{"doi":"10.1038/s41598-019-40731-2","title":"Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge","abstract":"<jats:title>Abstract</jats:title><jats:p>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<jats:sub>H</jats:sub>-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.</jats:p>","journal":"Scientific Reports","year":2019,"id":662639,"datarank":0.5333022092234121,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.0,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1278117,"name":"Maximilian Brinkhaus","orcid":"0000-0002-7426-9980","position":1,"is_corresponding":false},{"id":1309328,"name":"Kathryn L. Armour","orcid":null,"position":2,"is_corresponding":false},{"id":500499,"name":"Arthur E. H. Bentlage","orcid":"0000-0002-7924-554X","position":3,"is_corresponding":false},{"id":511480,"name":"Steven W. de Taeye","orcid":"0000-0001-7915-9230","position":4,"is_corresponding":false},{"id":1729927,"name":"A. Robin Temming","orcid":null,"position":5,"is_corresponding":false},{"id":1211703,"name":"Juk Yee Mok","orcid":null,"position":6,"is_corresponding":false},{"id":1729928,"name":"Giso Brasser","orcid":null,"position":7,"is_corresponding":false},{"id":1729929,"name":"Marielle Maas","orcid":null,"position":8,"is_corresponding":false},{"id":1729930,"name":"Wim J. E. van Esch","orcid":null,"position":9,"is_corresponding":false},{"id":1729931,"name":"Mike R. Clark","orcid":"0000-0002-5539-4997","position":10,"is_corresponding":false},{"id":1729932,"name":"Lorna M. Williamson","orcid":null,"position":11,"is_corresponding":false},{"id":500503,"name":"C. Ellen van der Schoot","orcid":"0000-0002-8065-3540","position":12,"is_corresponding":false},{"id":308475,"name":"Gestur Vidarsson","orcid":"0000-0001-5621-003X","position":13,"is_corresponding":false},{"id":1729926,"name":"Nigel M. Stapleton","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Reduced FcRn-mediated transcytosis of IgG2 due to a missing Glycine in its lower hinge","abstract":"<jats:title>Abstract</jats:title><jats:p>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<jats:sub>H</jats:sub>-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.</jats:p>","is_dataset_classified":null,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31089170","pmcid":"PMC6517591","openalex_id":"https://openalex.org/W2946174014","authors":[],"funders":[{"funder_name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","grant_id":"015.001.083","title":"Development of new diagnostic and therapeutic options to further prevent and/or treat allo-immunization against blood cells"},{"funder_name":"Landsteiner Foundation for Blood Transfusion Research","grant_id":"1527","title":null},{"funder_name":"NCRR NIH HHS","grant_id":"P41 RR001081","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P41RR001081-29","title":"FUNCTIONAL PROMISCUITY IN O-SUCCINYLBENZOATE SYNTHASE"}],"total_grants":4,"fwci":2.4463,"citation_percentile":0.88788746,"influential_citations":0,"citation_trend":[{"year":2020,"count":6},{"year":2021,"count":5},{"year":2022,"count":5},{"year":2023,"count":4},{"year":2024,"count":6},{"year":2025,"count":7},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41598-019-40731-2.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41598-019-40731-2.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41598-019-40731-2","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41598-019-40731-2","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31089170","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/en/publications/0d5dd656-a590-4c52-97b1-4f62374462c4","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6517591","host_type":"repository"},{"url":"https://pure.amc.nl/en/publications/reduced-fcrnmediated-transcytosis-of-igg2-due-to-a-missing-glycine-in-its-lower-hinge(f84fbefd-a845-47a2-9e43-d541e9e077d0).html","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/ws/files/157491190/Reduced-fcrn-mediated-transcytosis-of-igg2-due-to-a-missing-glycine-in-its-lower-hinge.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC6517591","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6517591?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1038/s41598-019-40731-2","host_type":""},{"url":"https://dx.doi.org/10.1038/s41598-019-40731-2","host_type":""}],"fields_of_study":["Monoclonal and Polyclonal Antibodies Research","Glycosylation and Glycoproteins Research","Blood groups and transfusion","0301 basic medicine","0303 health sciences","03 medical and health sciences","Binding Sites","Cell Line, Tumor","Female","Fetal Blood","Glycine","Histocompatibility Antigens Class I","Humans","Immunity, Maternally-Acquired","Immunoglobulin G","Infant, Newborn","Leukocytes","Maternal-Fetal Exchange","Mutation","Placental Circulation","Pregnancy","Primary Cell Culture","Receptors, Fc","Transcytosis"],"mesh_terms":["Binding Sites","Female","Fetal Blood","Glycine","Humans","Immunoglobulin G","Immunity, Maternally-Acquired","Infant, Newborn","Leukocytes","Maternal-Fetal Exchange","Mutation","Pregnancy","Receptors, Fc","Histocompatibility Antigens Class I","Placental Circulation","Cell Line, Tumor","Transcytosis","Primary Cell Culture"],"keywords":["Transcytosis","Neonatal Fc receptor","Antibody","Receptor","Fc receptor","Immunoglobulin G","Fragment crystallizable region","Cell biology","MHC class I","Chemistry","Biology","Major histocompatibility complex","Immunology","Endocytosis","Immune system","Biochemistry","Binding Sites","Histocompatibility Antigens Class I","Primary Cell Culture","Glycine","Infant, Newborn","Receptors, Fc","Fetal Blood","Article","Pregnancy","Cell Line, Tumor","Mutation","Leukocytes","Humans","Female","Placental Circulation","Immunity, Maternally-Acquired","Maternal-Fetal Exchange"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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