Ministry of Education Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Institute for Immunology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking-Tsinghua Center for Life Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100044, China.
Science. 2018 Nov 9;362(6415):700-705. doi: 10.1126/science.aap9310. Epub 2018 Oct 4.
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 Gly→Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly→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.
维持自身反应性 B 细胞的静止状态对于防止自身免疫至关重要。在这里，我们鉴定出一种人免疫球蛋白 G1（IgG1）的变体，其 Gly→Arg 取代（hIgG1-G396R）与系统性红斑狼疮呈正相关。在诱导性狼疮模型中，鼠同源 Gly→Arg（G390R）敲入小鼠产生大量浆细胞，导致广谱自身抗体的爆发。这种增强的抗体产生也在半抗原免疫的 G390R 小鼠以及流感疫苗接种的人类 G396R 纯合子携带者中观察到。这种变体增强了 IgG1 免疫球蛋白尾部酪氨酸（ITT）基序的磷酸化。反过来，这改变了磷酸化 ITT 的可用性，以触发免疫突触中更长的衔接蛋白 Grb2 停留时间，从而导致抗原结合后 Grb2-Bruton 的酪氨酸激酶（Btk）信号过度激活。因此，hIgG1-G396R 变体对于狼疮发病机制和疫苗接种后的抗体反应都很重要。
