| First Author | Chen X | Year | 2018 |
| Journal | Science | Volume | 362 |
| Issue | 6415 | Pages | 700-705 |
| PubMed ID | 30287618 | Mgi Jnum | J:266937 |
| Mgi Id | MGI:6257107 | Doi | 10.1126/science.aap9310 |
| Citation | Chen X, et al. (2018) An autoimmune disease variant of IgG1 modulates B cell activation and differentiation. Science 362(6415):700-705 |
| abstractText | 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(396)-->Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly(390)-->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. |
