作者
Xiangjun Chen,Xiaolin Sun,Wei Yang,Bing Yang,Xiaozhen Zhao,Shuting Chen,Lili He,Hui Chen,Changmei Yang,Le Xiao,Zai Chang,Jianping Guo,Jing He,Fuping Zhang,Fang Zheng,Zhibin Hu,Zhiyong Yang,Jizhong Lou,Wenjie Zheng,Hai Qi,Chenqi Xu,Hong Zhang,Hongying Shan,Xu‐jie Zhou,Qingwen Wang,Yi Shi,Luhua Lai,Zhanguo Li,Wanli Liu
摘要
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.