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• W2950802088 abstract "•NK cell-activating antibodies are selectively transferred across the placenta•Digalactosylated Fc glycans are preferentially transferred across the placenta•Digalactosylated antibodies bind more effectively to FcRn and FCGR3A•Although immature, neonatal NK cells are highly responsive to immune complexes Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. Vaccines, one of the most impactful public health interventions, have reduced global morbidity and mortality against infectious disease (Centers for Disease Control and Prevention (CDC), 1999Centers for Disease Control and Prevention (CDC)Impact of vaccines universally recommended for children--United States, 1990-1998.MMWR Morb. Mortal. Wkly. Rep. 1999; 48: 243-248Google Scholar, Pulendran and Ahmed, 2011Pulendran B. Ahmed R. Immunological mechanisms of vaccination.Nat. Immunol. 2011; 12: 509-517Google Scholar). However, vaccines have been less effective at reducing infection-related deaths in newborns (Amenyogbe et al., 2015Amenyogbe N. Levy O. Kollmann T.R. Systems vaccinology: a promise for the young and the poor.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; 370: 20140340Google Scholar). Compromised vaccine-induced immunity in infants has been attributed to the potentially tolerogenic nature of the neonatal immune system (Yu et al., 2018Yu J.C. Khodadadi H. Malik A. Davidson B. Salles É.D.S.L. Bhatia J. Hale V.L. Baban B. Innate Immunity of Neonates and Infants.Front. Immunol. 2018; 9: 1759Google Scholar), the reduced functionality of newborn immune cells (Lee and Lin, 2013Lee Y.C. Lin S.J. Neonatal natural killer cell function: relevance to antiviral immune defense.Clin. Dev. Immunol. 2013; 2013: 427696Google Scholar, Yu et al., 2018Yu J.C. Khodadadi H. Malik A. Davidson B. Salles É.D.S.L. Bhatia J. Hale V.L. Baban B. Innate Immunity of Neonates and Infants.Front. Immunol. 2018; 9: 1759Google Scholar), and dampened immunity from pre-existing maternal antibodies (Saso and Kampmann, 2017Saso A. Kampmann B. Vaccine responses in newborns.Semin. Immunopathol. 2017; 39: 627-642Google Scholar). Strategies have been proposed to drive more effective immunity in newborns, including designing vaccines and adjuvants tailored to neonates (Saso and Kampmann, 2017Saso A. Kampmann B. Vaccine responses in newborns.Semin. Immunopathol. 2017; 39: 627-642Google Scholar, Whittaker et al., 2018Whittaker E. Goldblatt D. McIntyre P. Levy O. Neonatal Immunization: Rationale, Current State, and Future Prospects.Front. Immunol. 2018; 9: 532Google Scholar). Maternal immunization, aimed at enhancing maternal-to-fetal transfer of antibodies, has shown significant promise in boosting newborn immunity (Forsyth et al., 2015Forsyth K. Plotkin S. Tan T. Wirsing von König C.H. Strategies to decrease pertussis transmission to infants.Pediatrics. 2015; 135: e1475-e1482Google Scholar), providing a non-invasive strategy to enhance immunity in this vulnerable population. However, epidemiologic studies focusing on matched mother:fetus pairs have found that the extent of immunity transferred varies significantly by antigen (Fu et al., 2016Fu C. Lu L. Wu H. Shaman J. Cao Y. Fang F. Yang Q. He Q. Yang Z. Wang M. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies.Sci. Rep. 2016; 6: 38874Google Scholar, Palmeira et al., 2012Palmeira P. Quinello C. Silveira-Lessa A.L. Zago C.A. Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies.Clin. Dev. Immunol. 2012; 2012: 985646Google Scholar). Specifically, while measles-specific antibodies are transferred efficiently (>100%), antibodies targeting other pathogens, including poliovirus and Coxsackie viruses, are less efficiently transferred (Fu et al., 2016Fu C. Lu L. Wu H. Shaman J. Cao Y. Fang F. Yang Q. He Q. Yang Z. Wang M. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies.Sci. Rep. 2016; 6: 38874Google Scholar). The neonatal Fc receptor, FcRn, is responsible for receptor-mediated trans-placental transport of IgG (Roopenian and Akilesh, 2007Roopenian D.C. Akilesh S. FcRn: the neonatal Fc receptor comes of age.Nat. Rev. Immunol. 2007; 7: 715-725Google Scholar). FcRn binds IgG in a pH-dependent manner within acidified endosomes in syncytiotrophoblasts and transits IgG to the interstitial space between the maternal and fetal circulation (Jennewein et al., 2017Jennewein M.F. Abu-Raya B. Jiang Y. Alter G. Marchant A. Transfer of maternal immunity and programming of the newborn immune system.Semin. Immunopathol. 2017; 39: 605-613Google Scholar, Roopenian and Akilesh, 2007Roopenian D.C. Akilesh S. FcRn: the neonatal Fc receptor comes of age.Nat. Rev. Immunol. 2007; 7: 715-725Google Scholar). While FcRn binds to the CH3 domain of all IgG subclasses (Vidarsson et al., 2014Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front. Immunol. 2014; 5: 520Google Scholar), differences in IgG subclass transfer have been noted (Einarsdottir et al., 2014Einarsdottir H.K. Stapleton N.M. Scherjon S. Andersen J.T. Rispens T. van der Schoot C.E. Vidarsson G. On the perplexingly low rate of transport of IgG2 across the human placenta.PLoS ONE. 2014; 9: e108319Google Scholar, Vidarsson et al., 2014Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front. Immunol. 2014; 5: 520Google Scholar), including enhanced binding to IgG1 and differential transfer efficiencies of allotypic variants of IgG3 known to bind FcRn with different affinities (Stapleton et al., 2011Stapleton N.M. Andersen J.T. Stemerding A.M. Bjarnarson S.P. Verheul R.C. Gerritsen J. Zhao Y. Kleijer M. Sandlie I. de Haas M. et al.Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential.Nat. Commun. 2011; 2: 599Google Scholar, Vidarsson et al., 2014Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front. Immunol. 2014; 5: 520Google Scholar). Given that FcRn binding occurs in the CH3 domain, IgG transport, and particularly antigen-specific IgG1 transport, should occur at the same rate. However, a transfer hierarchy exists across antigen-specific antibody subpopulations (Fu et al., 2016Fu C. Lu L. Wu H. Shaman J. Cao Y. Fang F. Yang Q. He Q. Yang Z. Wang M. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies.Sci. Rep. 2016; 6: 38874Google Scholar). Thus, other qualitative antibody features are likely to govern differential transfer of particular antibody populations. With the re-emergence of pertussis infections among newborns (Winter et al., 2014Winter K. Glaser C. Watt J. Harriman K. Centers for Disease Control and Prevention (CDC)Pertussis epidemic--California, 2014.MMWR Morb. Mortal. Wkly. Rep. 2014; 63: 1129-1132Google Scholar), efforts have emerged to understand the transfer of pertussis-specific immunity to neonates. Thus, we aimed to dissect the profile of transferred antibodies, focused on defining whether Fc features influence pertussis-specific antibody placental transfer, to help inform maternal vaccine campaigns and next-generation vaccine design. A global, unbiased, and antigen-specific systems serology antibody profiling approach was applied (Chung and Alter, 2017Chung A.W. Alter G. Systems serology: profiling vaccine induced humoral immunity against HIV.Retrovirology. 2017; 14: 57Google Scholar) to deeply and comprehensively define the specific qualitative Fc features of antibodies found in maternal and cord blood on the day of birth. Striking differences were observed in the functional profile of antibodies transferred to neonates, with preferential transfer of natural killer (NK) cell-activating antibodies. This preferential transfer, observed across many antigens, was linked to antigen-specific Fc-glycan profiles on the Fc-domain of antigen-specific antibodies, as well as to enhanced binding to FcRn and FCGR3A, two receptors found to be co-localized on syncytiotrophoblasts. The transfer of FCGR3A-binding, NK cell-activating antibodies coincided with the presence of fully competent NK cells in the cord blood, compared to less competent cord blood neutrophils. These data suggest an evolution of the placenta to selectively transfer antibodies with the most functional potential in the neonatal immune context to better provide protection to neonates. The placenta preferentially transfers IgG antibodies (Vidarsson et al., 2014Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front. Immunol. 2014; 5: 520Google Scholar). Although FcRn binds to all IgG subclasses, differences in transfer efficiencies have been noted across the subclasses (IgG1 > 4 > 3 > 2) (Palmeira et al., 2012Palmeira P. Quinello C. Silveira-Lessa A.L. Zago C.A. Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies.Clin. Dev. Immunol. 2012; 2012: 985646Google Scholar, Vidarsson et al., 2014Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front. Immunol. 2014; 5: 520Google Scholar, Wilcox et al., 2017Wilcox C.R. Holder B. Jones C.E. Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy.Front. Immunol. 2017; 8: 1294Google Scholar) and across IgG1 populations (Fu et al., 2016Fu C. Lu L. Wu H. Shaman J. Cao Y. Fang F. Yang Q. He Q. Yang Z. Wang M. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies.Sci. Rep. 2016; 6: 38874Google Scholar), raising the possibility for FcRn-mediated preferential selection of IgG1 transfer. Thus, to begin to define the characteristics of antibodies that are preferentially transferred across the placenta, we aimed to define whether the transferred antibodies possessed any qualitative functional differences from those in mothers, focusing on pertussis-specific immunity. Using samples drawn from a cohort of 14 mother:cord pairs on the day of birth (Figure S1; Table S1), we compared the functional activity of antibodies specific to the four pertussis antigens included in the Tdap vaccine: pertactin (PTN), filamentous hemagglutinin (FHA), fimbriae 2/3 (FIM), and pertussis toxin (PTX) (Edwards and Berbers, 2014Edwards K.M. Berbers G.A. Immune responses to pertussis vaccines and disease.J. Infect. Dis. 2014; 209: S10-S15Google Scholar). While significant differences existed in the magnitude of antibody-dependent monocyte phagocytosis (ADCP) across the pertussis antigens, including higher levels of PTX compared to FIM-specific phagocytic antibodies in mothers (Figures 1A and 1B ), overall transfer of phagocytic antibodies was relatively stable across all specificities (Figures 1B and 1C). Similarly, heterogeneous magnitudes of antibody-dependent neutrophil phagocytosis (ADNP) were observed across antigen specificities (Figures 1D and 1E). However, significant differences were observed in antigen-specific ADNP transfer across specificities (Figure 1F), where FIM- and PTX-ADNP-inducing antibodies were transferred with high efficiency compared to FHA- and PTN-specific antibodies. These data point to heterogeneity in overall levels and transfer efficiencies across pertussis-specific monocyte and neutrophil recruiting antibodies, driven in an antigen-specific manner. To define whether the same variability would be observed across NK cell-activating antibodies, we examined the ability of the maternal and cord antibodies to drive NK cell degranulation (CD107a upregulation), NK cell cytokine secretion (interferon-γ [IFNγ]), and chemokine secretion (macrophage inflammatory protein-1β [MIP-1β]). Strikingly, while lower levels of FHA-specific NK cell-activating antibodies were observed across all mothers, all mothers transferred elevated levels of NK cell-activating antibodies (across all three degranulation readouts) (Figures 1H–1J), albeit at different transfer ratios (Figures 1K–1M). Across all antigen specificities and mother:cord pairs, enhanced antibody transfer was consistently observed for NK cell-activating antibodies. Thus, our data demonstrate the preferential transfer of antibodies involved in NK cell activation to neonates, providing the first evidence of a functional, potentially Fc-specific, sieving across the placenta. To confirm that the preferential transfer of NK cell recruiting antibodies could be extended beyond pertussis-specific immunity, the functional characteristics of virus-specific antibodies were interrogated. Similar to the results observed for pertussis, significant variability existed in the levels of functional antibodies to respiratory syncytial virus (RSV) and influenza (Flu) across mothers (Figures 2A and 2B ), accompanied by variable ADCP and ADNP transfer across each antigen (Figures 2A–2D). Conversely, enhanced transfer of NK cell IFNγ- and MIP-1β-inducing antibodies were transferred across both specificities, as were degranulation (CD107a)-inducing antibodies to RSV (Figures 2E, 2F, and S2A). Additionally, the NK cell transfer signature was further validated in a second, geographically distinct cohort across pertussis, RSV, and measles, highlighting again, preferential transfer of NK-activating antibodies to neonates (Figure S2B). Thus, despite heterogeneous baseline pathogen-specific functional antibody levels, NK-cell-activating antibodies are consistently preferentially transferred across the placenta.Figure S2NK Degranulation Selection across Cohorts, Related to Figure 2Show full captionA. The dot-plots show NK-dependent degranulation to RSV pre-fusion F antigen plotted as the percentage of NK cells positive for CD107a, IFNγ and MIP-1β. B. The dot-plots show 28 mother:cord pairs from cohort 2 ability to drive NK degranulation (CD107a expression) in response to Pertussis toxin (PTX), Pertactin (PTN) and measles virus antigens. Significance in A, B evaluated for NK degranulation with paired t test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. C. A MLPLSDA was used to analyze the features separating mother and cord blood samples for RSV pre-fusion, RSV post-fusion and flu-specific antibody profiles. Each dot represents an individual blood sample (mother or cord) tested for one of these three antigens. LV1 and LV2 account for 18% and 22% of the variability in functional and glycan profiles across the antigens. The separation of mothers and cord is largely captured on LV1, which explains 36% of the Y variance in the direction of the maternal:cord separation. 5-fold cross validation was performed on the data, obtaining a Cross Validation (CV) accuracy of 96%. D. The bar graph represents the loading plot for LV1 of the MLPLSDA, that captures variation across mother and cord. The predictors are ordered according to their VIP scores. E. MLPLSDA was used to define the features that separate mother and cord blood samples for all seven antigens tested. Each dot represents an individual blood sample (mother or cord) tested for one of these three antigens. LV1 and LV2 account for 14% and 17% of the variability. The separation between mothers and cords is largely captured on LV1, which explains 37% of the Y variance in the direction of the maternal:cord separation. 5-fold cross validation was performed on the data, resulting in a CV accuracy of 94%. F. The bar graph represents the loading plot for LV1 of the MLPLSDA, that captures variation across mother and cord. The predictors are ordered according to their VIP scores. Significance across functional comparisons was defined using a paired t test, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A. The dot-plots show NK-dependent degranulation to RSV pre-fusion F antigen plotted as the percentage of NK cells positive for CD107a, IFNγ and MIP-1β. B. The dot-plots show 28 mother:cord pairs from cohort 2 ability to drive NK degranulation (CD107a expression) in response to Pertussis toxin (PTX), Pertactin (PTN) and measles virus antigens. Significance in A, B evaluated for NK degranulation with paired t test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. C. A MLPLSDA was used to analyze the features separating mother and cord blood samples for RSV pre-fusion, RSV post-fusion and flu-specific antibody profiles. Each dot represents an individual blood sample (mother or cord) tested for one of these three antigens. LV1 and LV2 account for 18% and 22% of the variability in functional and glycan profiles across the antigens. The separation of mothers and cord is largely captured on LV1, which explains 36% of the Y variance in the direction of the maternal:cord separation. 5-fold cross validation was performed on the data, obtaining a Cross Validation (CV) accuracy of 96%. D. The bar graph represents the loading plot for LV1 of the MLPLSDA, that captures variation across mother and cord. The predictors are ordered according to their VIP scores. E. MLPLSDA was used to define the features that separate mother and cord blood samples for all seven antigens tested. Each dot represents an individual blood sample (mother or cord) tested for one of these three antigens. LV1 and LV2 account for 14% and 17% of the variability. The separation between mothers and cords is largely captured on LV1, which explains 37% of the Y variance in the direction of the maternal:cord separation. 5-fold cross validation was performed on the data, resulting in a CV accuracy of 94%. F. The bar graph represents the loading plot for LV1 of the MLPLSDA, that captures variation across mother and cord. The predictors are ordered according to their VIP scores. Significance across functional comparisons was defined using a paired t test, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. To begin to define the specific biophysical characteristics of antibodies that are selectively sieved via the placenta, we next examined the transfer of both antigen-specific IgG subclass and Fc glycosylation, which both influence Fc effector functions (Davies et al., 2001Davies J. Jiang L. Pan L.Z. LaBarre M.J. Anderson D. Reff M. Expression of GnTIII in a recombinant anti-CD20 CHO production cell line: Expression of antibodies with altered glycoforms leads to an increase in ADCC through higher affinity for FC gamma RIII.Biotechnol. Bioeng. 2001; 74: 288-294Google Scholar, Jennewein and Alter, 2017Jennewein M.F. Alter G. The Immunoregulatory Roles of Antibody Glycosylation.Trends Immunol. 2017; 38: 358-372Google Scholar). As expected, total IgG was enhanced in the cords across the four pertussis antigens for all pairs (Figure 3A). IgG1 were transferred preferentially (Figure 3B), whereas, IgG2, IgG3, and IgG4 levels were largely equivalent across the mother and cord, with equivalent or lower transfer ratios across antigens (Figure 3B). As previously described (Fu et al., 2016Fu C. Lu L. Wu H. Shaman J. Cao Y. Fang F. Yang Q. He Q. Yang Z. Wang M. Placental antibody transfer efficiency and maternal levels: specific for measles, coxsackievirus A16, enterovirus 71, poliomyelitis I-III and HIV-1 antibodies.Sci. Rep. 2016; 6: 38874Google Scholar), differences were detected in transfer ratios across antigen specificities, with reduced transfer of FIM-specific IgG1 responses relative to other antigens, again highlighting qualitative differences in antigen-specific antibody transfer, beyond subclass differences, that may account for differences in transfer ratios. Importantly, while these data confirm the preferential transfer of IgG1, they fail to explain why some antigen specificities and functions transfer more efficiently than others. Beyond IgG subclass effects on Fc receptor (FcR) binding, Fc glycosylation is also linked to changes in regulating antibody effector function via altered FcR affinity (Jennewein and Alter, 2017Jennewein M.F. Alter G. The Immunoregulatory Roles of Antibody Glycosylation.Trends Immunol. 2017; 38: 358-372Google Scholar). While univariate analyses pointed to significant changes in Fc-galactosylation across mother:cord pairs (Figures 3D and S3), we explored Fc-glycan-driven sieving using transfer efficiencies (Figures 3E–3G and S4). Both bulk (all IgG in plasma) and FHA-specific agalactosylated (G0) antibodies were transferred poorly (Figures 3D–3F). Conversely, digalactosylated (G2) and total galactosylated (G) bulk and total galactosylated (G) FHA-specific antibodies were transferred preferentially to the cord (Figures 3E and 3F). Further comparison across antibody populations highlighted consistent inhibition of the transfer of agalactosylated and bisected antibodies and enhanced transfer of galactosylated and sialylated antibodies across bulk and most antigen-specific antibody populations, except PTX-specific antibodies (Figures 3G and S4). Combined, these data point to a potentially critical role for Fc glycosylation, in addition to subclass, in placental sieving of antibodies.Figure S4Transfer Ratio of Antigen-Specific Fc-Glycans, Related to Figure 3Show full captionA. The whisker plots show the transfer ratio (cord divided by mother) for each of the major Fc-glycan profiles for FIM, PTX and PTN specific antibodies. B,C. Representative raw CE plots highlight differences in mother:cord glycan profiles. A dotted line is centered at the top of the G0F peak to show relationships between the G0F, G2S1F and G2F peaks. D-G. The dot-plot shows mother to cord transfer of one of the most variable peaks, G2S1F., across all four pertussis antigens (D), FHA specific (E), PTN specific (F), and PTX specific (G). Statistics for transfer ratio were evaluated using a Wilcoxon signed rank test, variation of median from zero with Bonferroni correction. P values below 0.007 were considered significant. For G2S1F transfer statistics, a Mann-Whitney test was used, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A. The whisker plots show the transfer ratio (cord divided by mother) for each of the major Fc-glycan profiles for FIM, PTX and PTN specific antibodies. B,C. Representative raw CE plots highlight differences in mother:cord glycan profiles. A dotted line is centered at the top of the G0F peak to show relationships between the G0F, G2S1F and G2F peaks. D-G. The dot-plot shows mother to cord transfer of one of the most variable peaks, G2S1F., across all four pertussis antigens (D), FHA specific (E), PTN specific (F), and PTX specific (G). Statistics for transfer ratio were evaluated using a Wilcoxon signed rank test, variation of median from zero with Bonferroni correction. P values below 0.007 were considered significant. For G2S1F transfer statistics, a Mann-Whitney test was used, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. To gain a deeper appreciation for the key Fc signatures linked to antibody transfer, a multi-level partial least-squares discriminant analysis (MLPLSDA) was used. This analysis was aimed at defining the antibody features, independent of overall mother:cord pair variation, that contributed to the sieving effect (Westerhuis et al., 2010Westerhuis J.A. van Velzen E.J. Hoefsloot H.C. Smilde A.K. Multivariate paired data analysis: multilevel PLSDA versus OPLSDA.Metabolomics. 2010; 6: 119-128Google Scholar). Clear separation was observed across the maternal and cord antibody profiles (Figure 4A). Features were then ranked based on their overall contribution to separating the mother:cord Fc-profiles (Figure 4B). In agreement with the univariate analysis and non-paired conventional orthogonalized PLSDA analysis (Figures S5A and S5B), the ability of antibodies to drive NK cell activation were among the top 3 enriched features in the cord blood antibody profile. Additionally, the ability to drive neutrophil phagocytosis, IgG1 levels, and particular antigen-specific glycans were among the top features enriched in the cord antibody profiles. Conversely, monogalactosylated glycans (G1F/GIFB) and the ability to drive monocyte phagocytosis (ADCP) were retained in the mother’s plasma. Furthermore, validation on RSV-specific and Flu-specific antibody profiles, separately, as well as simultaneously across all seven tested antigens, replicated the clear split between intra-pair mother:cord antibody profiles, always driven by NK cell function and glycan patterns (G2S1F predominantly) (Figures S2C–S2F). These data provide a first glimpse of the individual functional and biophysical characteristics associated with placental transfer, across an array of antigen-specificities, and point to galactosylation as a key predictor of placental sieving.Figure S5Computational Analysis of Paired Maternal:Cord Samples, Related to Figure 5Show full captionAn OPLSDA was used to analyze the features separating mother and cord blood samples. Each dot represents an individual blood sample (mother or cord) tested for one of the four antigens. Latent variable 1 (LV1) and LV2 account for 17.5% and 20.8% of the variability in the analysis, respectively. The separation of mothers and cords was mostly captured on LV1, capturing 21% of Y-variation. Conversely, LV2 largely captured the variability in the antibody profiles that do not contribute to the difference in maternal and cord blood. 5-fold CV was performed on the data, obtaining a CV accuracy of 64%. B. The bar graph represents the loading plot for LV1 of the OPLSDA, that captured variation across mother:cord. The predictors are ordered according to their VIP scores. Features are colored according to feature type; functions (pink), glycans (red), subclasses (purple) and FcR binding (blue). C. A network was constructed based on the pairwise correlation coefficients between the 22 biophysical features and functional responses. Edges are weighted using the significant correlation coefficients, ρij, after removing the one with p value > 0.05.View Large Image Figure ViewerDownload Hi-res image Download (PPT) An OPLSDA was used to analyze the features separating mother and cord blood samples. Each dot represents an individual blood sample (mother or cord) tested for one of the four antigens. Latent variable 1 (LV1) and LV2 account for 17.5% and 20.8% of the variability in the analysis, respectively. The separation of mothers and cords was mostly captured on LV1, capturing 21% of Y-variation. Conversely, LV2 largely captured the variability in the antibody profiles that do not contribute to the difference in maternal and cord blood. 5-fold CV was performed on the data, obtaining a CV accuracy of 64%. B. The bar graph represents the loading plot for LV1 of the OPLSDA, that captured variation across mother:cord. The predictors are ordered according to their VIP scores. Features are colored according to feature type; functions (pink), glycans (red), subclasses (purple) and FcR binding (blue). C. A network was constructed based on the pairwise correlation coefficients betwee" @default.
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• W2950802088 title "Fc Glycan-Mediated Regulation of Placental Antibody Transfer" @default.
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• W2950802088 doi "https://doi.org/10.1016/j.cell.2019.05.044" @default.
• W2950802088 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6741440" @default.
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