IgG4 and asymmetric IgG as blocking antibodies in maternal-fetal Immune tolerance during pregnancy

Abstract Background Blocking antibody refers to antibody possessing the ability to block immunoreactions. Two distinct type of IgG i.e., IgG4 and asymmetric (asym) IgG, have been independently referred to as “blocking antibodies”. Besides, IgG4 has emerged as a potential immune regulatory molecule in cancer, but its mechanisms of action and impact on maternal-fetal immune interactions remain unclarified. Methods To investigate the similarity and relationship between IgG4 and asym IgG, as well as the regulation of IgG4 in maternal-fetal immune tolerance during pregnancy, structural and functional properties of these two antibodies were compared with Western blot(WB), immunohistochemistry, protein array, and immune turbid metric assay to study their distributions, densities, levels in maternal sera and possible interactions with other IgG subtypes. Results We found a significant overlap in molecular structure between IgG4 and asym IgG. IgG4 displayed an asymmetric Fab glycosylated pattern. Both IgG4 and asym IgG, unlike sym IgG or IgG1, bound to cross-species IgGs. Besides, IgG1 and IgG4 were distributed within the outer layer of placental villi and within the lumens of placental intravascular vessels. In early placental villi, IgG1 and IgG4 were present in the syncytiotrophoblast layer, while in decidua, they were predominantly observed in lymphocytes. Endogenous and exogenous IgG4 proteins exhibited Fc-Fc interactions with IgG1, and this reaction was found to be enhanced by glutathione (GSH), in a dose-dependent manner. IgG4 levels significantly increased in early pregnancy sera but declined in later stages, possibly participating in immune tolerance of the placenta during the early phase of pregnancy. Conclusion This study suggested that IgG4 and asym IgG are likely the same molecule with different degrees of purity and displaying similar biological properties. As maternal rejection and fetal defense reach immune equilibrium through these distinct mechanisms, it indicated that the steady state of Fc-Fc interactions of IgG4 may play an important role in immunotolerance in reproduction.