Neonatal Fc receptor

The neonatal Fc receptor (also FcRn, IgG receptor FcRn large subunit p51, or Brambell receptor) is a protein that in humans is encoded by the FCGRT gene.[1][2][3]. It is an Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin.[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. It has also been shown to play a role in monitoring IgG and serum albumin turnover.[4][5] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[6]

Fc fragment of IgG, receptor, transporter, alpha
Identifiers
SymbolFCGRT
NCBI gene2217
HGNC3621
OMIM601437
RefSeqNM_004107
UniProtP55899
Other data
LocusChr. 19 q13.3

Interactions with IgG and serum albumin

FCGRT has been shown to interact with Human serum albumin.[7]. 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.[6]

Recycling of IgG and serum albumin

FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells[8] and bone-marrow derived cells.[9] IgG, serum albumin and other serum proteins are continuously internalized through pinocytosis. Generally, serum proteins are transported from the endosomes to the lysosome, where they are degraded. The two most abundant serum proteins, IgG and serum albumin are bound by FcRn at the slightly acidic pH (<6.5), and recycled to the cell surface where they are released at the neutral pH (>7.0) of blood. In this way IgG and serum albumin avoids lysosomal degradation. This mechanism provides an explanation for the greater serum circulation half-life of IgG and serum albumin.[10][11]

Role in various organs

FcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[6] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.[12][13] 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.[14] Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[15]

Half-life extension of therapeutic proteins

It has been shown that conjugation of some drugs to the Fc domain of IgG or serum albumin significantly increases their half-life.[16][17]

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) . Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.[18]

Therapeutic potential

Several autoimmune disorders are caused by the reaction of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also extend the half-life of these pathogenic antibodies and promote autoimmune disease.[19] New therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of disease-causing IgG autoantibodies from the body. One such therapy is the infusion of intravenous immunoglobulin (IVIg) to saturate FcRn's IgG recycling capacity and proportionately reduce the levels of disease-causing IgG autoantibody binding to FcRn, thereby increasing disease-causing IgG autoantibody removal.[20][21] This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.[22]

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References
  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 2191771. PMID 7964511.
  2. Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O (July 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. "Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha".
  4. Kuo TT, Aveson VG (2011-01-01). "Neonatal Fc receptor and IgG-based therapeutics". mAbs. 3 (5): 422–30. doi:10.4161/mabs.3.5.16983. PMC 3225846. PMID 22048693.
  5. Roopenian DC, Akilesh S (September 2007). "FcRn: the neonatal Fc receptor comes of age". Nature Reviews. Immunology. 7 (9): 715–25. doi:10.1038/nri2155. PMID 17703228.
  6. Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, Blumberg RS (November 2010). "Neonatal Fc receptor: from immunity to therapeutics". Journal of Clinical Immunology. 30 (6): 777–89. doi:10.1007/s10875-010-9468-4. PMC 2970823. PMID 20886282.
  7. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL (February 2003). "The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan". J. Exp. Med. 197 (3): 315–22. doi:10.1084/jem.20021829. PMC 2193842. PMID 12566415.
  8. Roopenian DC, Akilesh S (September 2007). "FcRn: the neonatal Fc receptor comes of age". Nature Reviews. Immunology. 7 (9): 715–25. doi:10.1038/nri2155. PMID 17703228.
  9. Akilesh S, Christianson GJ, Roopenian DC, Shaw AS (October 2007). "Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism". Journal of Immunology. 179 (7): 4580–8. doi:10.4049/jimmunol.179.7.4580. PMID 17878355.
  10. 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". Molecular Biology of the Cell. 19 (12): 5490–505. doi:10.1091/mbc.E07-02-0101. PMC 2592658. PMID 18843053.
  11. Roopenian DC, Akilesh S (September 2007). "FcRn: the neonatal Fc receptor comes of age". Nature Reviews. Immunology. 7 (9): 715–25. doi:10.1038/nri2155. PMID 17703228.
  12. Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB, Miner JH, Roopenian DC, Unanue ER, Shaw AS (January 2008). "Podocytes use FcRn to clear IgG from the glomerular basement membrane". Proceedings of the National Academy of Sciences of the United States of America. 105 (3): 967–72. doi:10.1073/pnas.0711515105. PMC 2242706. PMID 18198272.
  13. Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT (August 2015). "The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery". Journal of Controlled Release. 211: 144–62. doi:10.1016/j.jconrel.2015.06.006. PMID 26055641.
  14. Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT (2015-01-26). "Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics". Frontiers in Immunology. 5: 682. doi:10.3389/fimmu.2014.00682. PMC 4306297. PMID 25674083.
  15. Gupta S, Gach JS, Becerra JC, Phan TB, Pudney J, Moldoveanu Z, Joseph SB, Landucci G, Supnet MJ, Ping LH, Corti D, Moldt B, Hel Z, Lanzavecchia A, Ruprecht RM, Burton DR, Mestecky J, Anderson DJ, Forthal DN (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. PMC 3836734. PMID 24278022.
  16. Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, et al. (March 2008). "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clinical Cancer Research. 14 (5): 1487–93. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573.
  17. Poznansky MJ, Halford J, Taylor D (October 1988). "Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance". FEBS Letters. 239 (1): 18–22. doi:10.1016/0014-5793(88)80537-4. PMID 3181423.
  18. Huang C (December 2009). "Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology". Current Opinion in Biotechnology. 20 (6): 692–9. doi:10.1016/j.copbio.2009.10.010. PMID 19889530.
  19. Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (May 2004). "The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease". The Journal of Clinical Investigation. 113 (9): 1328–33. doi:10.1172/JCI18838. PMC 398424. PMID 15124024.
  20. Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (May 2004). "The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease". The Journal of Clinical Investigation. 113 (9): 1328–33. doi:10.1172/JCI18838. PMC 398424. PMID 15124024.
  21. Sockolosky JT, Szoka FC (August 2015). "The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy". Advanced Drug Delivery Reviews. Editor's Collection 2015. 91: 109–24. doi:10.1016/j.addr.2015.02.005. PMC 4544678. PMID 25703189.
  22. Nimmerjahn F, Ravetch JV (2008-01-01). "Anti-inflammatory actions of intravenous immunoglobulin". Annual Review of Immunology. 26 (1): 513–33. doi:10.1146/annurev.immunol.26.021607.090232. PMID 18370923.

Further reading
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