An autoimmune disease variant of IgG1 modulates B cell activation and differentiation

Science. 2018 Nov 9;362(6415):700-705. doi: 10.1126/science.aap9310. Epub 2018 Oct 4.


The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly396→Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly390→Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper-Grb2-Bruton's tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Arginine / genetics
  • Autoantibodies / biosynthesis
  • Autoimmunity / genetics
  • B-Lymphocytes / immunology*
  • Cell Differentiation / genetics*
  • Cell Differentiation / immunology
  • Disease Models, Animal
  • GRB2 Adaptor Protein / genetics
  • Gene Knock-In Techniques
  • Glycine / genetics
  • Heterozygote
  • Humans
  • Immunoglobulin G
  • Immunological Synapses / immunology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Plasma Cells / immunology
  • Signal Transduction


  • Autoantibodies
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Immunoglobulin G
  • Arginine
  • Glycine