Neonatal Fc receptor: Difference between revisions

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[[File:FcRn-mediated IgG Recycling.png|thumb|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.]]
[[File:FcRn-mediated IgG Recycling.png|thumb|Proteins from the bloodstream are pinocytosed into epithelial cells. IgG and serum albumin is bound by the FcRn in the acidic environment of the endosome and is recycled back into the bloodstream where it is released at physiological pH. Other proteins are degraded in lysosomes.]]
The '''neonatal Fc receptor''' ('''FcRn'''), also known as the [[Francis Brambell|Brambell]] receptor, is a [[protein]] that in humans is encoded by the ''FCGRT'' [[gene]].<ref name="pmid7964511">{{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 = J. Exp. Med. | volume = 180 | issue = 6 | pages = 2377–81 |date=December 1994 | pmid = 7964511 | pmc = 2191771 | doi = 10.1084/jem.180.6.2377| url =  }}</ref><ref name="pmid8646894">{{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 = Cytogenet. Cell Genet. | volume = 73 | issue = 1–2 | pages = 97–8 | year = 1996 | pmid = 8646894 | doi = 10.1159/000134316| url =  }}</ref>
The '''neonatal Fc receptor''' ('''FcRn'''), also known as the [[Francis Brambell|Brambell]] receptor, is a [[protein]] that in humans is encoded by the ''FCGRT'' [[gene]].<ref name="pmid7964511">{{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 }}</ref><ref name="pmid8646894">{{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 }}</ref>


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|beta-2-microglobulin]].<ref name=":0">{{Cite journal|last=Kuo|first=Timothy T|last2=Aveson|first2=Victoria G|date=2011-01-01|title=Neonatal Fc receptor and IgG-based therapeutics|journal=mAbs|volume=3|issue=5|pages=422–430|doi=10.4161/mabs.3.5.16983|issn=1942-0862|pmc=3225846|pmid=22048693}}</ref> 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.<ref>{{cite journal | last1 = Jones | first1 = EA | last2 = Waldman | first2 = TA | year = 1972 | title = The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat | journal = J Clin Invest | volume = 51 | issue = | pages = 2916–2927 | doi=10.1172/jci107116 | pmid=5080417 | pmc=292442}}</ref>  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.<ref name=":0" /> Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, [[Tumor necrosis factor alpha|TNF-α]], and down-regulated by [[Interferon gamma|IFN-γ]].<ref name=":02" />
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|beta-2-microglobulin]].<ref name=":0">{{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 }}</ref> 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.<ref>{{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 }}</ref>  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.<ref name=":0" /><ref>{{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 | url = http://www.nature.com/articles/nri2155 }}</ref> Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, [[Tumor necrosis factor alpha|TNF-α]], and down-regulated by [[Interferon gamma|IFN-γ]].<ref name=":02" />


== Transcytosis and recycling of IgG ==
== Transcytosis of IgG ==


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 [[Lumen (anatomy)|intestinal lumen]] and ensure efficient, unidirectional transport to the basolateral side where the pH is neutral to slightly basic.<ref name=":02" />
FcRn helps transport IgG from suckled milk in 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 [[Lumen (anatomy)|intestinal lumen]] and ensure efficient, unidirectional transport to the basolateral side where the pH is neutral to slightly basic.<ref name=":02" />


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).<ref name="pmid18843053">{{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 = Mol. Biol. Cell | volume = 19 | issue = 12 | pages = 5490–505 |date=December 2008 | pmid = 18843053 | pmc = 2592658 | doi = 10.1091/mbc.E07-02-0101 | url =  }}</ref> It has been shown that conjugation of some drugs to the Fc domain of IgG significantly increases their half-life.<ref name="pmid18316573">{{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 = Clin. Cancer Res. | volume = 14 | issue = 5 | pages = 1487–93 |date=March 2008 | pmid = 18316573 | doi = 10.1158/1078-0432.CCR-07-1530 | url = }}</ref>
== Recycling of IgG and serum albumin ==
FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in [[endothelial cells]]<ref>{{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 | url = http://www.nature.com/articles/nri2155 }}</ref> and bone-marrow derived cells.<ref>{{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 | url = http://www.jimmunol.org/content/179/7/4580.long }}</ref> 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.<ref name="pmid18843053">{{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 }}</ref><ref>{{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 | url = http://www.nature.com/articles/nri2155 }}</ref>


== Role in various organs ==
== 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.<ref name=":02">{{cite journal | last1 = Kuo | first1 = Timothy T. | last2 = Baker | first2 = Kristi | last3 = Yoshida | first3 = Masaru | last4 = Qiao | first4 = Shuo-Wang | last5 = Aveson | first5 = Victoria G. | last6 = Lencer | first6 = Wayne I. | last7 = Blumberg | first7 = Richard S. | year = 2010 | title = Neonatal Fc receptor: from immunity to therapeutics | url = | journal = Journal of Clinical Immunology | volume = 30 | issue = 6| pages = 777–789 | doi=10.1007/s10875-010-9468-4}}</ref> In the kidneys, FcRn is expressed on epithelial cells called [[podocyte]]s to prevent IgG from clogging the glomeruli and albumin from being excreted.<ref>{{Cite journal|title = The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery|url = http://www.sciencedirect.com/science/article/pii/S0168365915006136|journal = Journal of Controlled Release|date = 2015-08-10|pages = 144–162|volume = 211|doi = 10.1016/j.jconrel.2015.06.006|first = Malin|last = Bern|first2 = Kine Marita Knudsen|last2 = Sand|first3 = Jeannette|last3 = Nilsen|first4 = Inger|last4 = Sandlie|first5 = Jan Terje|last5 = Andersen}}</ref> 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.<ref>{{Cite journal|title = Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics|journal = Frontiers in Immunology|date = 2015-01-26|issn = 1664-3224|pmc = 4306297|pmid = 25674083|volume = 5|doi = 10.3389/fimmu.2014.00682|first = Kine Marita Knudsen|last = Sand|first2 = Malin|last2 = Bern|first3 = Jeannette|last3 = Nilsen|first4 = Hanna Theodora|last4 = Noordzij|first5 = Inger|last5 = Sandlie|first6 = Jan Terje|last6 = Andersen}}</ref> Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.<ref>{{Cite journal|title = The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells|journal = PLoS Pathogens|date = 2013-11-01|issn = 1553-7366|pmc = 3836734|pmid = 24278022|volume = 9|issue = 11|doi = 10.1371/journal.ppat.1003776|first = Sandeep|last = Gupta|first2 = Johannes S.|last2 = Gach|first3 = Juan C.|last3 = Becerra|first4 = Tran B.|last4 = Phan|first5 = Jeffrey|last5 = Pudney|first6 = Zina|last6 = Moldoveanu|first7 = Sarah B.|last7 = Joseph|first8 = Gary|last8 = Landucci|first9 = Medalyn Jude|last9 = Supnet|pages=e1003776}}</ref>
FcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.<ref name=":02">{{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 }}</ref> In the kidneys, FcRn is expressed on epithelial cells called [[podocyte]]s to prevent IgG and albumin from clogging the glomerular filtration barrier.<ref>{{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 }}</ref><ref>{{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 | url = http://www.sciencedirect.com/science/article/pii/S0168365915006136 }}</ref> 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.<ref>{{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 }}</ref> Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.<ref>{{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 }}</ref>
 
== 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.<ref name="pmid18316573">{{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 }}</ref><ref>{{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}}</ref>
 
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, [[Tumor necrosis factor alpha|TNF-α.]]<ref>{{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 | url = http://www.sciencedirect.com/science/article/pii/S0958166909001384 | access-date = 2016-03-02 }}</ref>


== Therapeutic potential ==
== Therapeutic potential ==


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.<ref name=":1">{{Cite journal|title = The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy|url = http://www.sciencedirect.com/science/article/pii/S0169409X15000162|journal = Advanced Drug Delivery Reviews|date = 2015-08-30|pmc = 4544678|pmid = 25703189|pages = 109–124|volume = 91|series = Editor's Collection 2015|doi = 10.1016/j.addr.2015.02.005|first = Jonathan T.|last = Sockolosky|first2 = Francis C.|last2 = Szoka}}</ref> This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.<ref>{{Cite journal|title = Anti-Inflammatory Actions of Intravenous Immunoglobulin|url = https://dx.doi.org/10.1146/annurev.immunol.26.021607.090232|journal = Annual Review of Immunology|date = 2008-01-01|pmid = 18370923|pages = 513–533|volume = 26|issue = 1|doi = 10.1146/annurev.immunol.26.021607.090232|first = Falk|last = Nimmerjahn|first2 = Jeffrey V.|last2 = Ravetch}}</ref>
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.<ref>{{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 | url = https://www.jci.org/articles/view/18838 }}</ref> 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.<ref>{{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 | url = https://www.jci.org/articles/view/18838 }}</ref><ref name=":1">{{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 | url = http://www.sciencedirect.com/science/article/pii/S0169409X15000162 | series = Editor's Collection 2015 }}</ref> This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.<ref>{{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 }}</ref>
 
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, [[Tumor necrosis factor alpha|TNF-α.]]<ref>{{cite journal|url=http://www.sciencedirect.com/science/article/pii/S0958166909001384|title=Receptor-Fc fusion therapeutics, traps, and MIMETIBODY™ technology |access-date=2016-03-02 | doi=10.1016/j.copbio.2009.10.010|volume=20|journal=Current Opinion in Biotechnology|pages=692–699}}</ref>


==References==
== References ==
   
   
{{reflist}}
{{reflist}}


==External links==
== External links ==
* {{MeshName|neonatal+Fc+receptor}}
* {{MeshName|neonatal+Fc+receptor}}


Latest revision as of 05:08, 20 December 2018

Fc fragment of IgG, receptor, transporter, alpha
Identifiers
SymbolFCGRT
Entrez2217
HUGO3621
OMIM601437
RefSeqNM_004107
UniProtP55899
Other data
LocusChr. 19 q13.3
File:FcRn-mediated IgG Recycling.png
Proteins from the bloodstream are pinocytosed into epithelial cells. IgG and serum albumin is bound by the FcRn in the acidic environment of the endosome and is recycled back into the bloodstream where it is released 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. 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.[6]

Transcytosis of IgG

FcRn helps transport IgG from suckled milk in 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.[6]

Recycling of IgG and serum albumin

FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells[7] and bone-marrow derived cells.[8] 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.[9][10]

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.[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 proteins

It 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]. 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 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.[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]

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". The Journal of Experimental Medicine. 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 (1996). "The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3". Cytogenetics and Cell Genetics. 73 (1–2): 97–8. doi:10.1159/000134316. PMID 8646894.
  3. ↑ 3.0 3.1 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.
  4. ↑ Jones EA, Waldmann TA (November 1972). "The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat". The Journal of Clinical Investigation. 51 (11): 2916–27. doi:10.1172/jci107116. PMC 292442. PMID 5080417.
  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. ↑ 6.0 6.1 6.2 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. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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". Clinical Cancer Research. 14 (5): 1487–93. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573.
  16. ↑ Poznansky, Mark J.; Halford, Jennifer; Taylor, Donna (1988-10-24). "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. ISSN 1873-3468. PMID 3181423.
  17. ↑ 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. Retrieved 2016-03-02.
  18. ↑ 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.
  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. ↑ 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.
  21. ↑ 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.

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