The past, present and future of a germline variant in hIgG1 coding gene IGHG1

Abstract

Humans are armed with a powerful immune system: an ornate product of evolution forged by a constant battle between host and microbe, and one which can be dramatically influenced by genetic variation. We described the prevalence and provenance of a novel variant of human IgG1 antibody (hIgG1-G396R), which affects the antigen receptor signaling transduction, fate decision of IgG1+ memory B cells and humoral immunity to otherwise lethal biological insults. By analyzing clinical cohorts, we showed that hIgG1-G396R is closely correlated with the onset and progression of a series of human diseases including systemic lupus erythematosus (SLE), colorectal cancer (CRC) and even the newly emerging coronavirus disease 2019 (COVID-19). By constructing hIgG1-G396R equivalent murine homologue knock-in mice (G2R-KI mice), we validated the multifaceted roles of this variant in murine disease models. Mechanistically, the variant lowers the threshold for IgG1-BCR activation through a mechanism of potentiating the phosphorylation of IgG1 immunoglobulin tail tyrosine (ITT) motif by Lyn kinase, thereby altering the spatial organization and availability of phospho-ITT motif to enhance the recruitment of the Grb2 and Btk signaling molecules into the immunological synapses. Thus, our work reveals the past, present and future of a germline variant in hIgG1 coding gene IGHG1.