Research output: Contribution to journal › Article › Academic › peer-review
IgG Fab Glycans Hinder FcRn-Mediated Placental Transport. / Volkov, Mikhail; Brinkhaus, Maximilian; van Schie, Karin A. et al.
In: Journal of immunology (Baltimore, Md., Vol. 210, No. 2, 15.01.2023, p. 158-167.Research output: Contribution to journal › Article › Academic › peer-review
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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.
UR - http://www.scopus.com/inward/record.url?scp=85145492568&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2200438
DO - 10.4049/jimmunol.2200438
M3 - Article
C2 - 36480251
VL - 210
SP - 158
EP - 167
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
SN - 0022-1767
IS - 2
ER -
ID: 30456433