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

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 Fc?RIIa and Fc?RIIIa, 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.

SUBMITTER: Martinez DR

PROVIDER: S-EPMC6727200 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Martinez David R DR Fong Youyi Y Li Shuk Hang SH Yang Fang F Jennewein Madeleine F MF Weiner Joshua A JA Harrell Erin A EA Mangold Jesse F JF Goswami Ria R Seage George R GR Alter Galit G Ackerman Margaret E ME Peng Xinxia X Fouda Genevieve G GG Permar Sallie R SR

Cell 20190613 1

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 uninfect ...[more]

PMID: 31204101

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Project description:The transplacental transfer of maternal IgG to the developing fetus is critical for infant protection against infectious pathogens in the first year of life. However, factors that modulate the transplacental transfer efficiency of maternal IgG that could be harnessed for maternal vaccine design remain largely undefined. HIV-infected women have impaired placental IgG transfer, yet the mechanism underlying this impaired transfer is unknown, presenting an opportunity to explore factors that contribute to the efficiency of placental IgG transfer. We measured the transplacental transfer efficiency of maternal HIV and other pathogen-specific IgG in historical U.S. (n=120) and Malawian (n=47) cohorts of HIV-infected mothers and their HIV58 exposed uninfected and HIV-infected infants. We then examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, and IgG Fc region subclass and glycan signatures and their association with transplacental transfer efficiency of maternal antigen-specific IgG. We established 3 distinct phenotypes of placental IgG transfer efficiency in HIV-infected women, including: 1) efficient transfer of the majority of antigen-specific IgG populations; 2) generally poor IgG transfer phenotype that was strongly associated with maternal CD4+ T cell counts, hypergammaglobulinemia, and frequently yielded non-protective levels of vaccine-specific IgG; and 3) variable transfer of IgG across distinct antigen specificities. Interestingly, maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcgRIIa and FcgRIIIa, IgG subclass frequency, and Fc region glycan profiles were associated with placental IgG transfer efficiency. These maternal IgG transplacental transfer determinants were distinct among different antigen-specific IgG populations. Our findings suggest that in HIV-infected women, both maternal disease progression and Fc region characteristics modulate the selective placental transfer of distinct IgG subpopulations, with implications for both the health of HIV-exposed uninfected infants and maternal vaccine design.

Project description:Fetal and placental growth disorders are common in maternal human immunodeficiency virus (HIV) infection and can be attributed to both the infection and comorbidities not associated with HIV. We describe placental growth disorders and adverse reproductive outcomes in HIV-infected pregnant women whose delivery occurred between 2001-2014 in Vitoria, Brazil. Cases with gestational age (GA) ? than 22 weeks validated by ultrasonography, with placental and fetal weight dimensions at birth, were studied. Outcomes were summarized as proportions of small (SGA), appropriate (AGA), and large (LGA) for GA when the z-score values were below -1.28, between -1.28 and +1.28, or above +1.28, respectively. Of 187 fetal attachment requisitions, 122(65.2%) women and their newborns participated in the study. The median maternal age was 28 years and 81(66.4%) underwent ? 6 prenatal visits. A total of 81(66.4%) were diagnosed before current pregnancy; 68(55.7%) exhibited criteria for acquired immunodeficiency syndrome (AIDS); 64(52.4%) had detectable viral load; 25(20.5%) cases presented SGA placental weight and 6(4.9%) SGA placental thickness. SGA placental area was observed in 41(33.6%) cases, and among the SGA placental weight cases 12(48%) were also SGA fetal weight. Preterm birth (PTB) occurred in 15.6%(19/122) of cases; perinatal death in 4.1%(5/122) and HIV vertical transmission in 6 of 122 (4.9%). Women, ?36 years old, were 5.7 times more likely to have PTB than those under 36. Also, patients with AIDS-defining criteria were 3.7 times more likely to have PTB. Prenatal care was inversely associated with PTB. Statistically significant associations were observed between AGA placental area and Protease Inhibitor usage and between SGA placental weight and SGA area. We found a prevalence of placental growth disorders in HIV-infected pregnant women and values higher than international reference values. The restriction of placental growth was a common disorder, possibly attributed to virus effects or a combination of antiretroviral regimens.

Project description:BackgroundPlacental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women.Materials and methodsP. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses.ResultsPlacental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5-4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3-1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-alpha mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-alpha/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-alpha was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery.ConclusionsThese results show that P. falciparum infection profoundly modifies the placenta cytokine environment and acts as a confounding factor, masking the impact of HIV-1 in co-infected women. This interplay between the two infections might have implications in the in utero MTCT of HIV-1 in areas where HIV-1 and P. falciparum co-circulate.

Dataset Information

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

Publications

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

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