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. 2019 Jun 27;178(1):190-201.e11.
doi: 10.1016/j.cell.2019.05.046. Epub 2019 Jun 13.

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women

David R Martinez  1 , Youyi Fong  2 , Shuk Hang Li  3 , Fang Yang  4 , Madeleine F Jennewein  5 , Joshua A Weiner  6 , Erin A Harrell  4 , Jesse F Mangold  3 , Ria Goswami  3 , George R Seage 3rd  7 , Galit Alter  5 , Margaret E Ackerman  6 , Xinxia Peng  8 , Genevieve G Fouda  9 , Sallie R Permar  10
Affiliations

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women

David R Martinez et al. Cell. .

Abstract

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.

Keywords: HIV; IgG Fc region; antibodies; infant protection; maternal immunity; placental IgG transfer.

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Conflict of interest statement

DECLARATION OF INTERESTS

S.R.P. is a consultant for Pfizer, Moderna Therapeutics, Merck, and Sanofi vaccine programs. All other authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Distinct Phenotypes of Placental Transfer Efficiency of HIV and Vaccine Antigen-Specific IgG among HIV-Infected Pregnant Women
(A and B) Placental IgG transfer efficiency in HIV-infected mother infant pairs from the US (A) and Malawi (B). Gray squares denote uncalculated transfer ratios from concentrations outside the linear range. (C) Global placental IgG transfer score among HIV-infected women defined to have efficient, poor, and variable placental IgG transfer. Bar denotes median.
Figure 2.
Figure 2.. HEU Infants Receive Suboptimal Levels of Protective Maternal IgG against Vaccine-Preventable Infections
(A and B) Proportion of US (A) and Malawian (B) mothers with levels of vaccine-specific IgG below (red) and above (blue) the established protective concentrations against tetanus toxoid, rubella, diphtheria toxin, and Haemophilus influenzae type B (Hib). Larger pie graphs show the proportion of mothers with IgG levels above and below the protective concentration. Smaller pie graphs show the proportion of infants born to women with protective IgG levels that fall below (purple) and above (blue) the protective IgG levels at birth.
Figure 3.
Figure 3.. HIV gp120, Tetanus Toxoid, and Pertussis Toxin-Specific IgG Binding to Placental FcRs in HIV-Infected Malawian Women with Poor and Variable Placental IgG Transfer
(A–F) Maternal gp120, tetanus toxoid (TT), and pertussis toxin (PT)-specific IgG binding to FcRn (A), FcγRIIb (B), FcγRIIa H131 (C), FcγRIIa R131 (D), FcγRIIIa V158 (E), and FcγRIIIa F158 (F). FcγRIIa H131 and FcγRIIIa V158 are high-affinity IgG binding FcRs, whereas FcγRIIa R131 and FcγRIIIa F158 are lower-affinity IgG binding FcR polymorphisms. HIV-infected women with poor (P) placental IgG transfer efficiency are shown in red squares, and variable (V) placental IgG transfer efficiency are shown in blue circles. Log10 MFI denotes the mean fluorescent intensity. See also Figures S2–S4.
Figure 4.
Figure 4.. Differences in Fc Region Glycan Profiles of gp120, Tetanus Toxoid, and Pertussis Toxin-Specific IgG in US HIV-Infected Women with Variable Placental IgG Transfer
(A) Percentage of placental transfer efficiency of gp120, tetanus toxoid (TT), and pertussis toxin (PT)-specific IgG. (B–I) Frequency of G0 (B), G1 (C), G2 (D), fucose (E), bisected (F), di-sialic acid (G), mono-sialic acid (H), total sialic acid (I) of Fc region glycans of gp120, tetanus toxoid, and pertussis toxin-specific IgG. Displayed is p value from a Kruskal-Wallis test; the dotted line denotes 100% transfer. See also Figure S5.
Figure 5.
Figure 5.. Model of the Selective Placental Transfer of Maternal IgG in HIV-Infected Pregnant Women
See also Figures S1 and S4–S6.
See this image and copyright information in PMC

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