Neonatal Fc receptor

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Fc fragment of IgG, receptor, transporter, alpha
Symbol FCGRT
Entrez 2217
HUGO 3621
OMIM 601437
RefSeq NM_004107
UniProt P55899
Other data
Locus Chr. 19 q13.3
Proteins from the bloodstream are pinocytosed into epithelial cells. IgG binds to FcRn in an acidic endosome and is recycled back into the bloodstream at physiological pH. Other proteins are degraded in lysosomes.

The neonatal Fc receptor (FcRn), also known as the Brambell receptor, is a protein that in humans is encoded by the FCGRT gene.[1][2]

The neonatal Fc receptor is an Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin.[3] It was first discovered in rodents as a unique receptor capable of transporting IgG from mother's milk across the epithelium of newborn rodent's gut into the newborn's bloodstream.[4] Further studies revealed a similar receptor in humans, leading to the naming as a neonatal Fc receptor. In humans, however, it is found in the placenta to help facilitate transport of mother's IgG to the growing fetus and it has also been shown to play a role in monitoring IgG turnover.[3] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[5]

Transcytosis and recycling of IgG[edit]

FcRn helps transport IgG from the gut to the bloodstream. FcRn-mediated transcytosis of IgG across epithelial cells is possible because FcRn binds IgG at acidic pH (<6.5) but not at neutral or higher pH. Therefore, FcRn can bind IgG from the slightly acidic intestinal lumen and ensure efficient, unidirectional transport to the basolateral side where the pH is neutral to slightly basic.[5]

This receptor also helps with the recovery of IgG in adults through the process of endocytosis in endothelial cells. FcRn in acidic endosomes bind to IgG internalized through pinocytosis, recycling it to the cell surface and releasing it at the basic pH of blood, and thereby preventing IgG from undergoing lysosomal degradation. This mechanism may provide an explanation for the greater half-life of IgG in the blood compared to that of other antibody isotypes (3 weeks).[6] It has been shown that conjugation of some drugs to the Fc domain of IgG significantly increases their half-life.[7]

Role in various organs[edit]

FcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[5] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG from clogging the glomeruli and albumin from being excreted.[8] Current studies are investigating FcRn in the liver because there are relatively low concentrations of both IgG and albumin in liver bile despite high concentrations in the blood.[9] Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[10]

Therapeutic potential[edit]

Several autoimmune disorders are caused by the reaction of IgG to self antigens. New therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of pathogenic IgG antibodies from the body. One such therapy is the infusion of intravenous immunoglobulin (IVIg) to bind available FcRn and prevent pathogenic IgG binding, thereby increasing pathogenic IgG removal.[11] This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.[12]

There are several drugs on the market that have Fc portions fused to the effector proteins in order to increase their half-lives through FcRn. They include: Amevive (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept)[citation needed]. Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.[13]


  1. ^ Story CM, Mikulska JE, Simister NE (December 1994). "A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus". J. Exp. Med. 180 (6): 2377–81. doi:10.1084/jem.180.6.2377. PMC 2191771Freely accessible. PMID 7964511. 
  2. ^ Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O (1996). "The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3". Cytogenet. Cell Genet. 73 (1–2): 97–8. doi:10.1159/000134316. PMID 8646894. 
  3. ^ a b Kuo, Timothy T; Aveson, Victoria G (2011-01-01). "Neonatal Fc receptor and IgG-based therapeutics". mAbs. 3 (5): 422–430. doi:10.4161/mabs.3.5.16983. ISSN 1942-0862. PMC 3225846Freely accessible. PMID 22048693. 
  4. ^ Jones, EA; Waldman, TA (1972). "The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat". J Clin Invest. 51: 2916–2927. doi:10.1172/jci107116. PMC 292442Freely accessible. PMID 5080417. 
  5. ^ a b c Kuo, Timothy T.; Baker, Kristi; Yoshida, Masaru; Qiao, Shuo-Wang; Aveson, Victoria G.; Lencer, Wayne I.; Blumberg, Richard S. (2010). "Neonatal Fc receptor: from immunity to therapeutics". Journal of Clinical Immunology. 30 (6): 777–789. doi:10.1007/s10875-010-9468-4. 
  6. ^ Goebl NA, Babbey CM, Datta-Mannan A, Witcher DR, Wroblewski VJ, Dunn KW (December 2008). "Neonatal Fc Receptor Mediates Internalization of Fc in Transfected Human Endothelial Cells". Mol. Biol. Cell. 19 (12): 5490–505. doi:10.1091/mbc.E07-02-0101. PMC 2592658Freely accessible. PMID 18843053. 
  7. ^ Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K (March 2008). "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clin. Cancer Res. 14 (5): 1487–93. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573. 
  8. ^ Bern, Malin; Sand, Kine Marita Knudsen; Nilsen, Jeannette; Sandlie, Inger; Andersen, Jan Terje (2015-08-10). "The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery". Journal of Controlled Release. 211: 144–162. doi:10.1016/j.jconrel.2015.06.006. 
  9. ^ Sand, Kine Marita Knudsen; Bern, Malin; Nilsen, Jeannette; Noordzij, Hanna Theodora; Sandlie, Inger; Andersen, Jan Terje (2015-01-26). "Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00682. ISSN 1664-3224. PMC 4306297Freely accessible. PMID 25674083. 
  10. ^ Gupta, Sandeep; Gach, Johannes S.; Becerra, Juan C.; Phan, Tran B.; Pudney, Jeffrey; Moldoveanu, Zina; Joseph, Sarah B.; Landucci, Gary; Supnet, Medalyn Jude (2013-11-01). "The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells". PLoS Pathogens. 9 (11): e1003776. doi:10.1371/journal.ppat.1003776. ISSN 1553-7366. PMC 3836734Freely accessible. PMID 24278022. 
  11. ^ Sockolosky, Jonathan T.; Szoka, Francis C. (2015-08-30). "The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy". Advanced Drug Delivery Reviews. Editor's Collection 2015. 91: 109–124. doi:10.1016/j.addr.2015.02.005. PMC 4544678Freely accessible. PMID 25703189. 
  12. ^ Nimmerjahn, Falk; Ravetch, Jeffrey V. (2008-01-01). "Anti-Inflammatory Actions of Intravenous Immunoglobulin". Annual Review of Immunology. 26 (1): 513–533. doi:10.1146/annurev.immunol.26.021607.090232. PMID 18370923. 
  13. ^ "Receptor-Fc fusion therapeutics, traps, and MIMETIBODY™ technology". Current Opinion in Biotechnology. 20: 692–699. doi:10.1016/j.copbio.2009.10.010. Retrieved 2016-03-02. 

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