An IgG1 SNP enhances autoimmunity

Immunology 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][1] [1]: /lookup/doi/10.1126/science.aap9310