Antibodies | Mechanisms of Transplacental IgG Antibody Transfer from Mother to Fetus, Pregnancy-Related Disorders, and Emerging Experimental Models

This article systematically reviews the molecular mechanisms, influencing factors, and existing research models of maternal IgG transfer across the placenta, revealing the impact of pregnancy complications and biologics on neonatal immune protection, thereby providing a theoretical basis for optimizing prenatal vaccination strategies.

 

Literature Overview

The article 'Transplacental Antibody Transfer: Mechanisms, Pregnancy-Related Disruptions, and Emerging Experimental Models,' published in the journal Antibodies, reviews and summarizes the biological mechanisms of maternal immunoglobulin G (IgG) transfer across the placenta. It explores the effects of various pathophysiological factors—such as preterm birth, hypergammaglobulinemia, maternal pathogenic IgG, infections, hyperglycemia, and the use of biologics—on this process. The article also systematically outlines current experimental models used to study placental IgG transfer, including humanized mice, in vitro cell models, organoids, and computational models. It emphasizes the importance of understanding placental antibody transfer mechanisms for optimizing maternal-neonatal immunization strategies.

Background Knowledge

Maternal IgG transfer across the placenta is a key pathway through which newborns acquire passive immune protection, primarily mediated by the neonatal Fc receptor (FcRn) via transcytosis. This process is most efficient during the third trimester, often resulting in higher IgG levels in full-term newborns than in their mothers. However, various pregnancy-related conditions—such as preterm birth, preeclampsia, and infections including HIV and malaria—have been reported to impair transfer efficiency, leading to suboptimal antibody levels in neonates. Furthermore, the increasing use of biologics such as monoclonal antibodies during pregnancy raises safety concerns due to their potential to compete for FcRn-mediated transport. Although models like BeWo cells, placental perfusion, and humanized mice are commonly used to study IgG transfer, they still have limitations in mimicking the dynamic environment of human pregnancy. Therefore, a deeper understanding of the transfer mechanisms, identification of influencing factors, and development of more physiologically relevant experimental systems are crucial for improving maternal-neonatal immune protection strategies.

 

 

Research Methods and Experiments

This study employed a literature review methodology to systematically retrieve and analyze research related to the mechanisms of placental IgG transfer, influencing factors, and experimental models. The authors focused on summarizing the FcRn-mediated transcytosis pathway of IgG, including the endocytosis of IgG in syncytiotrophoblast cells, its binding to FcRn in acidic endosomes, transcellular transport, and release at the fetal side under neutral pH conditions. The review also integrates data from multiple clinical cohort studies assessing changes in the cord-to-maternal IgG ratio (C/M ratio) under various pregnancy complications. Additionally, the article compares various experimental models—including transgenic mice, humanized FcRn mice, BeWo cell lines, trophoblast organoids, placental explants, and computational models—and evaluates their utility and limitations in mechanistic studies.

Key Conclusions and Perspectives

• FcRn is the primary receptor mediating maternal IgG transfer across the placenta, with its expression peaking during the third trimester, explaining the highest transfer efficiency in late pregnancy
• The efficiency of IgG subclass transfer varies in the order: IgG1 > IgG3 > IgG2 ≈ IgG4, and post-translational modifications such as Fc glycosylation and methionine oxidation can affect IgG’s binding affinity to FcRn
• Hypergammaglobulinemia can saturate FcRn, leading to competitive inhibition of IgG transfer, thereby reducing the efficiency of antigen-specific antibody transport and compromising neonatal immune protection
• Maternal infections such as HIV, malaria, and SARS-CoV-2 can indirectly or directly impair IgG transfer by altering B-cell function, modifying IgG glycosylation patterns, or inducing placental inflammation
• Maternal hyperglycemia may affect IgG–FcRn affinity through non-enzymatic glycation of IgG, although current evidence remains inconsistent
• Therapeutic monoclonal antibodies (e.g., anti-TNFα agents) can cross the placenta via FcRn, potentially affecting neonatal B-cell development and vaccine responses, necessitating individualized timing of administration
• Existing experimental models each have strengths and limitations: humanized mice are suitable for in vivo mechanistic studies, BeWo cells and organoids allow high-throughput screening, while placental perfusion models more closely mimic physiological conditions but lack long-term dynamic observation capabilities

Research Significance and Prospects

This review comprehensively integrates multidisciplinary advances in placental IgG transfer, highlighting the significant impact of maternal health status and immunological interventions on neonatal passive immunity. It suggests that optimizing the timing of prenatal vaccination (e.g., early pregnancy administration of SARS-CoV-2 vaccines) can enhance antibody transfer efficiency, informing public health strategies.

Future research should focus on developing more precise dynamic models, such as 'placenta-on-a-chip' or AI-integrated multiscale computational models, to simulate antibody transfer throughout pregnancy. Additionally, deeper exploration of the structural basis of IgG modifications and their interaction with FcRn will aid in designing more effective or safer maternal vaccines and therapeutic antibodies.

 

 

Conclusion

Maternal IgG transfer across the placenta is a core mechanism ensuring neonatal immune defense, primarily mediated by the FcRn receptor. This process is most efficient in late gestation but can be disrupted by various factors including preterm birth, infections, hypergammaglobulinemia, hyperglycemia, and therapeutic antibodies. This article systematically summarizes the molecular mechanisms, influencing factors, and existing research models, emphasizing the critical roles of maternal immune status and antibody characteristics in transfer efficiency. Current evidence supports vaccinating during the second trimester to maximize antibody transfer, especially in cases with high risk of preterm delivery. Meanwhile, the widespread use of biologics requires careful clinical assessment of maternal therapeutic needs against fetal exposure risks. Future research should focus on developing more physiologically relevant dynamic models and further elucidating the structural regulation mechanisms of IgG–FcRn interactions, guiding the design of next-generation maternal vaccines and antibody therapeutics to ultimately improve maternal and child health outcomes.

 

Qiqi Li, Zhengyuan Huang, Zainab Saeed, James A Harker, and Nishel M Shah. Transplacental Antibody Transfer: Mechanisms, Pregnancy-Related Disruptions, and Emerging Experimental Models. Antibodies.