Names of the four human IgG subtypes were based on their sequence of discoveries time and relative abundance in human serum, with approximately 61 % IgG1, 32 % IgG2, 4 % IgG3, and 3 % IgG4. IgG4 is the least concentrated subtype of which the function has not bean well understood (Vidarsson et al., 2014, Schur, 1988). IgG4 has a unique Fab arm exchange (FAE) property in which the two heavy and light chains of different IgG4 antibodies with different specificities are exchanged, to form asym bispecific antibodies resulting in a reduced ability to bind antigens (van der Neut Kolfschoten et al., 2007, Rispens et al., 2009). Another unique feature of IgG4 is its ability to act as a "blocking antibody", which can block classic antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cell cytotoxicity (CDC) immune reactions by reacting with other IgG fragments via its Fc fragment (Aalberse et al., 2009, Karagiannis et al., 2013, Overdijk et al., 2012, Niwa et al., 2005, Bruhns et al., 2009). The unique feature of IgG4 is similar to another "blocking antibody" asym IgG, which is named after its uneven glycosylation modification on the two Fab arms. The term “blocking antibody” was first introduced due to the protective role of asym IgG, blocking antibody-mediated immune responses in pregnancy and ovarian cancer (ZENCLUSSEN et al., 2001, Gerçel-Taylor et al., 2001). IgG4 antibody has selective affinity for the inhibitory receptor FcγRIIb but not the excitatory receptors on immune cells (Aalberse et al., 1983). These common features led us to hypothesize that IgG4 and asymmetrically Fab-glycosylated IgG contain similar structures and functions. Our previous work indicated that asym IgG may contribute to tumor immune escape, while sym IgG had the opposite effect (Huang et al., 2016). Asym IgG may mediate tumor growth by blocking tumor-specific IgG1 (Karagiannis et al., 2013). Interestingly, we also found that IgG4 could inhibit IgG1-mediated cytotoxicity as a blocking antibody (Xu et al., 2019). These two antibodies share some common biological features of immune inhibition and were given the same name by different investigators at separate occasions. However, the relationship between the two has not been clarified.

Karagiannis et al. conducted extensive research on IgG4 and cancer, examining the potential role of cancer-specific IgG4 in inhibiting melanoma cancer immunity and suggesting that competition between cancer-specific IgG4 and IgG1 in binding cancer antigens is the reason for immune inhibition (Karagiannis et al., 2013). We later obtained evidence to suggest that Fc-Fc reactions i.e. the Fc fragment of IgG4 reacting to the Fc fragment of other IgGs, may be the basic mechanism of this immune suppression. In vitro, an increase in GSH enhanced the unique Fc-Fc reactions of IgG4 with other IgG molecules (van der Neut Kolfschoten et al., 2007, Rispens et al., 2009, Rispens et al., 2011, Rispens et al., 2013, Schuurman et al., 2001). We reported IgG4-driven immune escape mechanisms in cancer immunity (Wang et al., 2020, Zhang et al., 2023, Zhang et al., 2024, Li et al., 2025).

The immune balance at the close contact between the fetal and the maternal cells in placenta is crucial for a successful pregnancy. Due to the underdeveloped immune system of fetuses and newborns, immune protection is provided during pregnancy and relies on the supply of maternal antibodies though the placenta to the fetus, which are transferred from the maternal blood into the fetal circulation. The transmission of this antibody to fetal tissue is limited to IgG and its subtypes, and mainly occurs in the second half of pregnancy (Malek, 2013). The immunoglobulin in fetal circulation are almost entirely composed of maternal IgG, and various specific antibodies have been described, such as specific IgG against tetanus toxoids, anti-group A streptococcal carbohydrates, and anti-herpes simplex virus (Malek, 2013). Therefore, IgG subtypes present in fetal circulation is an important feature of pregnancy, providing passive immunity for the survival of fetus.

In this study, we attempted to verify the hypothesis that these two blocking antibodies i.e., IgG4 and asym IgG are biologically very similar and structurally the same. They exert the same biological effects with the same or similar mechanisms and therefore are likely the same active molecule with differences in purity. In addition, we investigated the dynamic changes of IgG subtypes throughout pregnancy and verified the hypothesis that IgG4 plays an important role in immune escape mechanism during pregnancy. Their Fc-Fc reaction may be one of the basic mechanisms of the maternal-fetal immune regulation.