| First Author | Borghi S | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 23 | Pages | 12943-12951 |
| PubMed ID | 32461366 | Mgi Jnum | J:289872 |
| Mgi Id | MGI:6435070 | Doi | 10.1073/pnas.2004325117 |
| Citation | Borghi S, et al. (2020) FcRn, but not FcgammaRs, drives maternal-fetal transplacental transport of human IgG antibodies. Proc Natl Acad Sci U S A 117(23):12943-12951 |
| abstractText | The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fcgamma receptors (FcgammaRs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by FcgammaRs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and FcgammaRs, recent studies have suggested that FcgammaRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcgammaRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcgammaRIIIa or FcRn binding, half-life, or their ability to deplete target cells in FcgammaR/FcRn humanized mice. Modeling maternal-fetal transport in FcgammaR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcgammaRIIIa binding did not result in enhanced maternal-fetal transport. These results argue against a role for FcgammaRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG. |
