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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An autoimmune disease variant of IgG1 modulates B cell activation and differentiation, Science, 09 Nov 2018
Science, 09 November, 2018, DOI: http://dx.doi.org/10.1126/science.aap9310
An autoimmune disease variant of IgG1 modulates B cell activation and differentiation
Xiangjun Chen1, Xiaolin Sun2,*, Wei Yang3,*, Bing Yang1,*, Xiaozhen Zhao2, Shuting Chen1, Lili He1, Hui Chen4, Changmei Yang1, Le Xiao1, Zai Chang3, Jianping Guo2, Jing He2, Fuping Zhang5, Fang Zheng6, Zhibin Hu7, Zhiyong Yang8, Jizhong Lou4, Wenjie Zheng9, Hai Qi10, Chenqi Xu11, Hong Zhang12, Hongying Shan13, Xu-jie Zhou12, Qingwen Wang13, Yi Shi14,15, Luhua Lai16, Zhanguo Li2,？, Wanli Liu1,17,？
Abstract
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.
文章链接：http://science.sciencemag.org/content/362/6415/700