| 词条 | Neonatal Fc receptor |
| 释义 |
|Name=Fc fragment of IgG, receptor, transporter, alpha |caption= |image= |width= |HGNCid=3621 |Symbol=FCGRT |AltSymbols= |EntrezGene=2217 |OMIM=601437 |RefSeq=NM_004107 |UniProt=P55899 |PDB= |ECnumber= |Chromosome=19 |Arm=q |Band=13.3 |LocusSupplementaryData= }} 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. It has also been shown to play a role in monitoring IgG and serum albumin turnover.[3][5] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[7] Transcytosis of IgGFcRn-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.[7] Recycling of IgG and serum albuminFcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells[6] and bone-marrow derived cells.[7] 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.[8][9] Role in various organsFcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[10] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.[11][12] 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.[13] Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[14] Half-life extension of therapeutic proteinsIt has been shown that conjugation of some drugs to the Fc domain of IgG or serum albumin significantly increases their half-life.[15][16] 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|date=March 2016}}. Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.[17] Therapeutic potentialSeveral 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.[18] 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.[19][20] This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.[21] References1. ^{{cite journal | vauthors = Story CM, Mikulska JE, Simister NE | title = A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus | journal = The Journal of Experimental Medicine | volume = 180 | issue = 6 | pages = 2377–81 | date = December 1994 | pmid = 7964511 | pmc = 2191771 | doi = 10.1084/jem.180.6.2377 }} 2. ^{{cite journal | vauthors = Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O | title = The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3 | journal = Cytogenetics and Cell Genetics | volume = 73 | issue = 1–2 | pages = 97–8 | year = 1996 | pmid = 8646894 | doi = 10.1159/000134316 }} 3. ^1 {{cite journal | vauthors = Kuo TT, Aveson VG | title = Neonatal Fc receptor and IgG-based therapeutics | journal = mAbs | volume = 3 | issue = 5 | pages = 422–30 | date = 2011-01-01 | pmid = 22048693 | pmc = 3225846 | doi = 10.4161/mabs.3.5.16983 }} 4. ^{{cite journal | vauthors = Jones EA, Waldmann TA | title = The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat | journal = The Journal of Clinical Investigation | volume = 51 | issue = 11 | pages = 2916–27 | date = November 1972 | pmid = 5080417 | pmc = 292442 | doi = 10.1172/jci107116 }} 5. ^{{cite journal | vauthors = Roopenian DC, Akilesh S | title = FcRn: the neonatal Fc receptor comes of age | language = En | journal = Nature Reviews. Immunology | volume = 7 | issue = 9 | pages = 715–25 | date = September 2007 | pmid = 17703228 | doi = 10.1038/nri2155 }} 6. ^{{cite journal | vauthors = Roopenian DC, Akilesh S | title = FcRn: the neonatal Fc receptor comes of age | language = En | journal = Nature Reviews. Immunology | volume = 7 | issue = 9 | pages = 715–25 | date = September 2007 | pmid = 17703228 | doi = 10.1038/nri2155 }} 7. ^{{cite journal | vauthors = Akilesh S, Christianson GJ, Roopenian DC, Shaw AS | title = Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism | journal = Journal of Immunology | volume = 179 | issue = 7 | pages = 4580–8 | date = October 2007 | pmid = 17878355 | doi = 10.4049/jimmunol.179.7.4580 }} 8. ^{{cite journal | vauthors = Goebl NA, Babbey CM, Datta-Mannan A, Witcher DR, Wroblewski VJ, Dunn KW | title = Neonatal Fc receptor mediates internalization of Fc in transfected human endothelial cells | journal = Molecular Biology of the Cell | volume = 19 | issue = 12 | pages = 5490–505 | date = December 2008 | pmid = 18843053 | pmc = 2592658 | doi = 10.1091/mbc.E07-02-0101 }} 9. ^{{cite journal | vauthors = Roopenian DC, Akilesh S | title = FcRn: the neonatal Fc receptor comes of age | language = En | journal = Nature Reviews. Immunology | volume = 7 | issue = 9 | pages = 715–25 | date = September 2007 | pmid = 17703228 | doi = 10.1038/nri2155 }} 10. ^1 2 {{cite journal | vauthors = Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, Blumberg RS | title = Neonatal Fc receptor: from immunity to therapeutics | journal = Journal of Clinical Immunology | volume = 30 | issue = 6 | pages = 777–89 | date = November 2010 | pmid = 20886282 | pmc = 2970823 | doi = 10.1007/s10875-010-9468-4 }} 11. ^{{cite journal | vauthors = Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB, Miner JH, Roopenian DC, Unanue ER, Shaw AS | title = Podocytes use FcRn to clear IgG from the glomerular basement membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 967–72 | date = January 2008 | pmid = 18198272 | pmc = 2242706 | doi = 10.1073/pnas.0711515105 | url = http://www.jimmunol.org/content/179/7/4580.long }} 12. ^{{cite journal | vauthors = Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT | title = The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery | journal = Journal of Controlled Release | volume = 211 | pages = 144–62 | date = August 2015 | pmid = 26055641 | doi = 10.1016/j.jconrel.2015.06.006 }} 13. ^{{cite journal | vauthors = Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT | title = Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics | journal = Frontiers in Immunology | volume = 5 | pages = 682 | date = 2015-01-26 | pmid = 25674083 | pmc = 4306297 | doi = 10.3389/fimmu.2014.00682 }} 14. ^{{cite journal | vauthors = 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 | title = The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells | journal = PLoS Pathogens | volume = 9 | issue = 11 | pages = e1003776 | date = 2013-11-01 | pmid = 24278022 | pmc = 3836734 | doi = 10.1371/journal.ppat.1003776 }} 15. ^{{cite journal | vauthors = Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K | title = Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy | journal = Clinical Cancer Research | volume = 14 | issue = 5 | pages = 1487–93 | date = March 2008 | pmid = 18316573 | doi = 10.1158/1078-0432.CCR-07-1530 }} 16. ^{{Cite journal|last=Poznansky|first=Mark J.|last2=Halford|first2=Jennifer|last3=Taylor|first3=Donna|date=1988-10-24|title=Growth hormone-albumin conjugates Reduced renal toxicity and altered plasma clearance|journal=FEBS Letters|language=en|volume=239|issue=1|pages=18–22|doi=10.1016/0014-5793(88)80537-4|pmid=3181423|issn=1873-3468}} 17. ^{{cite journal | vauthors = Huang C | title = Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology | journal = Current Opinion in Biotechnology | volume = 20 | issue = 6 | pages = 692–9 | date = December 2009 | pmid = 19889530 | doi = 10.1016/j.copbio.2009.10.010 }} 18. ^{{cite journal | vauthors = Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D | title = The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease | journal = The Journal of Clinical Investigation | volume = 113 | issue = 9 | pages = 1328–33 | date = May 2004 | pmid = 15124024 | pmc = 398424 | doi = 10.1172/JCI18838 }} 19. ^{{cite journal | vauthors = Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D | title = The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease | journal = The Journal of Clinical Investigation | volume = 113 | issue = 9 | pages = 1328–33 | date = May 2004 | pmid = 15124024 | pmc = 398424 | doi = 10.1172/JCI18838 }} 20. ^{{cite journal | vauthors = Sockolosky JT, Szoka FC | title = The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy | journal = Advanced Drug Delivery Reviews | volume = 91 | pages = 109–24 | date = August 2015 | pmid = 25703189 | pmc = 4544678 | doi = 10.1016/j.addr.2015.02.005 | series = Editor's Collection 2015 }} 21. ^{{cite journal | vauthors = Nimmerjahn F, Ravetch JV | title = Anti-inflammatory actions of intravenous immunoglobulin | journal = Annual Review of Immunology | volume = 26 | issue = 1 | pages = 513–33 | date = 2008-01-01 | pmid = 18370923 | doi = 10.1146/annurev.immunol.26.021607.090232 }} External links
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