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

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Science  04 Oct 2018:
eaap9310
DOI: 10.1126/science.aap9310

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Abstract

The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here, we identify a variant of human IgG1 (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog G390R knock-in 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 IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer Grb2 dwell times in immunological synapses, leading to hyper-Grb2-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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