An IgG1 SNP enhances autoimmunity One common feature of autoimmune diseases like systemic lupus erythematosus (SLE) is the presence of high titers of self-reactive antibodies. These result in immune complexes, inflammation, and tissue pathology. Consequently, the checkpoints that normally keep immunoglobulin G (IgG)–positive autoreactive B cells in check are of intense interest. Chen et al. report the presence of a common IgG1 single-nucleotide polymorphism (SNP) in East Asian populations (hIgG1-G396R). This SNP was enriched in SLE patients and associated with increased disease severity. Humans with this SNP, as well as knockin mice, showed enhanced plasma cell accumulation and antibody production. This SNP enhanced IgG1 immunoglobulin tail tyrosine motif phosphorylation, triggering longer adaptor protein Grb2 dwell times in immunological synapses and hyper–Grb2–Bruton's tyrosine kinase signaling after antigen binding. Science, this issue p. 700 A variant of IgG1 modulates B cell responses and autoimmunity. 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.

中文翻译：

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IgG1 的自身免疫性疾病变体调节 B 细胞活化和分化

IgG1 SNP 增强自身免疫系统性红斑狼疮 (SLE) 等自身免疫性疾病的一个共同特征是存在高滴度的自身反应性抗体。这些导致免疫复合物、炎症和组织病理学。因此，通常对免疫球蛋白 G (IgG) 阳性自身反应性 B 细胞进行检查的检查点备受关注。陈等人。报告东亚人群 (hIgG1-G396R) 中存在常见的 IgG1 单核苷酸多态性 (SNP)。这种 SNP 在 SLE 患者中富集，并与疾病严重程度增加有关。具有这种 SNP 的人类以及敲入小鼠显示出浆细胞积累和抗体产生增强。这种 SNP 增强了 IgG1 免疫球蛋白尾部酪氨酸基序磷酸化，在抗原结合后触发免疫突触中更长的衔接蛋白 Grb2 停留时间和 hyper-Grb2-Bruton 酪氨酸激酶信号传导。科学，这个问题 p。700 IgG1 的 A 变体调节 B 细胞反应和自身免疫。保持自身反应性 B 细胞处于静止状态对于预防自身免疫至关重要。在这里，我们鉴定了具有 Gly396→Arg 取代 (hIgG1-G396R) 的人免疫球蛋白 G1 (IgG1) 变体，其与系统性红斑狼疮呈正相关。在诱导狼疮模型中，小鼠同源 Gly390→Arg (G390R) 敲入小鼠产生过多的浆细胞，导致广谱自身抗体的爆发。在半抗原免疫的 G390R 小鼠以及接种流感疫苗的人 G396R 纯合载体中也观察到了这种增强的抗体产生。该变体增强了 IgG1 免疫球蛋白尾部酪氨酸 (ITT) 基序的磷酸化。反过来，这会改变磷酸化 ITT 的可用性，以触发更长的衔接蛋白 Grb2 在免疫突触中的停留时间，从而在抗原结合时导致 hyper-Grb2-Bruton 酪氨酸激酶 (Btk) 信号传导。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。