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 journalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)158-167
Number of pages10
JournalJournal of immunology (Baltimore, Md.
Issue number2
Publication statusPublished - 15 Jan 2023

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