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FcRn: the neonatal Fc receptor comes of age

Key Points

  • The neonatal Fc receptor for IgG (FcRn) is responsible for the transfer of passive humoral immunity from the mother to the newborn in rodents and humans. Throughout life, FcRn contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation.

  • FcRn is expressed in various tissues in adults. The vascular endothelium is proposed to be the main site of IgG recycling, but myeloid-derived antigen-presenting cells also contribute significantly to extend the serum half-life of IgG.

  • FcRn is expressed in the epithelium of lungs and kidneys. IgG therapeutics delivered to the lungs can be absorbed via FcRn-mediated transcytosis.

  • FcRn binds tightly to the Fc portion of IgG at acidic pH (pH 6.0) but not at physiological pH (pH 7.4). The hydrophobic interactions between FcRn and Fc are stabilized by salt-bridges that form between anionic residues on FcRn and titratable histidine residues of the IgG Fc region.

  • Mutagenesis of Fc-region residues at the FcRn–Fc interface can increase or decrease binding to FcRn. Improved pH-dependent binding to FcRn generally translates into increased half-life of IgG in the circulation.

  • The affinity of the FcRn–IgG interaction is highly dependent on the species and isotype of IgG. Consequently, transgenic mice expressing human FcRn transgenes are required for the initial evaluation of the pharmacokinetics of recombinant human IgG therapeutics before more focused testing in primate systems.

Abstract

The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology.

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Figure 1: FcRn mediates the perinatal transfer of IgG.
Figure 2: FcRn has a MHC-class-I-like structure and binds the CH2–CH3 hinge region of IgG.
Figure 3: Proposed roles for FcRn at various anatomical sites in the adult.
Figure 4: Structural basis of the FcRn–IgG interaction.

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Acknowledgements

We thank the reviewers for their insightful comments and careful review. We apologize to authors whose work could not be cited due to space limitations.

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The Jackson laboratory holds an issued patent on mice with a human FcRn transgene. Derry Roopenian receives royalties when these mice are licensed to pharmaceutical companies.

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Glossary

Syncytiotrophoblast

The outermost multinucleated syncytial cell layer of the trophoblast, which covers the chorionic villi. It is formed by fusion of the underlying layer of mononuclear trophoblast cells, and forms a barrier between the fetus and the mother.

Transcytosis

The process of transport of material across a cell layer by uptake on one side of the cell into a coated vesicle. The vesicle might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Brush border

The surface layer of the normal small intestine that is comprised of small microvilli coated in a rich glycocalyx of mucus and other glycoproteins. The microvilli contain many of the digestive enzymes and transporter systems that are involved in the surface digestion and uptake of dietary materials. It provides a large surface area for absorption.

MHC class I fold

The prototypic structure of MHC class I molecules and the related MHC class Ib molecules. The heavy chain polypeptide forms an α-helical sandwich that sits on top of an immunoglobulin domain. The heavy chain polypeptide pairs non-covalently with β2-microglobulin.

Immune privilege

Immune-privileged sites are areas in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and placenta.

Blood–brain barrier

A barrier formed by tight junctions between endothelial cells that markedly limits entry to the central nervous system by leukocytes and all large molecules, including to some extent immunoglobulins, cytokines and complement proteins.

Amyloid plaques

Sites of amyloid-β accumulation and dystrophic neurites in the brains of mouse models and patients with Alzheimer's disease.

Hinge region

A sequence of amino acids, which is often rich in cysteine and proline residues, that is present in the constant region of immunoglobulin heavy chains. It provides increased molecular flexibility. This region might be involved in the disulphide bonds that link adjacent immunoglobulin heavy chains.

Staphylococcal protein A and streptococcal protein G

Proteins expressed on the cell surface of Staphylococcal or Streptococcal species. These proteins bind to the heavy chain of IgG antibodies from various species and therefore can be used in antibody isolation and purification.

Rheumatoid factor

An antibody (usually IgM) that binds to the Fc region of IgG thereby forming immune complexes. Rheumatoid factors are sometimes found in patients with rheumatoid arthritis and other autoimmune diseases such as systemic lupus erythematosus.

Humanized mice

Mice lacking certain genes of interest but transgenically expressing the human equivalent. Such mice provide an easy model system to study the biology of human genes.

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Roopenian, D., Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7, 715–725 (2007). https://doi.org/10.1038/nri2155

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