IgG Fab Glycans Hinder FcRn-Mediated Placental Transport

Mikhail Volkov; Maximilian Brinkhaus; Karin A van Schie; Albert Bondt; Theresa Kissel; Elvera J van der Kooi; Arthur E H Bentlage; Carolien A M Koeleman; Steven W de Taeye; Ninotska I Derksen; Radboud J E M Dolhain; Ute Braig-Scherer; Tom W J Huizinga; Manfred Wuhrer; René E M Toes; Gestur Vidarsson; Diane van der Woude

doi:10.4049/jimmunol.2200438

IgG Fab Glycans Hinder FcRn-Mediated Placental Transport

Mikhail Volkov, Maximilian Brinkhaus, Karin A van Schie, Albert Bondt, Theresa Kissel, Elvera J van der Kooi, Arthur E H Bentlage, Carolien A M Koeleman, Steven W de Taeye, Ninotska I Derksen, Radboud J E M Dolhain, Ute Braig-Scherer, Tom W J Huizinga, Manfred Wuhrer, René E M Toes, Gestur Vidarsson, Diane van der Woude

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

Abstract

Abs can be glycosylated in both their Fc and Fab regions with marked effects on Ab function and binding. High levels of IgG Fab glycosylation are associated with malignant and autoimmune conditions, exemplified by rheumatoid arthritis and highly Fab-glycosylated (∼90%) anti-citrullinated protein Abs (ACPAs). Important properties of IgG, such as long half-life and placental transport, are facilitated by the human neonatal Fc receptor (hFcRn). Although it is known that glycosylation of Abs can affect binding to Fc receptors, little is known on the impact of IgG Fab glycosylation on hFcRn binding and transplacental transport. Therefore, we analyzed the interaction between hFcRn and IgG with and without Fab glycans in vitro with various methods as well as in vivo by studying placental transfer of Fab-glycosylated Abs from mothers to newborns. No effect of Fab glycosylation on IgG binding to hFcRn was found by surface plasmon resonance and hFcRn affinity chromatography. In contrast, studies in a cell membrane context revealed that Fab glycans negatively impacted IgG-hFcRn interaction. In line with this, we found that Fab-glycosylated IgGs were transported ∼20% less efficiently across the placenta. This appeared to be a general phenomenon, observed for ACPAs, non-ACPAs, as well as total IgG in rheumatoid arthritis patients and healthy controls. Our results suggest that, in a cellular context, Fab glycans inhibit IgG-hFcRn interaction and thus negatively affect the transplacental transfer of IgG. As Fab-glycosylated Abs are frequently associated with autoimmune and malignant disorders and may be potentially harmful, this might encompass a regulatory mechanism, limiting the half-life and transport of such Abs.

Original language	English
Pages (from-to)	158-167
Number of pages	10
Journal	Journal of Immunology
Volume	210
Issue number	2
DOIs	https://doi.org/10.4049/jimmunol.2200438
Publication status	Published - 15 Jan 2023
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)–funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial

Funding Information:
support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26).

Funding Information:
This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)-funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26). We thank Dr. Theo Rispens for providing the SNA+ and SNA− IVIg fractions and for fruitful discussions, as well as Gerrie Stoeken-Rijsbergen, Nivine Levarht, and Astrid Brehler for help with IgG production.

Publisher Copyright:
Copyright © 2023 by The American Association of Immunologists, Inc.

Keywords

Pregnancy
Humans
Female
Infant, Newborn
Placenta
Receptors, Fc/metabolism
Immunoglobulin G
Arthritis, Rheumatoid
Autoimmune Diseases
Histocompatibility Antigens Class I
Polysaccharides

UN SDGs

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

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10.4049/jimmunol.2200438

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Volkov, M., Brinkhaus, M., van Schie, K. A., Bondt, A., Kissel, T., van der Kooi, E. J., Bentlage, A. E. H., Koeleman, C. A. M., de Taeye, S. W., Derksen, N. I., Dolhain, R. J. E. M., Braig-Scherer, U., Huizinga, T. W. J., Wuhrer, M., Toes, R. E. M., Vidarsson, G., & van der Woude, D. (2023). IgG Fab Glycans Hinder FcRn-Mediated Placental Transport. Journal of Immunology, 210(2), 158-167. https://doi.org/10.4049/jimmunol.2200438

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title = "IgG Fab Glycans Hinder FcRn-Mediated Placental Transport",

abstract = "Abs can be glycosylated in both their Fc and Fab regions with marked effects on Ab function and binding. High levels of IgG Fab glycosylation are associated with malignant and autoimmune conditions, exemplified by rheumatoid arthritis and highly Fab-glycosylated (∼90\%) anti-citrullinated protein Abs (ACPAs). Important properties of IgG, such as long half-life and placental transport, are facilitated by the human neonatal Fc receptor (hFcRn). Although it is known that glycosylation of Abs can affect binding to Fc receptors, little is known on the impact of IgG Fab glycosylation on hFcRn binding and transplacental transport. Therefore, we analyzed the interaction between hFcRn and IgG with and without Fab glycans in vitro with various methods as well as in vivo by studying placental transfer of Fab-glycosylated Abs from mothers to newborns. No effect of Fab glycosylation on IgG binding to hFcRn was found by surface plasmon resonance and hFcRn affinity chromatography. In contrast, studies in a cell membrane context revealed that Fab glycans negatively impacted IgG-hFcRn interaction. In line with this, we found that Fab-glycosylated IgGs were transported ∼20\% less efficiently across the placenta. This appeared to be a general phenomenon, observed for ACPAs, non-ACPAs, as well as total IgG in rheumatoid arthritis patients and healthy controls. Our results suggest that, in a cellular context, Fab glycans inhibit IgG-hFcRn interaction and thus negatively affect the transplacental transfer of IgG. As Fab-glycosylated Abs are frequently associated with autoimmune and malignant disorders and may be potentially harmful, this might encompass a regulatory mechanism, limiting the half-life and transport of such Abs.",

keywords = "Pregnancy, Humans, Female, Infant, Newborn, Placenta, Receptors, Fc/metabolism, Immunoglobulin G, Arthritis, Rheumatoid, Autoimmune Diseases, Histocompatibility Antigens Class I, Polysaccharides",

author = "Mikhail Volkov and Maximilian Brinkhaus and \{van Schie\}, \{Karin A\} and Albert Bondt and Theresa Kissel and \{van der Kooi\}, \{Elvera J\} and Bentlage, \{Arthur E H\} and Koeleman, \{Carolien A M\} and \{de Taeye\}, \{Steven W\} and Derksen, \{Ninotska I\} and Dolhain, \{Radboud J E M\} and Ute Braig-Scherer and Huizinga, \{Tom W J\} and Manfred Wuhrer and Toes, \{Ren{\'e} E M\} and Gestur Vidarsson and \{van der Woude\}, Diane",

note = "Funding Information: This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)–funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial Funding Information: support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26). Funding Information: This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)-funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26). We thank Dr. Theo Rispens for providing the SNA+ and SNA− IVIg fractions and for fruitful discussions, as well as Gerrie Stoeken-Rijsbergen, Nivine Levarht, and Astrid Brehler for help with IgG production. Publisher Copyright: Copyright {\textcopyright} 2023 by The American Association of Immunologists, Inc.",

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month = jan,

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doi = "10.4049/jimmunol.2200438",

language = "English",

volume = "210",

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Volkov, M, Brinkhaus, M, van Schie, KA, Bondt, A, Kissel, T, van der Kooi, EJ, Bentlage, AEH, Koeleman, CAM, de Taeye, SW, Derksen, NI, Dolhain, RJEM, Braig-Scherer, U, Huizinga, TWJ, Wuhrer, M, Toes, REM, Vidarsson, G & van der Woude, D 2023, 'IgG Fab Glycans Hinder FcRn-Mediated Placental Transport', Journal of Immunology, vol. 210, no. 2, pp. 158-167. https://doi.org/10.4049/jimmunol.2200438

TY - JOUR

T1 - IgG Fab Glycans Hinder FcRn-Mediated Placental Transport

AU - Volkov, Mikhail

AU - Brinkhaus, Maximilian

AU - van Schie, Karin A

AU - Bondt, Albert

AU - Kissel, Theresa

AU - van der Kooi, Elvera J

AU - Bentlage, Arthur E H

AU - Koeleman, Carolien A M

AU - de Taeye, Steven W

AU - Derksen, Ninotska I

AU - Dolhain, Radboud J E M

AU - Braig-Scherer, Ute

AU - Huizinga, Tom W J

AU - Wuhrer, Manfred

AU - Toes, René E M

AU - Vidarsson, Gestur

AU - van der Woude, Diane

N1 - Funding Information: This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)–funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial Funding Information: support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26). Funding Information: This work was supported by the ReumaNederland Project LLP5), as well as by the Innovative Medicines Initiative (IMI)-funded projects RTCure 777357 and Target-to-B LSHM18055-SGF (to R.E.M.T.). The work of M.B. and E.J.d.v.K. was funded by argenx. The PreCARA study was supported by UCB where UCB provided financial support; moreover, the PreCARA study was supported by the Dutch Arthritis Foundation (ReumaNederland Project LLP26). We thank Dr. Theo Rispens for providing the SNA+ and SNA− IVIg fractions and for fruitful discussions, as well as Gerrie Stoeken-Rijsbergen, Nivine Levarht, and Astrid Brehler for help with IgG production. Publisher Copyright: Copyright © 2023 by The American Association of Immunologists, Inc.

PY - 2023/1/15

Y1 - 2023/1/15

N2 - Abs can be glycosylated in both their Fc and Fab regions with marked effects on Ab function and binding. High levels of IgG Fab glycosylation are associated with malignant and autoimmune conditions, exemplified by rheumatoid arthritis and highly Fab-glycosylated (∼90%) anti-citrullinated protein Abs (ACPAs). Important properties of IgG, such as long half-life and placental transport, are facilitated by the human neonatal Fc receptor (hFcRn). Although it is known that glycosylation of Abs can affect binding to Fc receptors, little is known on the impact of IgG Fab glycosylation on hFcRn binding and transplacental transport. Therefore, we analyzed the interaction between hFcRn and IgG with and without Fab glycans in vitro with various methods as well as in vivo by studying placental transfer of Fab-glycosylated Abs from mothers to newborns. No effect of Fab glycosylation on IgG binding to hFcRn was found by surface plasmon resonance and hFcRn affinity chromatography. In contrast, studies in a cell membrane context revealed that Fab glycans negatively impacted IgG-hFcRn interaction. In line with this, we found that Fab-glycosylated IgGs were transported ∼20% less efficiently across the placenta. This appeared to be a general phenomenon, observed for ACPAs, non-ACPAs, as well as total IgG in rheumatoid arthritis patients and healthy controls. Our results suggest that, in a cellular context, Fab glycans inhibit IgG-hFcRn interaction and thus negatively affect the transplacental transfer of IgG. As Fab-glycosylated Abs are frequently associated with autoimmune and malignant disorders and may be potentially harmful, this might encompass a regulatory mechanism, limiting the half-life and transport of such Abs.

AB - Abs can be glycosylated in both their Fc and Fab regions with marked effects on Ab function and binding. High levels of IgG Fab glycosylation are associated with malignant and autoimmune conditions, exemplified by rheumatoid arthritis and highly Fab-glycosylated (∼90%) anti-citrullinated protein Abs (ACPAs). Important properties of IgG, such as long half-life and placental transport, are facilitated by the human neonatal Fc receptor (hFcRn). Although it is known that glycosylation of Abs can affect binding to Fc receptors, little is known on the impact of IgG Fab glycosylation on hFcRn binding and transplacental transport. Therefore, we analyzed the interaction between hFcRn and IgG with and without Fab glycans in vitro with various methods as well as in vivo by studying placental transfer of Fab-glycosylated Abs from mothers to newborns. No effect of Fab glycosylation on IgG binding to hFcRn was found by surface plasmon resonance and hFcRn affinity chromatography. In contrast, studies in a cell membrane context revealed that Fab glycans negatively impacted IgG-hFcRn interaction. In line with this, we found that Fab-glycosylated IgGs were transported ∼20% less efficiently across the placenta. This appeared to be a general phenomenon, observed for ACPAs, non-ACPAs, as well as total IgG in rheumatoid arthritis patients and healthy controls. Our results suggest that, in a cellular context, Fab glycans inhibit IgG-hFcRn interaction and thus negatively affect the transplacental transfer of IgG. As Fab-glycosylated Abs are frequently associated with autoimmune and malignant disorders and may be potentially harmful, this might encompass a regulatory mechanism, limiting the half-life and transport of such Abs.

KW - Pregnancy

KW - Humans

KW - Female

KW - Infant, Newborn

KW - Placenta

KW - Receptors, Fc/metabolism

KW - Immunoglobulin G

KW - Arthritis, Rheumatoid

KW - Autoimmune Diseases

KW - Histocompatibility Antigens Class I

KW - Polysaccharides

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DO - 10.4049/jimmunol.2200438

M3 - Article

C2 - 36480251

SN - 0022-1767

VL - 210

SP - 158

EP - 167

JO - Journal of Immunology

JF - Journal of Immunology

IS - 2

ER -

IgG Fab Glycans Hinder FcRn-Mediated Placental Transport

Abstract

Bibliographical note

Keywords

UN SDGs

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