Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport

Stapleton, Nigel M.; Armstrong-Fisher, S.S.; Andersen, Jan Terje; Schoot, C. Ellen van der; Porter, Charlene; Page, K.R.; Falconer, Donald W.; Haas, Masja de; Williamson, Lorna M.; Clark, Mike; Vidarsson, Gestur; Armour, Kathryn L.

doi:10.1016/j.molimm.2018.01.006

Cited by 17 publications

(14 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, deglycosylated IgGs were transported in mice [ 84 ]. Furthermore, a comparison of glycosylation patterns between fetal and maternal IgG by Stapelton et al in 2018 concluded that IgG transport was not glycosylation selective [ 85 ]. Regardless, the differences in permeation rate between WT and DG IgG, together with the differential transport of IgG subclasses described in several studies, suggests that there is at least one factor X involved in IgG transport in the nasal mucosa in addition to FcRn [ 61 , 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

et al. 2020

View full text Add to dashboard Cite

Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa. IgGs were used in their wild type and deglycosylated form to investigate the impact of glycosylation. Further, the expression of FcRn and Fc-gamma receptor (FCGR) and their interaction with IgG were analyzed. Comparable permeation rates for human and porcine IgG were observed in OEPC, which display the highest expression of FcRn. Only traces of porcine IgGs could be recovered at the basolateral compartment in ex vivo olfactory tissue, while human IgGs reached far higher levels. Deglycosylated human IgG showed significantly higher permeation in comparison to the wild type in RPMI 2650 and OEPC, but insignificantly elevated in the ex vivo model. An immunoprecipitation with porcine primary cells and tissue identified FCGR2 as a potential interaction partner in the nasal mucosa. Glycosylation sensitive receptors appear to be involved in the uptake, transport, but also degradation of therapeutic IgGs in the airway epithelial layer.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We have also recently generated a IgG variant lacking Fc-receptor effector functions by engrafting IgG2- and IgG4-derived amino acids onto IgG1 (Δnab 35 ), which still binds FcRn. However, this variant showed surprisingly low FcRn-mediated transport 36 , warranting further investigation. Here we present a study on FcRn mediated IgG1 and IgG2 transcytosis and describe new findings on the differential transport of these subclasses.…”

Section: Introductionmentioning

confidence: 90%

Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge

Stapleton

Brinkhaus

Armour

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Neonatal Fc-receptor (FcRn), the major histocompatibility complex (MHC) class I-like Fc-receptor, transports immunoglobuline G (IgG) across cell layers, extending IgG half-life in circulation and providing newborns with humoral immunity. IgG1 and IgG2 have similar half-lives, yet IgG2 displays lower foetal than maternal concentration at term, despite all known FcRn binding residues being preserved between IgG1 and IgG2. We investigated FcRn mediated transcytosis of V H -matched IgG1 and IgG2 and mutated variants thereof lacking Fc-gamma receptor (FcγR) binding in human cells expressing FcRn. We observed that FcγR binding was not required for transport and that FcRn transported less IgG2 than IgG1. Transport of IgG1 with a shortened lower hinge (ΔGly236, absent in germline IgG2), was reduced to levels equivalent to IgG2. Conversely, transport of IgG2 + Gly236 was increased to IgG1 levels. Gly236 is not a contact residue between IgG and FcRn, suggesting that its absence leads to an altered conformation of IgG, possibly due to a less flexible Fab, positioned closer to the Fc portion. This may sterically hinder FcRn binding and transport. We conclude that the lack of Gly236 is sufficient to explain the reduced FcRn-mediated IgG2 transcytosis and accounts for the low maternal/fetal IgG2 ratio at term.

show abstract

“…Of the four IgG subclasses IgG1 and IgG4 are transported readily, whereas IgG2 and IgG3 show somewhat less efficient transplacental passage (28, 142, 143). In ex vivo human placenta transport studies, model IgG molecules disabled in FcRn binding did not cross to the fetal circulation (66, 144), while, conversely, an IgG variant with improved affinity for FcRn was transported more efficiently (145). Also, polarized human trophoblast-derived BeWo cells exhibited apical to basolateral IgG transcytosis and apical IgG recycling (146).…”

Section: Functional Consequence Of Fcrn Expression In Epitheliummentioning

confidence: 99%

The Neonatal Fc Receptor (FcRn): A Misnomer?

et al. 2019

Self Cite

View full text Add to dashboard Cite

Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface receptors as well as atypical intracellular receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.

show abstract

Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport

Cited by 17 publications

References 60 publications

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge

The Neonatal Fc Receptor (FcRn): A Misnomer?

Contact Info

Product

Resources

About