Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Madeleine F. Jennewein; Ilona Goldfarb; Sepideh Dolatshahi; Patrick Gerard Cormac Cosgrove; Francesca J. Noelette; Marina Krykbaeva; Jishnu Das; Aniruddh Sarkar; Matthew J. Gorman; Stephanie Fischinger; Carolyn M. Boudreau; Joelle Brown; Jennifer H. Cooperrider; Jasneet Aneja; Todd J. Suscovich; Barney S. Graham; Georg M. Lauer; Tessa Goetghebuer; Arnaud Marchant; Douglas Lauffenburger; Arthur Y. Kim; Laura E. Riley; Galit Alter

doi:10.1016/j.cell.2019.05.044

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Madeleine F. Jennewein, Ilona Goldfarb, Sepideh Dolatshahi, Patrick Gerard Cormac Cosgrove, Francesca J. Noelette, Marina Krykbaeva, Jishnu Das, Aniruddh Sarkar, Matthew J. Gorman, Stephanie Fischinger, Carolyn M. Boudreau, Joelle Brown, Jennifer H. Cooperrider, Jasneet Aneja, Todd J. Suscovich, Barney S. Graham, Georg M. Lauer, Tessa Goetghebuer, Arnaud Marchant, Douglas LauffenburgerArthur Y. Kim, Laura E. Riley^*, Galit Alter

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

Abstract

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. Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate.

Original language	English (US)
Pages (from-to)	202-215.e14
Journal	Cell
Volume	178
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.05.044
State	Published - Jun 27 2019

Funding

We would like to thank Adam Barb for his insightful thoughts. This work was supported by the Ragon Institute , the Samana Cay MGH scholar program , and NIH grants AI080289 ( 5R37AI080289-09 ), AI102660-01 ( 5R01AI102660-04 ), and AI129797-01 ( 1R01A1129797-01 ). We would also like to acknowledge Harvard CFAR for ongoing support ( P30 AI060354-02 ). We would like to thank Adam Barb for his insightful thoughts. This work was supported by the Ragon Institute, the Samana Cay MGH scholar program, and NIH grants AI080289 (5R37AI080289-09), AI102660-01 (5R01AI102660-04), and AI129797-01 (1R01A1129797-01). We would also like to acknowledge Harvard CFAR for ongoing support (P30 AI060354-02). Conceptualization, M.F.J. I.G. A.K. L.E.R. and G.A.; Methodology, M.F.J. and G.A.; Formal Analysis, S.D. and J.D.; Investigation, M.F.J. I.G. C.C. F.J.N. M.K. A.S. M.G. S.F. C.B. J.B. J.H.C. and J.A.; Resources, I.G. B.G. G.M.L. T.G. A.M. A.Y.K. and L.E.R.; Writing, M.F.J. T.J.S. and G.A. Supervision, D.L. A.Y.K. L.E.R. and G.A.; Funding Acquisition, G.A. The authors declare no competing interests

Keywords

ADCC
antibody functionality
antibody glycosylation
maternal vaccination
neonatal immunology
trans-placental transfer

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2019.05.044

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Jennewein, M. F., Goldfarb, I., Dolatshahi, S., Cosgrove, P. G. C., Noelette, F. J., Krykbaeva, M., Das, J., Sarkar, A., Gorman, M. J., Fischinger, S., Boudreau, C. M., Brown, J., Cooperrider, J. H., Aneja, J., Suscovich, T. J., Graham, B. S., Lauer, G. M., Goetghebuer, T., Marchant, A., ... Alter, G. (2019). Fc Glycan-Mediated Regulation of Placental Antibody Transfer. Cell, 178(1), 202-215.e14. https://doi.org/10.1016/j.cell.2019.05.044

@article{5854984a4b984ca88655c477e4cb9916,

title = "Fc Glycan-Mediated Regulation of Placental Antibody Transfer",

abstract = "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. Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate.",

keywords = "ADCC, antibody functionality, antibody glycosylation, maternal vaccination, neonatal immunology, trans-placental transfer",

author = "Jennewein, {Madeleine F.} and Ilona Goldfarb and Sepideh Dolatshahi and Cosgrove, {Patrick Gerard Cormac} and Noelette, {Francesca J.} and Marina Krykbaeva and Jishnu Das and Aniruddh Sarkar and Gorman, {Matthew J.} and Stephanie Fischinger and Boudreau, {Carolyn M.} and Joelle Brown and Cooperrider, {Jennifer H.} and Jasneet Aneja and Suscovich, {Todd J.} and Graham, {Barney S.} and Lauer, {Georg M.} and Tessa Goetghebuer and Arnaud Marchant and Douglas Lauffenburger and Kim, {Arthur Y.} and Riley, {Laura E.} and Galit Alter",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

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doi = "10.1016/j.cell.2019.05.044",

language = "English (US)",

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Jennewein, MF, Goldfarb, I, Dolatshahi, S, Cosgrove, PGC, Noelette, FJ, Krykbaeva, M, Das, J, Sarkar, A, Gorman, MJ, Fischinger, S, Boudreau, CM, Brown, J, Cooperrider, JH, Aneja, J, Suscovich, TJ, Graham, BS, Lauer, GM, Goetghebuer, T, Marchant, A, Lauffenburger, D, Kim, AY, Riley, LE & Alter, G 2019, 'Fc Glycan-Mediated Regulation of Placental Antibody Transfer', Cell, vol. 178, no. 1, pp. 202-215.e14. https://doi.org/10.1016/j.cell.2019.05.044

TY - JOUR

T1 - Fc Glycan-Mediated Regulation of Placental Antibody Transfer

AU - Jennewein, Madeleine F.

AU - Goldfarb, Ilona

AU - Dolatshahi, Sepideh

AU - Cosgrove, Patrick Gerard Cormac

AU - Noelette, Francesca J.

AU - Krykbaeva, Marina

AU - Das, Jishnu

AU - Sarkar, Aniruddh

AU - Gorman, Matthew J.

AU - Fischinger, Stephanie

AU - Boudreau, Carolyn M.

AU - Brown, Joelle

AU - Cooperrider, Jennifer H.

AU - Aneja, Jasneet

AU - Suscovich, Todd J.

AU - Graham, Barney S.

AU - Lauer, Georg M.

AU - Goetghebuer, Tessa

AU - Marchant, Arnaud

AU - Lauffenburger, Douglas

AU - Kim, Arthur Y.

AU - Riley, Laura E.

AU - Alter, Galit

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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. Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate.

AB - 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. Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate.

KW - ADCC

KW - antibody functionality

KW - antibody glycosylation

KW - maternal vaccination

KW - neonatal immunology

KW - trans-placental transfer

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DO - 10.1016/j.cell.2019.05.044

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AN - SCOPUS:85067640096

SN - 0092-8674

VL - 178

SP - 202-215.e14

JO - Cell

JF - Cell

IS - 1

ER -

Fc Glycan-Mediated Regulation of Placental Antibody Transfer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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