Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice
Open accessAbstract
The MHC class I-related receptor FcRn regulates the levels and persistence of IgG in vivo. This receptor salvages IgG from lysosomal degradation within cells, and the binding properties of an IgG for FcRn correlate with in vivo half-life. FcRn is expressed at multiple different sites throughout adult life. However, the cell types and sites at which FcRn maintains IgG homeostasis are not well defined. Toward understanding the sites of FcRn function, we have generated a mouse strain in which this Fc receptor can be conditionally deleted. In combination with mice that express Cre recombinase under the control of the Tie2 promoter (Tie2-Cre), the effect of site-specific deletion of floxed FcRn in endothelial and hematopoietic cells on IgG persistence was analyzed. The pharmacokinetics and steady-state levels of IgG in Tie2-Cre mice that are homozygous for the floxed FcRn allele reveal a complete loss of FcRn function in regulating the half-lives of wild-type IgG. The primary sites for the maintenance of endogenous IgGs in mice are therefore endothelial and hematopoietic cells.
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Endothelial cells are regarded as the major site for IgG salvage in vivo.
“The current study has focused on the behavior of FcRn inhibitors in endothelial cells, since those cells are regarded as the major site for IgG salvage in vivo [3,4].”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [3]
The Discussion (page not specified) says endothelial cells make an important contribution to maintaining IgG levels in mice. It identifies endothelial and hematopoietic cells together as the primary cell types controlling IgG clearance, rather than establishing endothelial cells alone as the major site of salvage. (LLM, conf=0.86)
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Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics
Schoch, A., Kettenberger, H., Mundigl, O., Winter, G., Engert, J., Heinrich, J., & Emrich, T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408766112 · Cited by 202 · see citing works
Extending Serum Half-life of Albumin by Engineering Neonatal Fc Receptor (FcRn) Binding
Andersen, J. T., Dalhus, B., Viuff, D., Ravn, B. T., Gunnarsen, K. S., Plumridge, A., Bunting, K., Antunes, F., Williamson, R., Athwal, S., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.549832 · Cited by 167 · see citing works
The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Brinkhaus, M., Pannecoucke, E., van der Kooi, E. J., Bentlage, A. E. H., Derksen, N. I. L., Andries, J., Balbino, B., Sips, M., Ulrichts, P., Verheesen, P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33764-1 · Cited by 51 · see citing works
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Self-citationSirina, 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
- Montoyo, H. P., Vaccaro, C., Hafner, M., Ober, R. J., Mueller, W., & Ward, E. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Helmholtz Centre for Infection Research (DE)
- The University of Texas at Dallas (US)
- Helmholtz Centre for Infection Research, Braunschweig 38124, Germany;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-24
- Volume
- 106
- Issue
- 8
- Pages
- 2788-2793
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2650344
- OpenAlex
- W2138611681
- Cited by
- 211
- References
- 3
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 10 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 9 · 2019: 14 · 2018: 13 · 2017: 8 · 2016: 12 · 2015: 23 · 2014: 16 · 2013: 14 · 2012: 11
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM071048, R01 GM71048)
- National Institute of Allergy and Infectious Diseases (R01AI039167, R01 AI39167)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- neonatal Fc receptor, IgG half-life, conditional gene deletion, Tie2-Cre, endothelial cells, hematopoietic cells, lysosomal degradation, pharmacokinetics
- MeSH terms
- Animals, Bone Marrow Cells, Endothelium, Hydrogen-Ion Concentration, Immunoglobulin G, Mice, Inbred C57BL, Receptors, Fc, Histocompatibility Antigens Class I, Polymerase Chain Reaction, Gene Deletion, Surface Plasmon Resonance, Receptor, TIE-1, Mice
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