Z35 - Pro-Angiogenic and Vascular Signaling Molecules as Biomarkers of Maternal-Fetal Immune Transfer

Friday, October 10, 2025

10:00 AM - 11:00 AM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

Caitlin Sullivan

PhD Student
University of Virginia
Charlottesville, Virginia, United States

Co-Author(s)

AS

Anna Sawik

Visiting Graduate Researcher
University of Virginia, United States
RE

Remziye R. Erdogan Wessel, PhD

Postdoctoral Fellow
Massachusetts Institute of Technology, United States

Primary Investigator(s)

SD

Sepideh Dolatshahi, PhD

Assistant Professor
University of Virginia
Charlottesville, Virginia, United States

Introduction: : Neonates exhibit an immature adaptive immune system, rendering them highly susceptible to infection and limiting effectiveness of direct immunization1. For this reason, pre-natal immunization has been implemented to leverage maternal transfer of immunity, namely transfer of Immunoglobulin G (IgG) across the placenta, to confer immunity to newborns. Placental Fc receptors (FcRs) and maternal IgG Fc characteristics – such as subclass and N-glycosylation– have been identified as mediators of antibody transfer across the placenta. IgG transport occurs via syncytiotrophoblasts (STBs), the stroma, and endothelial cells (ECs) through a receptor mediated process driven by neonatal Fc receptor (FcRn) and FcγRIIIa on STBs, and FcRn and FcγRIIb on ECs2,3. Previous work has shown di-galactosylation and sialylation are associated with better transfer, while agalactosylation is associated with worse transfer4. Both FcR expression and glycosylation are modulated by inflammatory signaling5,6. However, a systematic quantitative characterization of how the variation in plasma cytokines of individuals is associated with these modulators and in turn the efficient transfer of IgG antibodies is lacking. Based on this, our central hypothesis is that maternal peripheral blood cytokines can be used as predictors of the variability in antibody transfer and can as such be used as biomarkers for optimal transfer and identify vulnerable individuals as candidates for vaccination or supplementation solutions.

Materials and

Methods: : Immunoglobulin Isotyping and 47-Plex Luminex
Maternal and cord plasma samples were characterized using Milliplex Human Cytokine/Chemokine/Growth Factor Panel A (Millipore Sigma, HCTYA-60K) and isotyped using the Milliplex Map Human Isotyping Magnetic Bead Panel Kit (Millipore Sigma, HGAMMAG-301k) according to the manufacturer’s protocol courtesy of the UVA Flow Cytometry Core Facility. Concentrations were calculated using a 5-parameter logistic regression.
FcR Expression
Multiplex immunofluorescence (mIF) imaging was performed on formalin-fixed paraffin-embedded (FFPE) sections of human placental tissue from ten patients of a UVA patient cohort. Imaging was conducted using the Vectra imaging system and Halo image analysis software. To quantify cell type specific FcR expression, a random forest tissue classifier algorithm was used to identify villous tissue which was then used for quantification of FcR and STB or EC colocalization, normalized to STB or EC positive area.
Glycoproteomics
IgG-subclass specific Fc-glycans were quantified in human maternal and umbilical cord plasma from a University of Virginia (UVA) patient cohort using liquid chromatography-mass spectrometry (LC-MS) at the Complex Carbohydrate Research Center at the University of Georgia. IgG was separated by retention time into three clusters: IgG1, IgG2/3, and IgG3/4. IgG3 could not be resolved independently because of a single nucleotide polymorphism (SNP) of IgG3 allotypes causing co-elution.
Multivariate Statistical Analysis
Models were generated in MATLAB R2024b using Partial Least Squares Regression (PLSR). Data were log-transferred, centered, and scaled prior to PLSR. The model’s predictive power (Q2) was determined through 5-fold cross validation against 1,000 randomly permuted models.

Results, Conclusions, and Discussions:: To investigate soluble immune mediators as biomarkers for transplacental antibody transfer, we examined the relationship between maternal inflammatory milieu and Fc receptor (FcR) expression on various placental cell types. Pro-angiogenic and vascular remodeling associated cytokines, such as FGF2, GM-CSF, M-CSF, and VEGF-A, were associated with increased expression of FcγRIIIa on syncytiotrophoblasts (STBs) and FcRn and FcγRIIb on endothelial cells (ECs). Conversely, lower expression of these FcRs was linked to a shift toward an angiostatic and pro-inflammatory, specifically Th1/Th17 profile, which included cytokines such as IFN-γ, IFN-α2, IL-6, and IL-18. Analysis of fetal plasma revealed that cytokines, such as IL-6, G-CSF, and IP-10, known to suppress angiogenesis, were associated with decreased FcRn and FcγRIIb expression in endothelial cells. Together, these data suggest that vascular activation supports FcR expression and thus IgG transport, whereas angiostasis and tissue repair phases limit it.
To further understand the role of inflammation, we investigated IgG Fc glycosylation. Fully galactosylated and sialylated (G2FS) IgG, which exhibits optimal transfer efficiency, were associated with angiogenic signals including TGF-α, IL-17F, and VEGF-A. Intermediately transferred G2F, was associated with MIP-1α, IL-16, and GM-CSF, while poorly transferred agalacosylated IgG (G0) displayed an angiostatic signature as reflected by IL-8, IFN-α2, and MIG. These data suggest that pro-inflammatory signals alone may hinder antibody transfer, but inflammation within an angiogenic context may support it. Interestingly, IgG1 and IgG3 strongly correlated with angiogenic profiles, consistent with the known transfer hierarchy: IgG1>IgG3>IgG4>IgG2.
To validate our findings, we developed a multivariate statistical regression model that predicted IgG subclass specific transfer based on maternal inflammatory milieu, FcR expression, and Fc glycosylation data. Similarly, angiogenic signals were positively associated with more favorably transferred subclasses, IgG1 and IgG3, as reflected by VEGF-A, IL-17F, and PDGF-AA/AB. Less efficiently transferred subclasses, IgG2 and IgG4, were linked with Th1/Th17 via IL-2, MIG, and IL-17F.
In conclusion, we developed a predictive model of transplacental IgG transfer integrating maternal inflammatory profile, Fc glycosylation, and FcR expression. These data demonstrate that inflammatory milieu can predict transfer and thus some variability observed across the population. These data also highlight the role of angiogenic signaling in transplacental antibody transfer.

Acknowledgements and/or References (Optional): : 1. WHO Recommendations for Management of Serious Bacterial Infections in Infants Aged 0-59 Days. (World Health Organization, Geneva, 2025).
2. Wessel, R. E. & Dolatshahi, S. Regulators of placental antibody transfer through a modeling lens. Nat. Immunol. 25, 2024–2036 (2024).
3. Jennewein, M. F., Abu-Raya, B., Jiang, Y., Alter, G. & Marchant, A. Transfer of maternal immunity and programming of the newborn immune system. Semin. Immunopathol. 39, 605–613 (2017).
4. Jennewein, M. F. et al. Fc glycan-mediated regulation of placental antibody transfer. Cell 178, 202-215.e14 (2019).
5. Sepúlveda-Delgado, J., Llorente, L. & Hernández-Doño, S. A Comprehensive Review of Fc Gamma Receptors and Their Role in Systemic Lupus Erythematosus. Int. J. Mol. Sci. 26, 1851 (2025).
6. Alter, G., Ottenhoff, T. H. M. & Joosten, S. A. Antibody glycosylation in inflammation, disease and vaccination. Semin. Immunol. 39, 102–110 (2018).
7. Clements, T. et al. Update on Transplacental Transfer of IgG Subclasses: Impact of Maternal and Fetal Factors. Front. Immunol. 11, (2020).
8. Wessel, R. E. & Dolatshahi, S. Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies. PLOS Comput. Biol. 19, e1011109 (2023).