An autoimmune disease variant of IgG1 modulates B cell activation and differentiation

• Published in: Science (American Association for the Advancement of Science) 2018-11, Vol.362 (6415), p.700-705
• Main Authors: Chen, Xiangjun, Sun, Xiaolin, Yang, Wei, Yang, Bing, Zhao, Xiaozhen, Chen, Shuting, He, Lili, Chen, Hui, Yang, Changmei, Xiao, Le, Chang, Zai, Guo, Jianping, He, Jing, Zhang, Fuping, Zheng, Fang, Hu, Zhibin, Yang, Zhiyong, Lou, Jizhong, Zheng, Wenjie, Qi, Hai, Xu, Chenqi, Zhang, Hong, Shan, Hongying, Zhou, Xu-Jie, Wang, Qingwen, Shi, Yi, Lai, Luhua, Li, Zhanguo, Liu, Wanli
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animal models; Animals; Antibodies; Antigen-antibody complexes; Antigens; Arginine - genetics; Autoantibodies; Autoantibodies - biosynthesis; Autoimmune diseases; Autoimmunity - genetics; B-Lymphocytes - immunology; Binding; Bruton's tyrosine kinase; Cell activation; Cell Differentiation - genetics; Cell Differentiation - immunology; Chronic conditions; Disease Models, Animal; Dwell time; Gene Knock-In Techniques; Glycine - genetics; GRB2 Adaptor Protein - genetics; Grb2 protein; Heterozygote; Homology; Humans; Immunization; Immunoglobulin G; Immunoglobulins; Immunological synapses; Immunological Synapses - immunology; Immunology; Individualized Instruction; Influenza; Literary Devices; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation - genetics; Lymphocytes B; Mice; Mice, Inbred C57BL; Pathogenesis; Phosphorylation; Plasma cells; Plasma Cells - immunology; Polymorphism; Protein-tyrosine kinase; Proteins; Signal Transduction; Signaling; Single-nucleotide polymorphism; Synapses; Systemic lupus erythematosus; Tyrosine; Vaccination; Vaccines
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aap9310

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.