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

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2020635118. doi: 10.1073/pnas.2020635118.


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.

Keywords: IgG4; MuSK; autoimmunity; monoclonal antibodies; myasthenia gravis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / administration & dosage
  • Antibodies, Bispecific / genetics
  • Antibodies, Bispecific / immunology
  • Autoantibodies / administration & dosage
  • Autoantibodies / genetics
  • Autoantibodies / immunology*
  • Cell Line
  • Disease Models, Animal
  • Female
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology*
  • Male
  • Mice
  • Myasthenia Gravis / immunology*
  • Myasthenia Gravis / pathology
  • Myoblasts
  • Neuromuscular Junction / immunology
  • Neuromuscular Junction / pathology
  • Phosphorylation / immunology
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Cholinergic / immunology*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology


  • Antibodies, Bispecific
  • Autoantibodies
  • Immunoglobulin G
  • Receptors, Cholinergic
  • Recombinant Proteins
  • MUSK protein, human
  • MuSK protein, mouse
  • Receptor Protein-Tyrosine Kinases