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

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.

Source: ScienceNOW - November 8, 2018 Category: Science Authors: Chen, X., Sun, X., Yang, W., Yang, B., Zhao, X., Chen, S., He, L., Chen, H., Yang, C., Xiao, L., Chang, Z., Guo, J., He, J., Zhang, F., Zheng, F., Hu, Z., Yang, Z., Lou, J., Zheng, W., Qi, H., Xu, C., Zhang, H., Shan, H., Zhou, X.-j., Wang, Q., Shi, Y., L Tags: Immunology, Medicine, Diseases reports Source Type: news