Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn
Open accessAbstract
The MHC class I-related receptor, FcRn, plays a central role in regulating the serum levels of IgG. FcRn is expressed in endothelial cells, suggesting that these cells may be involved in maintaining IgG levels. We have used live cell imaging of FcRn-green fluorescent protein transfected human endothelial cells to analyze the intracellular events that control IgG homeostasis. We show that segregation of FcRn-IgG complexes from unbound IgG occurs in the sorting endosome. FcRn or FcRn-IgG complexes are gradually depleted from sorting endosomes to ultimately generate multivesicular bodies whose contents are destined for lysosomal degradation. In addition, the pathways taken by FcRn and the transferrin receptor overlap, despite distinct mechanisms of ligand uptake. The studies provide a dynamic view of the trafficking of FcRn and its ligand and have relevance to understanding how FcRn functions to maintain IgG homeostasis.
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IgG is transcytosed to the basal cell surface, where a return to physiological pH causes dissociation of IgG from FcRn.
“IgG is then transcytosed to the basal cell surface, where a return to physiological pH causes dissociation of IgG from FcRn.”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [59]
The paper says IgG binds FcRn in acidic vesicles, is transported to the cell surface, and is released at near-neutral pH. It does not specify transport to the basal surface; the Discussion says the polarity of the endothelial cells studied was uncertain. The cited paper spans pp. 2021–2029, but our copy does not give page numbers for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFcRn may be recycled back to the maternal membrane to perform more cycles of transcytosis.
“FcRn may then be recycled back to the maternal membrane to perform more cycles of transcytosis.”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [59]
The introduction describes FcRn’s role in transferring maternal IgG, and the sorting-endosome results show FcRn entering tubules associated with a recycling pathway. But the study examines endothelial cells, not maternal transcytosis, and does not show FcRn returning to a maternal membrane for repeated cycles. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIgG is taken up from the extracellular fluid on the apical side of the syncytiotrophoblast by endocytosis.
“These studies suggest that IgG is taken up from the extracellular fluid on the apical side of the synctiotrophoblast by endocytosis.”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [59]
The paper describes IgG uptake by fluid-phase pinocytosis, which supports the endocytic-uptake part of the claim. Its discussion and experiments concern endothelial cells, however; our copy does not establish uptake specifically at the apical side of the syncytiotrophoblast. No page number is available for the decisive passage. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInvestigating the return of recycled FcRn to the cell surface is problematic in endothelial cells, largely due to low cell surface expression and slow kinetics of intracellular FcRn return, which has necessitated (over)transfection of FcRn to study such pathways in endothelial cells.
“Investigating the return of recycled FcRn to the cell surface has proved to be problematic in endothelial cells, largely due to the low cell surface expression and the slow kinetics for the return of intracellular FcRn, which, for practical reasons, has necessitated (over)transfection of FcRn to study such pathways in endothelial cells [6,8,37,39].”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [6]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredWithin the acidic environment of endosomes, IgG binds with membrane-bound FcRn and is protected from proteolytic degradation by lysosomal enzymes.
“Within the acidic environment of endosomes, IgG binds with membrane-bound FcRn and is protected from proteolytic degradation by lysosomal enzymes.”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [59]
Monomeric IgG bound to FcRn is directed into sorting tubules and back to the cell surface.
“which then directs monomeric IgG bound to FcRn into sorting tubules and, ultimately, back to the cell surface.”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [6]
The site of IgG salvage is the recycling (or sorting) endosome.
“Studies employing cellular imaging of fluorescently labeled proteins have shown that the site of IgG salvage is the recycling (or sorting) endosome [5–7]”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [6]
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Cites
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Sorted by citations
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Neonatal Fc receptor – biology and therapeutics
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Sirina, J., D'Hooghe, L. E., Singhvi-Hanns, L. A., Cole, S. L., Shock, A., Holliday, N. D., & Stoddart, L. A. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105128
- Authors
- Ober, R. J., Martinez, C., Vaccaro, C., Zhou, J., & Ward, E. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-02
- Volume
- 172
- Issue
- 4
- Pages
- 2021-2029
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1636327287
- Cited by
- 314
- References
- 2
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 11 · 2023: 10 · 2022: 19 · 2021: 13 · 2020: 20 · 2019: 14 · 2018: 24 · 2017: 10 · 2016: 17 · 2015: 17 · 2014: 12 · 2013: 18 · 2012: 13
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R21AI053748, R01AI039167, R21 AI 53748, R01AI050747, R01 AI39167, R01AI54707)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- neonatal Fc receptor, endothelial cells, sorting endosomes, multivesicular bodies, lysosomal degradation, transferrin receptor, receptor trafficking, live-cell imaging
- MeSH terms
- Binding Sites, Antibody, Cell Line, Endothelium, Vascular, Homeostasis, Humans, Immunoglobulin G, Ligands, Luminescent Proteins, Microtubules, Receptors, Fc, Receptors, Transferrin, Endosomes, Recombinant Fusion Proteins, Transfection, Histocompatibility Antigens Class I, Microscopy, Video, Protein Transport, Cytoplasmic Vesicles, Green Fluorescent Proteins
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