An autoimmune disease variant of IgG1 modulates B cell activation and differentiation.
Xiangjun ChenXiaolin SunWei YangBing YangXiaozhen ZhaoShuting ChenLili HeHui ChenChangmei YangLe XiaoZai ChangJianping GuoJing HeFuping ZhangFang ZhengZhibin HuZhiyong YangJizhong LouWenjie ZhengHai QiChenqi XuHong ZhangHongying ShanXu-Jie ZhouQingwen WangYi ShiLuhua LaiZhan-Guo LiWanli LiuPublished in: Science (New York, N.Y.) (2018)
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.
Keyphrases
- systemic lupus erythematosus
- tyrosine kinase
- endothelial cells
- disease activity
- epidermal growth factor receptor
- high glucose
- induced apoptosis
- induced pluripotent stem cells
- pluripotent stem cells
- multiple sclerosis
- rheumatoid arthritis
- drug induced
- type diabetes
- binding protein
- diabetic rats
- skeletal muscle
- metabolic syndrome
- signaling pathway
- adipose tissue
- physical activity
- cell cycle arrest
- high frequency
- transcription factor
- oxidative stress
- neural stem cells
- pi k akt