/pathology MH - Phosphorylation/immunology MH - Receptor Protein-Tyrosine Kinases/*immunology/metabolism MH - Receptors, Cholinergic/*immunology MH - Recombinant Proteins/administration & dosage/genetics/immunology PMC - PMC8020787 OTO - NOTNLM OT - IgG4 OT - MuSK OT - autoimmunity OT - monoclonal antibodies OT - myasthenia gravis COIS- 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. EDAT- 2021/03/24 06:00 MHDA- 2021/10/21 06:00 PMCR- 2021/03/22 CRDT- 2021/03/23 06:22 PHST- 2021/03/23 06:22 [entrez] PHST- 2021/03/24 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2021/03/22 00:00 [pmc-release] AID - 2020635118 [pii] AID - 202020635 [pii] AID - 10.1073/pnas.2020635118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2020635118. doi: 10.1073/pnas.2020635118.