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

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...

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Autores principales: Stapleton, Nigel M., Brinkhaus, Maximilian, Armour, Kathryn L., Bentlage, Arthur E. H., de Taeye, Steven W., Temming, A. Robin, Mok, Juk Yee, Brasser, Giso, Maas, Marielle, van Esch, Wim J. E., Clark, Mike R., Williamson, Lorna M., van der Schoot, C. Ellen, Vidarsson, Gestur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517591/
https://www.ncbi.nlm.nih.gov/pubmed/31089170
http://dx.doi.org/10.1038/s41598-019-40731-2
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author Stapleton, Nigel M.
Brinkhaus, Maximilian
Armour, Kathryn L.
Bentlage, Arthur E. H.
de Taeye, Steven W.
Temming, A. Robin
Mok, Juk Yee
Brasser, Giso
Maas, Marielle
van Esch, Wim J. E.
Clark, Mike R.
Williamson, Lorna M.
van der Schoot, C. Ellen
Vidarsson, Gestur
author_facet Stapleton, Nigel M.
Brinkhaus, Maximilian
Armour, Kathryn L.
Bentlage, Arthur E. H.
de Taeye, Steven W.
Temming, A. Robin
Mok, Juk Yee
Brasser, Giso
Maas, Marielle
van Esch, Wim J. E.
Clark, Mike R.
Williamson, Lorna M.
van der Schoot, C. Ellen
Vidarsson, Gestur
author_sort Stapleton, Nigel M.
collection PubMed
description 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.
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spelling pubmed-65175912019-05-24 Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge Stapleton, Nigel M. Brinkhaus, Maximilian Armour, Kathryn L. Bentlage, Arthur E. H. de Taeye, Steven W. Temming, A. Robin Mok, Juk Yee Brasser, Giso Maas, Marielle van Esch, Wim J. E. Clark, Mike R. Williamson, Lorna M. van der Schoot, C. Ellen Vidarsson, Gestur Sci Rep Article 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. Nature Publishing Group UK 2019-05-14 /pmc/articles/PMC6517591/ /pubmed/31089170 http://dx.doi.org/10.1038/s41598-019-40731-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Stapleton, Nigel M.
Brinkhaus, Maximilian
Armour, Kathryn L.
Bentlage, Arthur E. H.
de Taeye, Steven W.
Temming, A. Robin
Mok, Juk Yee
Brasser, Giso
Maas, Marielle
van Esch, Wim J. E.
Clark, Mike R.
Williamson, Lorna M.
van der Schoot, C. Ellen
Vidarsson, Gestur
Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title_full Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title_fullStr Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title_full_unstemmed Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title_short Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge
title_sort reduced fcrn-mediated transcytosis of igg2 due to a missing glycine in its lower hinge
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517591/
https://www.ncbi.nlm.nih.gov/pubmed/31089170
http://dx.doi.org/10.1038/s41598-019-40731-2
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