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The therapeutic age of the neonatal Fc receptor

Nature Reviews Immunology volume 23, pages 415–432 (2023)Cite this article

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Abstract

IgGs are essential soluble components of the adaptive immune response that evolved to protect the body from infection. Compared with other immunoglobulins, the role of IgGs is distinguished and enhanced by their high circulating levels, long half-life and ability to transfer from mother to offspring, properties that are conferred by interactions with neonatal Fc receptor (FcRn). FcRn binds to the Fc portion of IgGs in a pH-dependent manner and protects them from intracellular degradation. It also allows their transport across polarized cells that separate tissue compartments, such as the endothelium and epithelium. Further, it is becoming apparent that FcRn functions to potentiate cellular immune responses when IgGs, bound to their antigens, form IgG immune complexes. Besides the protective role of IgG, IgG autoantibodies are associated with numerous pathological conditions. As such, FcRn blockade is a novel and effective strategy to reduce circulating levels of pathogenic IgG autoantibodies and curtail IgG-mediated diseases, with several FcRn-blocking strategies on the path to therapeutic use. Here, we describe the current state of knowledge of FcRn–IgG immunobiology, with an emphasis on the functional and pathological aspects, and an overview of FcRn-targeted therapy development.

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Fig. 1: Structure of FcRn and its ligands.
Fig. 2: FcRn-mediated recycling provides a long half-life to monomeric IgG or small IgG immune complexes whereas multimeric IgG immune complexes are degraded.
Fig. 3: FcRn-mediated transplacental transfer of maternal IgG to the offspring.
Fig. 4: Active immune functions of FcRn in innate immune cells.

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Acknowledgements

We thank T. Hanley for assistance with revisions of the manuscript and D. Humphries for critical discussions. This work was funded by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant DK053056, Harvard Digestive Diseases Center (HDDC) grant DK034854 and a Canadian Institutes of Health Research (CIHR) fellowship grant (L.K.K). Finally, we apologize to all colleagues whose work has not been included in this review owing to space limitations.

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  1. These authors contributed equally: Michal Pyzik, Lisa K. Kozicky.

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  1. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Michal Pyzik, Lisa K. Kozicky, Amit K. Gandhi & Richard S. Blumberg

  2. Harvard Digestive Diseases Center, Boston, MA, USA

    Richard S. Blumberg

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M.P., L.K.K. and A.G. researched data for the article and together with R.S.B. wrote the manuscript.

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Correspondence to Michal Pyzik or Richard S. Blumberg.

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Competing interests

R.S.B. had equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune Inc. was a wholly owned subsidiary of Alexion Pharmaceuticals Inc., which was acquired by AstraZeneca. M.P., L.K.K. and A.G. declare no competing interests.

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The Human Protein Atlas: https://www.proteinatlas.org/ENSG00000104870-FCGRT/single+cell+type

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Pyzik, M., Kozicky, L.K., Gandhi, A.K. et al. The therapeutic age of the neonatal Fc receptor. Nat Rev Immunol 23, 415–432 (2023). https://doi.org/10.1038/s41577-022-00821-1

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