Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis.
Animals
Antibodies, Bispecific
/ administration & dosage
Autoantibodies
/ administration & dosage
Cell Line
Disease Models, Animal
Female
Humans
Immunoglobulin G
/ administration & dosage
Male
Mice
Myasthenia Gravis
/ immunology
Myoblasts
Neuromuscular Junction
/ immunology
Phosphorylation
/ immunology
Receptor Protein-Tyrosine Kinases
/ immunology
Receptors, Cholinergic
/ immunology
Recombinant Proteins
/ administration & dosage
IgG4
MuSK
autoimmunity
monoclonal antibodies
myasthenia gravis
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
30 03 2021
30 03 2021
Historique:
entrez:
23
3
2021
pubmed:
24
3
2021
medline:
21
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33753489
pii: 2020635118
doi: 10.1073/pnas.2020635118
pmc: PMC8020787
pii:
doi:
Substances chimiques
Antibodies, Bispecific
0
Autoantibodies
0
Immunoglobulin G
0
Receptors, Cholinergic
0
Recombinant Proteins
0
MUSK protein, human
EC 2.7.10.1
MuSK protein, mouse
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
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.
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