Placental Transfer Of IgG Research Articles

HIV-related immune activation attenuates polyfunctional IgG and memory B-cell responses to Tdap immunization during pregnancy

Maternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown. In this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline. One month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH. Maternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants. This work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIHNIAID1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.

Evidence for the Role of a Second Fc-Binding Receptor in Placental IgG Transfer in Nonhuman Primates.

Transplacental transfer of maternal antibodies provides the fetus and newborn with passive protection against infectious diseases. While the role of the highly conserved neonatal Fc receptor (FcRn) in transfer of IgG in mammals is undisputed, recent reports have suggested that a second receptor may contribute to transport in humans. We report poor transfer efficiency of plant-expressed recombinant HIV-specific antibodies, including engineered variants with high FcRn affinity, following subcutaneous infusion into rhesus macaques close to parturition. Unexpectedly, unlike those derived from mammalian tissue culture, plant-derived antibodies were essentially unable to cross macaque placentas. This defect was associated with poor Fcγ receptor binding and altered Fc glycans and was not recapitulated in mice. These results suggest that maternal-fetal transfer of IgG across the three-layer primate placenta may require a second receptor and suggest a means of providing maternal antibody treatments during pregnancy while avoiding fetal harm. IMPORTANCE This study compared the ability of several human HIV envelope-directed monoclonal antibodies produced in plants with the same antibodies produced in mammalian cells for their ability to cross monkey and mouse placentas. We found that the two types of antibodies have comparable transfer efficiencies in mice, but they are differentially transferred across macaque placentas, consistent with a two-receptor IgG transport model in primates. Importantly, plant-produced monoclonal antibodies have excellent binding characteristics for human FcRn receptors, permitting desirable pharmacokinetics in humans. The lack of efficient transfer across the primate placenta suggests that therapeutic plant-based antibody treatments against autoimmune diseases and cancer could be provided to the mother while avoiding transfer and preventing harm to the fetus.

Human IgE does not bind to human FcRn

The neonatal Fc receptor (FcRn) is known to mediate placental transfer of IgG from mother to unborn. IgE is widely known for triggering immune responses to environmental antigens. Recent evidence suggests FcRn-mediated transplacental passage of IgE during pregnancy. However, direct interaction of FcRn and IgE was not investigated. Here, we compared binding of human IgE and IgG variants to recombinant soluble human FcRn with β2-microglobulin (sFcRn) in surface plasmon resonance (SPR) at pH 7.4 and pH 6.0. No interaction was found between human IgE and human sFcRn. These results imply that FcRn can only transport IgE indirectly, and thereby possibly transfer allergenic sensitivity from mother to fetus.

Blocking Placental Class G Immunoglobulin Transfer Prevents NMDA Receptor Antibody Effects in Newborn Mice.

Background and ObjectivesTo determine in a mouse model whether neonatal Fc receptor (FcRn) blockade prevents the placental transfer of class G immunoglobulin (IgG) derived from patients with anti-NMDA receptor (NMDAR) encephalitis and their pathogenic effects on the fetuses and offspring.MethodsPregnant C57BL/6J mice were administered via tail vein FcRn antibody (FcRn-ab) or saline solution 6 hours before administration of patients' or controls' IgG on days 14, 15, and 16 of gestation. Three experimental groups were established: mice receiving controls' IgG, patients' IgG, or patients' IgG along with pretreatment with FcRn-ab. Immunohistochemical staining, confocal microscopy, hippocampal long-term potentiation, and standardized developmental and behavioral tasks were used to assess the efficacy of treatment with FcRn-ab.ResultsIn pregnant mice that received patients' IgG, treatment with FcRn-ab prevented the IgG from reaching the fetal brain, abrogating the decrease of NMDAR clusters and the reduction of cortical plate thickness that were observed in fetuses from untreated pregnant mice. Moreover, among the offspring of mothers that received patients' IgG, those whose mothers were treated with FcRn-ab did not develop the alterations that occurred in offspring of untreated mothers, including impairment in hippocampal plasticity, delay in innate reflexes, and visuospatial memory deficits.DiscussionFcRn blockade prevents placental transfer of IgG from patients with anti-NMDAR encephalitis and abrogates the synaptic and neurodevelopmental alterations caused by patients' antibodies. This model has potential therapeutic implications for other antibody-mediated diseases of the CNS during pregnancy.

Reduced Placental Transfer of Antibodies Against a Wide Range of Microbial and Vaccine Antigens in HIV-Infected Women in Mozambique.

Transplacental transfer of antibodies is essential for conferring protection in newborns against infectious diseases. We assessed the impact of different factors, including gestational age and maternal infections such as HIV and malaria, on the efficiency of cord blood levels and placental transfer of IgG subclasses. We measured total IgG and IgG subclasses by quantitative suspension array technology against 14 pathogens and vaccine antigens, including targets of maternal immunization, in 341 delivering HIV-uninfected and HIV-infected mother-infant pairs from southern Mozambique. We analyzed the association of maternal HIV infection, Plasmodium falciparum exposure, maternal variables and pregnancy outcomes on cord antibody levels and transplacental transfer. Our results show that maternal antibody levels were the main determinant of cord antibody levels. Univariable and multivariable analysis showed that HIV reduced the placental transfer and cord levels of IgG and IgG1 principally, but also IgG2 to half of the antigens tested. P. falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer, but this was antigen-subclass dependent. Our findings suggest that lower maternally transferred antibodies may underlie increased susceptibility to infections of HIV-exposed infants. This could affect efficacy of maternal vaccination, especially in sub-Saharan Africa, where there is a high prevalence of HIV, malaria and unfavorable environmental factors.

HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women

Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses. In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer. Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2. We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children.

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

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.

Teaching hemolytic disease of the newborn (Erythroblastalis fetalis) to undergraduate immunology students through the use of an interactive simulation

Abstract Hemolytic disease of the newborn (HDN, Erythroblastalis fetalis) is a potentially fatal condition. It is initiated due to Rhesus (Rh) antigens on fetal red blood cells (RBCs) being seen as foreign by the mothers Rh− immune system. In the first pregnancy, exposure of the maternal immune system to fetal Rh+ RBCs leads to immune activation, IgM production and memory cell formation. A subsequent pregnancy with another Rh+ fetus, activates memory cells, leading to class switching and IgG production, which is placentally transferred to the fetus. Through multiple effector functions, the IgG leads to hemolysis, causing anemia and in severe cases even death of the fetus. The role of the immune response is key to this disease, hence it is taught to undergraduate immunology students at the University of South Australia. Topics include the primary and secondary immune responses, placental transfer of IgG, deletion of self reactive cells and use of mAbs as therapeutic agents are addressed. Experience has shown that students find this topic challenging. In an attempt to enhance understanding, I developed an interactive simulation to teach these principles which was trialed in 2018. The simulation gave students the opportunity to blood group expecting parents and then discuss possible HDN issues and the treatment option. As with other simulations I have generated, (e.g. flow cytometry and mAbs), I suggest this approach is a new approach to teach complex immunological concepts. This approach can enhance student understanding as well as provide a new means of information transferal. The HDN simulation is freely available to all teaching staff who may wish to use it as part of their teaching approach.

An interspecies comparison of placental antibody transfer: New insights into developmental toxicity testing of monoclonal antibodies

There are profound differences in maternofetal transfer of immunoglobulins between species with extensive gestational transfer of maternal immunoglobulins in primates (including humans) via the chorioallantoic placenta as well as in rabbits and guinea pigs via the inverted yolk sac splanchnopleure. In contrast, other neonatal rodents (rats and mice) receive passive immunity predominantly postnatally. This transfer is mediated principally via FcRn receptors. Therapeutic monoclonal antibodies (mAbs) are most commonly of the IgG1 subclass, which is transported most efficiently to the fetus. In all animal species used for testing developmental toxicity, fetal exposure to IgG is very low during organogenesis, but this increases during the latter half of gestation such that the neonate is born with an IgG1 concentration similar to the mother (but not rats and mice). Review of mAb developmental toxicity studies of licensed products reveals Cynomolgus monkey as the species used in the majority of the cases (10 out of 15). Pregnancy outcome data from women gestationally exposed to mAb is limited. In general, the findings are consistent with the expected low exposure during organogenesis. Guinea-pigs and rabbits are potential candidates as "alternatives" to the use of nonhuman primates as the maternofetal transfer in the last part of gestation is at a level similar in humans. Based on the pattern of placental transfer of IgG in humans, study designs that allow detection of both the indirect effects in early gestation plus the effects of direct fetal exposure in mid and late gestation are recommended for developmental toxicity of mAbs.

High Maternal HIV-1 Viral Load During Pregnancy Is Associated With Reduced Placental Transfer of Measles IgG Antibody

Studies among HIV-1-infected women have demonstrated reduced placental transfer of IgG antibodies against measles and other pathogens. As a result, infants born to women with HIV-1 infection may not acquire adequate passive immunity in utero and this could contribute to high infant morbidity and mortality in this vulnerable population. To determine factors associated with decreased placental transfer of measles IgG, 55 HIV-1-infected pregnant women who were enrolled in a Nairobi perinatal HIV-1 transmission study were followed. Maternal CD4 count, HIV-1 viral load, and HIV-1-specific gp41 antibody concentrations were measured antenatally and at delivery. Measles IgG concentrations were assayed in maternal blood and infant cord blood obtained during delivery to calculate placental antibody transfer. Among 40 women (73%) with positive measles titers, 30 (75%) were found to have abnormally low levels of maternofetal IgG transfer (<95%). High maternal HIV-1 viral load at 32 weeks' gestation and at delivery was associated with reductions in placental transfer (P < 0.0001 and P = 0.0056, respectively) and infant measles IgG concentrations in cord blood (P < 0.0001 and P = 0.0073, respectively). High maternal HIV-1-specific gp41 antibody titer was also highly correlated with both decreased placental transfer (P = 0.0080) and decreased infant IgG (P < 0.0001). This is the first study to evaluate the relationship between maternal HIV-1 viremia, maternal HIV-1 antibody concentrations, and passive immunity among HIV-1-exposed infants. These data support the hypothesis that high HIV-1 viral load during the last trimester may impair maternofetal transfer of IgG and increases risk of measles and other serious infections among HIV-1-exposed infants.

IgG Infusions Do Not Prevent Infections in Premature Babies

Premature neonates are especially prone to nosocomial infections for many reasons, including inadequate placental transfer of IgG before 32 weeks'

Variable inhibition of placental IgG transfer in vitro with commercial IVIgG preparations

Variable inhibition of placental IgG transfer in vitro with commercial IVIgG preparations

Variable inhibition of placental IgG transfer in vitro with commercial IVgG preparations.

Maternal administration of high-dose intravenous immunoglobulin (IVIgG) for treating fetal RhD haemolytic disease and alloimmune thrombocytopenias may be beneficial. Treatment failures, even when IVIgG is used optimally, may result from product differences. Using an in vitro placental perfusion model there was significant inhibition of placental anti-D IgG transfer with three commercial IVIgG preparations where circulating maternal IgG concentrations were > 20 g/l. One IVIgG product, which was not inhibitory, had lower circulating IgG levels (16.5 +/- 0.9 g/l) and significantly reduced placental transfer of total IgG, suggesting that the reduced functional activity of IgG from IVIgG preparations may correlate with poor clinical efficacy.

The influence of prematurity and low birthweight on transplacental antibody transfer in Sri Lanka

The influence of gestational age, the neonate's birthweight, and maternal age, weight, height and parity on transplacental antibody transfer was assessed in 141 mothers from Sri Lanka and their neonates. Paired blood samples were collected from the mothers and the umbilical cords of the newborns. The sera separated from these samples were categorized as: preterm but adequate birthweight (< 37 weeks' gestation and birthweight &≥ 2500 g); term but low birthweight (≥ 37 weeks' gestation and birthweight < 2500 g); or term and adequate birthweight (≥ 37 weeks' gestation and birthweight ≥ 2500 g). Neonatal and maternal sera were assessed, in ELISA, for specific IgG antibodies against measles virus (MeV), herpes simplex virus type-1 (HSV1), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), tetanus toxoid (TT), diphtheria toxoid (DT), and Streptococcus pneumoniae (Pn) and Haemophilus influenzae type-b (Hib) capsular antigens.Placental antibody transfer to certain antibody specificities was significantly lower in preterm neonates than term neonates. Thus the ratios between geometric mean cord antibody levels and geometric mean maternal antibody levels (the antibody-transfer ratios) were lower in preterm sera than term sera, for MeV (1.51 v. 2.03; P = 0.03), HSV1 (1.29 v. 1.76; P = 0.04), VZV (0.96 v. 2.50; P = 0.01), TT (1.13 v. 1.33; P = 0.04), DT (1.03 v. 2.39; P = 0.02), Pn (0.68 v. 0.98; P=0.01) and Hib (0.58 v. 0.98; P = 0.00). Geometric mean levels of antibody to MeV, VZV, TT, DT and Pn were also significantly lower in preterm neonates than term. Compared with the values for ‘adequate-birthweight’ sera, low birthweight was independently associated with significantly lower levels of antibody transfer, for MeV (with antibody-transfer ratios of 1.51 v. 2.03; P = 0.02), VZV (0.99 v. 2.50; P = 0.03), TT (1.01 v. 1.33; P = 0.04) and DT (1.16 v. 2.39; P = 0.04), and significantly lower levels of antibodies to MeV, HSV1, VZV, TT, DT and Pn in the neonates. Maternal age, weight, height and parity had no independent influence on placental IgG transfer for antibodies to any of the pathogens investigated. These results demonstrate that prematurity and low birthweight may influence the level of maternally acquired immunity in Sri Lankan neonates.

The influence of prematurity and low birthweight on transplacental antibody transfer in Sri Lanka.

The influence of gestational age, the neonate's birthweight, and maternal age, weight, height and parity on transplacental antibody transfer was assessed in 141 mothers from Sri Lanka and their neonates. Paired blood samples were collected from the mothers and the umbilical cords of the newborns. The sera separated from these samples were categorized as: preterm but adequate birthweight (< 37 weeks' gestation and birthweight > or = 2500 g); term but low birthweight (> or = 37 weeks' gestation and birthweight < 2500 g); or term and adequate birthweight (> or = 37 weeks' gestation and birthweight > or = 2500 g). Neonatal and maternal sera were assessed, in ELISA, for specific IgG antibodies against measles virus (MeV), herpes simplex virus type-1 (HSV1), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), tetanus toxoid (TT), diphtheria toxoid (DT), and Streptococcus pneumoniae (Pn) and Haemophilus influenzae type-b (Hib) capsular antigens. Placental antibody transfer to certain antibody specificities was significantly lower in preterm neonates than term neonates. Thus the ratios between geometric mean cord antibody levels and geometric mean maternal antibody levels (the antibody-transfer ratios) were lower in preterm sera than term sera, for MeV (1.51 v. 2.03; P = 0.03), HSV1 (1.29 v. 1.76; P = 0.04), VZV (0.96 v. 2.50; P = 0.01), TT (1.13 v. 1.33; P = 0.04), DT (1.03 v. 2.39; P = 0.02), Pn (0.68 v. 0.98; P = 0.01) and Hib (0.58 v. 0.98; P = 0.00). Geometric mean levels of antibody to MeV, VZV, TT, DT and Pn were also significantly lower in preterm neonates than term. Compared with the values for 'adequate-birthweight' sera, low birthweight was independently associated with significantly lower levels of antibody transfer, for MeV (with antibody-transfer ratios of 1.51 v. 2.03; P = 0.02), VZV (0.99 v. 2.50; P = 0.03), TT (1.01 v. 1.33; P = 0.04) and DT (1.16 v. 2.39; P = 0.04) and significantly lower levels of antibodies to MeV, HSV1, VZV, TT, DT and Pn in the neonates. Maternal age, weight, height and parity had no independent influence on placental IgG transfer for antibodies to any of the pathogens investigated. These results demonstrate that prematurity and low birthweight may influence the level of maternally acquired immunity in Sri Lankan neonates.

Transmissão mãe-filho de imunoglobulinas G.

The placental transfer of immunoglobulins is made by active transport and only IgG class of immunoglobulins is transferred. In a full-term gestation IgG concentration is usually higher in the cord serum than in the mother serum. It has been shown that the ratio of cord/maternal IgG is higher when maternal IgG values are low. A series of 44 mother-child pairs from the north of Portugal were studied. Quantitative determination of IgG in all sera was made by single radial immunodiffusion and results were expressed in milligrams/deciliter (mg/dl). In the first 48 hours after delivery, mothers were interviewed and clinical, social and demographic data were collected. In 35 pairs, cord IgG exceeded the corresponding maternal concentration. The ratio of cord/maternal IgG ranged from 0.75 to 2.86 (mean 1.27). From all studied variables only maternal IgG concentration and age were correlated with that ratio. Transplacental concentration (ratio of cord/maternal IgG) was higher for lower levels of maternal IgG. Significant contribution of maternal age did not stand when a woman with extreme values of IgG and age was withdrawn from the analysis. Values found for this series of Portuguese mother-child pairs were similar to those found for other caucasian populations and are in agreement with current proposed models for placental transfer of IgG.

Vulnerability of placental antibody transfer and fetal complement synthesis to disturbance of the pregnant monkey

Maternal and fetal/infant antibody levels were assessed across pregnancy and at birth to evaluate the prenatal transmission of IgG in the rhesus monkey. Although some antibody was evident in the fetus by midpregnancy, the marked increase in IgG occurred primarily during the last two weeks of pregnancy. This delay until the end of pregnancy would result in low antibody titers in premature infants. In contrast, when gestation length was normal, the placental transfer of IgG was resistant to both dexamethasone treatment and a prolonged period of stress during pregnancy. This resiliency occurred despite an effect of prenatal stress on other aspects of infant development, including physical growth and the fetal synthesis of complement proteins.

Maternally acquired immunity in newborns from women infected by the human immunodeficiency virus.

Maternally acquired immunity was studied in 16 pairs of human immunodeficiency virus (HIV)-seropositive women and their newborns, and was compared to 18 control mother-newborn pairs. The HIV-infected women had higher IgG levels than the control subjects, but no difference was observed between newborn samples, presumably due to the limited placental IgG transfer in the HIV group. A poor type 2 poliovirus antibody transfer was also noted in this group. The population of newborns lacking demonstrable measles antibodies was higher in the HIV group than in the control group, probably because many of the HIV-infected mothers lacked measles antibodies also. These results show that maternally acquired immunity may be affected to newborns from HIV-infected women, either because of low maternal serum antibody levels or deficient transplacental transfer. If so, the measles vaccine schedule should be revised for these children and the same should be done for future passive immunization regarding fetus protection in pregnant HIV-seropositive women.

Placental transfer of IgG subclass‐specific antibodies to varicella‐zoster virus

Commercially available mouse monoclonal antibodies to human IgG subclasses (IgG 1 to IgG 4) were used in an enzyme-linked immunosorbent assay to examine the placental transfer of IgG subclass-specific antibodies to varicella-zoster virus (VZV). All 46 mothers had total IgG antibody to VZV, and an equal level of antibody was found in the cord blood. All of the mothers had high antibody activities to VZV in IgG 1 and IgG 4 subclasses. The majority of the mothers were negative for IgG 2 and IgG 3 VZV antibodies, and the level of antibody found to be positive was very low. The IgG 1 antibody activity in the cord blood was almost equal to that of the maternal, and significantly higher level of IgG 4 antibody was found in the cord than maternal blood.

The placental transfer of IgG in the cynomolgus monkey.

The placental transfer of IgG from the mother to her fetus was investigated with colony-bred cynomolgus monkeys. Very low levels of IgG were detected in sera of 84 days old fetus, indicating that transplacental transfer of IgG had started by this fetal age. Afterwards, gradual increase in the IgG level continued till 140 days of fetal age. A marked increase in the level was noted after 140 days of fetal age, during the last 4 weeks of full gestation term. Fetal anti-measles antibody increased in a pattern similar to that in the IgG level. The IgG level and anti-measles and anti-streptolysin O antibody titers of newborns never exceeded those of their mothers.