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

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Science  09 Nov 2018:
Vol. 362, Issue 6415, pp. 700-705
DOI: 10.1126/science.aap9310

An IgG1 SNP enhances autoimmunity

One common feature of autoimmune diseases like systemic lupus erythematosus (SLE) is the presence of high titers of self-reactive antibodies. These result in immune complexes, inflammation, and tissue pathology. Consequently, the checkpoints that normally keep immunoglobulin G (IgG)–positive autoreactive B cells in check are of intense interest. Chen et al. report the presence of a common IgG1 single-nucleotide polymorphism (SNP) in East Asian populations (hIgG1-G396R). This SNP was enriched in SLE patients and associated with increased disease severity. Humans with this SNP, as well as knockin mice, showed enhanced plasma cell accumulation and antibody production. This SNP enhanced IgG1 immunoglobulin tail tyrosine motif phosphorylation, triggering longer adaptor protein Grb2 dwell times in immunological synapses and hyper–Grb2–Bruton's tyrosine kinase signaling after antigen binding.

Science, this issue p. 700


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.

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