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The '''neonatal Fc receptor''' (also '''FcRn''', '''IgG receptor FcRn large subunit p51''', or [[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 }}</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 | date = July 1996 | pmid = 8646894 | doi = 10.1159/000134316 }}</ref><ref>{{cite web | title = Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2217}}</ref> It 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>{{Cite journal|last=Simister|first=NE|last2=Mostov|first2=KE|date=1989|title=Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog|url=https://pubmed.ncbi.nlm.nih.gov/2534798/|journal=Cold Spring Harbor Symposia on Quantitative Biology|volume=54 Pt 1|pages=571–580|doi=10.1101/sqb.1989.054.01.068|issn=0091-7451|pmid=2534798}}</ref><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> In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor.<ref name=":2">{{Cite journal|last1=Rodewald|first1=R|last2=Kraehenbuhl|first2=JP|date=1984|title=Receptor-mediated transport of IgG|journal=Journal of Cell Biology|volume=99 (1 Pt 2)|issue=1 Pt 2|pages=159s–64s|doi=10.1083/jcb.99.1.159s|pmid=6235233|pmc=2275593}}</ref><ref name=":3">{{Cite journal|last1=Simister|first1=NE|last2=Rees|first2=AR|date=1985|title=Isolation and characterization of an Fc receptor from neonatal rat small intestine|journal=European Journal of Immunology|volume=15|issue=7|pages=733–8|doi=10.1002/eji.1830150718|pmid=2988974|s2cid=42396197}}</ref> In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.<ref name="pmid7964511" /><ref>{{Cite journal|last=Firan|first=M.|last2=Bawdon|first2=R.|last3=Radu|first3=C.|last4=Ober|first4=R. J.|last5=Eaken|first5=D.|last6=Antohe|first6=F.|last7=Ghetie|first7=V.|last8=Ward|first8=E. S.|date=2001|title=The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans|url=https://pubmed.ncbi.nlm.nih.gov/11470769/|journal=International Immunology|volume=13|issue=8|pages=993–1002|doi=10.1093/intimm/13.8.993|issn=0953-8178|pmid=11470769}}</ref> FcRn has also been shown to play a role in regulating IgG and [[serum albumin]] turnover.<ref name=":6">{{Cite journal|last=Ghetie|first=V.|last2=Hubbard|first2=JG|last3=Kim|first3=JK|last4=Tsen|first4=MF|last5=Lee|first5=Y|last6=Ward|first6=ES|date=1996|title=Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice|url=https://pubmed.ncbi.nlm.nih.gov/8605939/|journal=European Journal of Immunology|volume=26|issue=3|pages=690–696|doi=10.1002/eji.1830260327|issn=0014-2980|pmid=8605939}}</ref><ref name="pmid12566415" /><ref name=":7">{{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 | s2cid = 6980400 }}</ref><ref name=":5">{{Cite journal|last=Ward|first=ES|last2=Ober|first2=RJ|date=2009|title=Multitasking by exploitation of intracellular transport functions the many faces of FcRn|url=https://pubmed.ncbi.nlm.nih.gov/19755184/|journal=Advances in Immunology|volume=103|pages=77–115|doi=10.1016/S0065-2776(09)03004-1|issn=1557-8445|pmc=4485553|pmid=19755184}}</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" />
The '''neonatal Fc receptor''' (also '''FcRn''', '''IgG receptor FcRn large subunit p51''', or [[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 }}</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 | date = July 1996 | pmid = 8646894 | doi = 10.1159/000134316 }}</ref><ref>{{cite web | title = Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2217}}</ref> It 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>{{Cite journal|last1=Simister|first1=NE|last2=Mostov|first2=KE|date=1989|title=Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog|url=https://pubmed.ncbi.nlm.nih.gov/2534798/|journal=Cold Spring Harbor Symposia on Quantitative Biology|volume=54 Pt 1|pages=571–580|doi=10.1101/sqb.1989.054.01.068|issn=0091-7451|pmid=2534798}}</ref><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> In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor.<ref name=":2">{{Cite journal|last1=Rodewald|first1=R|last2=Kraehenbuhl|first2=JP|date=1984|title=Receptor-mediated transport of IgG|journal=Journal of Cell Biology|volume=99 (1 Pt 2)|issue=1 Pt 2|pages=159s–64s|doi=10.1083/jcb.99.1.159s|pmid=6235233|pmc=2275593}}</ref><ref name=":3">{{Cite journal|last1=Simister|first1=NE|last2=Rees|first2=AR|date=1985|title=Isolation and characterization of an Fc receptor from neonatal rat small intestine|journal=European Journal of Immunology|volume=15|issue=7|pages=733–8|doi=10.1002/eji.1830150718|pmid=2988974|s2cid=42396197}}</ref> In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.<ref name="pmid7964511" /><ref>{{Cite journal|last1=Firan|first1=M.|last2=Bawdon|first2=R.|last3=Radu|first3=C.|last4=Ober|first4=R. J.|last5=Eaken|first5=D.|last6=Antohe|first6=F.|last7=Ghetie|first7=V.|last8=Ward|first8=E. S.|date=2001|title=The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans|url=https://pubmed.ncbi.nlm.nih.gov/11470769/|journal=International Immunology|volume=13|issue=8|pages=993–1002|doi=10.1093/intimm/13.8.993|issn=0953-8178|pmid=11470769}}</ref> FcRn has also been shown to play a role in regulating IgG and [[serum albumin]] turnover.<ref name=":6">{{Cite journal|last1=Ghetie|first1=V.|last2=Hubbard|first2=JG|last3=Kim|first3=JK|last4=Tsen|first4=MF|last5=Lee|first5=Y|last6=Ward|first6=ES|date=1996|title=Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice|url=https://pubmed.ncbi.nlm.nih.gov/8605939/|journal=European Journal of Immunology|volume=26|issue=3|pages=690–696|doi=10.1002/eji.1830260327|issn=0014-2980|pmid=8605939|s2cid=85730132}}</ref><ref name="pmid12566415" /><ref name=":7">{{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 | s2cid = 6980400 }}</ref><ref name=":5">{{Cite journal|last1=Ward|first1=ES|last2=Ober|first2=RJ|date=2009|title=Multitasking by exploitation of intracellular transport functions the many faces of FcRn|journal=Advances in Immunology|volume=103|pages=77–115|doi=10.1016/S0065-2776(09)03004-1|issn=1557-8445|pmc=4485553|pmid=19755184}}</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" />


== Interactions with IgG and serum albumin ==
== Interactions with IgG and serum albumin ==
In addition to binding to IgG, FCGRT has been shown to [[Protein-protein interaction|interact]] with [[Human serum albumin]].<ref name=pmid12566415>{{cite journal | vauthors = Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL | title = The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan | journal = J. Exp. Med. | volume = 197 | issue = 3 | pages = 315–22 | date = February 2003 | pmid = 12566415 | pmc = 2193842 | doi = 10.1084/jem.20021829 }}</ref><ref>{{Cite journal|last=Andersen|first=JT|last2=Dee Qian|first2=J|last3=Sandlie|first3=I|date=2006|title=The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin|url=https://pubmed.ncbi.nlm.nih.gov/17048273/|journal=European Journal of Immunology|volume=36|issue=11|pages=3044–3051|doi=10.1002/eji.200636556|issn=0014-2980|pmid=17048273}}</ref> 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.<ref name=":2" /><ref name=":3" /><ref name=":4">{{Cite journal|last=Dickinson|first=BL|last2=Badizadegan|first2=K|last3=Wu|first3=Z|last4=Ahouse|first4=JC|last5=Zhu|first5=X|last6=Simister|first6=NE|last7=Blumberg|first7=RS|last8=Lencer|first8=WI|date=1999|title=Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line|url=https://pubmed.ncbi.nlm.nih.gov/10510331/|journal=The Journal of Clinical Investigation|volume=104|issue=7|pages=903–911|doi=10.1172/JCI6968|issn=0021-9738|pmid=10510331}}</ref> 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=":4" />
In addition to binding to IgG, FCGRT has been shown to [[Protein-protein interaction|interact]] with [[Human serum albumin]].<ref name=pmid12566415>{{cite journal | vauthors = Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL | title = The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan | journal = J. Exp. Med. | volume = 197 | issue = 3 | pages = 315–22 | date = February 2003 | pmid = 12566415 | pmc = 2193842 | doi = 10.1084/jem.20021829 }}</ref><ref>{{Cite journal|last1=Andersen|first1=JT|last2=Dee Qian|first2=J|last3=Sandlie|first3=I|date=2006|title=The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin|url=https://pubmed.ncbi.nlm.nih.gov/17048273/|journal=European Journal of Immunology|volume=36|issue=11|pages=3044–3051|doi=10.1002/eji.200636556|issn=0014-2980|pmid=17048273|s2cid=22024929}}</ref> 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.<ref name=":2" /><ref name=":3" /><ref name=":4">{{Cite journal|last1=Dickinson|first1=BL|last2=Badizadegan|first2=K|last3=Wu|first3=Z|last4=Ahouse|first4=JC|last5=Zhu|first5=X|last6=Simister|first6=NE|last7=Blumberg|first7=RS|last8=Lencer|first8=WI|date=1999|title=Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line|url=https://pubmed.ncbi.nlm.nih.gov/10510331/|journal=The Journal of Clinical Investigation|volume=104|issue=7|pages=903–911|doi=10.1172/JCI6968|issn=0021-9738|pmid=10510331|pmc=408555}}</ref> 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=":4" />


== Recycling of IgG and serum albumin ==
== 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|last=Ward|first=ES|last2=Zhou|first2=J|last3=Ghetie|first3=V|last4=Ober|first4=RJ|date=2003|title=Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans|url=https://pubmed.ncbi.nlm.nih.gov/12578848/|journal=International Immunology|volume=15|issue=2|pages=187–195|doi=10.1093/intimm/dxg018|issn=0953-8178|pmid=12578848}}</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 | doi-access = free }}</ref><ref>{{Cite journal|last=Qiao|first=SW|last2=Kobayashi|first2=K|last3=Johansen|first3=F-E|last4=Sollid|first4=LM|last5=Andersen|first5=JT|last6=Milford|first6=E|last7=Roopenian|first7=DC|last8=Lencer|first8=WI|last9=Blumberg|first9=RS|date=2008|title=Dependence of antibody-mediated presentation of antigen on FcRn|url=https://pubmed.ncbi.nlm.nih.gov/18599440/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=27|pages=9337–9342|doi=10.1073/pnas.0801717105|issn=1091-6490|pmc=2453734|pmid=18599440}}</ref><ref>{{Cite journal|last=Montoyo|first=HP|last2=Vaccaro|first2=C|last3=Hafner|first3=M|last4=Ober|first4=RJ|last5=Mueller|first5=W|last6=Ward|first6=ES|date=2009|title=Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice|url=https://pubmed.ncbi.nlm.nih.gov/19188594/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=8|pages=2788–2793|doi=10.1073/pnas.0810796106|issn=1091-6490|pmc=2650344|pmid=19188594}}</ref> The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.<ref name=":6" /><ref name="pmid12566415" /> 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.<ref name=":8" /><ref name=":9" /> In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.<ref name=":8">{{Cite journal|last=Ober|first=RJ|last2=Martinez|first2=C|last3=Vaccaro|first3=C|last4=Zhou|first4=J|last5=Ward|first5=ES|date=2004|title=Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn|url=https://pubmed.ncbi.nlm.nih.gov/14764666/|journal=Journal of Immunology |volume=172|issue=4|pages=2021–2029|doi=10.4049/jimmunol.172.4.2021|issn=0022-1767|pmid=14764666}}</ref><ref name=":9">{{Cite journal|last=Ober|first=RJ|last2=Martinez|first2=C|last3=Lai|first3=X|last4=Zhou|first4=J|last5=Ward|first5=ES|date=2004|title=Exocytosis of IgG as mediated by the receptor, FcRn: An analysis at the single-molecule level|url=https://www.pnas.org/content/101/30/11076|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=30|pages=11076–11081|doi=10.1073/pnas.0402970101|issn=0027-8424|pmid=15258288}}</ref><ref>{{Cite journal|last=Larsen|first=MT|last2=Rawsthorne|first2=H|last3=Schelde|first3=KK|last4=Dagnæs-Hansen|first4=F|last5=Cameron|first5=J|last6=Howard|first6=KA|date=2018|title=Cellular recycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor (FcRn) engagement|url=https://pubmed.ncbi.nlm.nih.gov/30016735/|journal=Journal of Controlled Release: Official Journal of the Controlled Release Society|volume=287|pages=132–141|doi=10.1016/j.jconrel.2018.07.023|issn=1873-4995|pmid=30016735}}</ref> This mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin.<ref name=":7" /><ref name=":5" />
FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in [[endothelial cells]]<ref>{{Cite journal|last1=Ward|first1=ES|last2=Zhou|first2=J|last3=Ghetie|first3=V|last4=Ober|first4=RJ|date=2003|title=Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans|url=https://pubmed.ncbi.nlm.nih.gov/12578848/|journal=International Immunology|volume=15|issue=2|pages=187–195|doi=10.1093/intimm/dxg018|issn=0953-8178|pmid=12578848}}</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 | doi-access = free }}</ref><ref>{{Cite journal|last1=Qiao|first1=SW|last2=Kobayashi|first2=K|last3=Johansen|first3=F-E|last4=Sollid|first4=LM|last5=Andersen|first5=JT|last6=Milford|first6=E|last7=Roopenian|first7=DC|last8=Lencer|first8=WI|last9=Blumberg|first9=RS|date=2008|title=Dependence of antibody-mediated presentation of antigen on FcRn|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=27|pages=9337–9342|doi=10.1073/pnas.0801717105|issn=1091-6490|pmc=2453734|pmid=18599440|bibcode=2008PNAS..105.9337Q|doi-access=free}}</ref><ref>{{Cite journal|last1=Montoyo|first1=HP|last2=Vaccaro|first2=C|last3=Hafner|first3=M|last4=Ober|first4=RJ|last5=Mueller|first5=W|last6=Ward|first6=ES|date=2009|title=Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=106|issue=8|pages=2788–2793|doi=10.1073/pnas.0810796106|issn=1091-6490|pmc=2650344|pmid=19188594|bibcode=2009PNAS..106.2788M|doi-access=free}}</ref> The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.<ref name=":6" /><ref name="pmid12566415" /> 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.<ref name=":8" /><ref name=":9" /> In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.<ref name=":8">{{Cite journal|last1=Ober|first1=RJ|last2=Martinez|first2=C|last3=Vaccaro|first3=C|last4=Zhou|first4=J|last5=Ward|first5=ES|date=2004|title=Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn|url=https://pubmed.ncbi.nlm.nih.gov/14764666/|journal=Journal of Immunology |volume=172|issue=4|pages=2021–2029|doi=10.4049/jimmunol.172.4.2021|issn=0022-1767|pmid=14764666|s2cid=30526875}}</ref><ref name=":9">{{Cite journal|last1=Ober|first1=RJ|last2=Martinez|first2=C|last3=Lai|first3=X|last4=Zhou|first4=J|last5=Ward|first5=ES|date=2004|title=Exocytosis of IgG as mediated by the receptor, FcRn: An analysis at the single-molecule level|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=30|pages=11076–11081|doi=10.1073/pnas.0402970101|issn=0027-8424|pmid=15258288|pmc=503743|bibcode=2004PNAS..10111076O|doi-access=free}}</ref><ref>{{Cite journal|last1=Larsen|first1=MT|last2=Rawsthorne|first2=H|last3=Schelde|first3=KK|last4=Dagnæs-Hansen|first4=F|last5=Cameron|first5=J|last6=Howard|first6=KA|date=2018|title=Cellular recycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor (FcRn) engagement|url=https://pubmed.ncbi.nlm.nih.gov/30016735/|journal=Journal of Controlled Release: Official Journal of the Controlled Release Society|volume=287|pages=132–141|doi=10.1016/j.jconrel.2018.07.023|issn=1873-4995|pmid=30016735|s2cid=51677989}}</ref> This mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin.<ref name=":7" /><ref name=":5" />


== 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 | 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 | doi-access = free }}</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 }}</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 | doi-access = free }}</ref><ref>{{Cite journal|last=Pyzik|first=M|last2=Rath|first2=T|last3=Kuo|first3=TT|last4=Win|first4=S|last5=Baker|first5=K|last6=Hubbard|first6=JJ|last7=Grenha|first7=R|last8=Gandhi|first8=A|last9=Krämer|first9=TD|last10=Mezo|first10=AR|last11=Taylor|first11=ZS|date=2017|title=Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury|url=https://pubmed.ncbi.nlm.nih.gov/28330995/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=114|issue=14|pages=E2862–E2871|doi=10.1073/pnas.1618291114|issn=1091-6490|pmc=5389309|pmid=28330995}}</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>
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 | doi-access = free }}</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 }}</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 | doi-access = free }}</ref><ref>{{Cite journal|last1=Pyzik|first1=M|last2=Rath|first2=T|last3=Kuo|first3=TT|last4=Win|first4=S|last5=Baker|first5=K|last6=Hubbard|first6=JJ|last7=Grenha|first7=R|last8=Gandhi|first8=A|last9=Krämer|first9=TD|last10=Mezo|first10=AR|last11=Taylor|first11=ZS|date=2017|title=Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=114|issue=14|pages=E2862–E2871|doi=10.1073/pnas.1618291114|issn=1091-6490|pmc=5389309|pmid=28330995|doi-access=free}}</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 ==
== Half-life extension of therapeutic proteins ==
The engineering of IgG and albumin to increase their in vivo persistence has been achieved to generate half-life extended therapeutics.<ref>{{Cite journal|last=Ghetie|first=V.|last2=Popov|first2=S.|last3=Borvak|first3=J.|last4=Radu|first4=C.|last5=Matesoi|first5=D.|last6=Medesan|first6=C.|last7=Ober|first7=R. J.|last8=Ward|first8=E. S.|date=1997|title=Increasing the serum persistence of an IgG fragment by random mutagenesis|url=https://pubmed.ncbi.nlm.nih.gov/9219265/|journal=Nature Biotechnology|volume=15|issue=7|pages=637–640|doi=10.1038/nbt0797-637|issn=1087-0156|pmid=9219265}}</ref><ref>{{Cite journal|last=Dall'Acqua|first=WF|last2=Kiener|first2=PA|last3=Wu|first3=H|date=2006|title=Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn)|url=https://pubmed.ncbi.nlm.nih.gov/16793771/|journal=The Journal of Biological Chemistry|volume=281|issue=33|pages=23514–23524|doi=10.1074/jbc.M604292200|issn=0021-9258|pmid=16793771}}</ref><ref>{{Cite journal|last=Zalevsky|first=J|last2=Chamberlain|first2=AK|last3=Horton|first3=HM|last4=Karki|first4=S|last5=Leung|first5=IWL|last6=Sproule|first6=TJ|last7=Lazar|first7=GA|last8=Roopenian|first8=DC|last9=Desjarlais|first9=JR|date=2010|title=Enhanced antibody half-life improves in vivo activity|url=https://pubmed.ncbi.nlm.nih.gov/20081867/|journal=Nature Biotechnology|volume=28|issue=2|pages=157–159|doi=10.1038/nbt.1601|issn=1546-1696|pmc=2855492|pmid=20081867}}</ref><ref>{{Cite journal|last=Ward|first=ES|last2=Ober|first2=RJ|date=2018|title=Targeting FcRn to Generate Antibody-Based Therapeutics|url=https://pubmed.ncbi.nlm.nih.gov/30143244/|journal=Trends in Pharmacological Sciences|volume=39|issue=10|pages=892–904|doi=10.1016/j.tips.2018.07.007|issn=1873-3735|pmc=6169532|pmid=30143244}}</ref> For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has recently been approved for the treatment of autoimmunity.<ref>{{Cite web|title=Ultomiris® (ravulizumab-cwvz) {{!}} Alexion|url=https://alexion.com/|access-date=2021-10-03|website=https://alexion.com|language=en}}</ref> It has also been shown that conjugation of some drugs to the Fc region 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 | display-authors = 6 | 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 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Poznansky MJ, Halford J, Taylor D | title = Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance | journal = FEBS Letters | volume = 239 | issue = 1 | pages = 18–22 | date = October 1988 | pmid = 3181423 | doi = 10.1016/0014-5793(88)80537-4 | s2cid = 38592689 }}</ref><ref>{{Cite journal|last=Strohl|first=WR|date=2015|title=Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters|url=https://pubmed.ncbi.nlm.nih.gov/26177629/|journal=BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy|volume=29|issue=4|pages=215–239|doi=10.1007/s40259-015-0133-6|issn=1179-190X|pmc=4562006|pmid=26177629}}</ref>
The engineering of IgG and albumin to increase their in vivo persistence has been achieved to generate half-life extended therapeutics.<ref>{{Cite journal|last1=Ghetie|first1=V.|last2=Popov|first2=S.|last3=Borvak|first3=J.|last4=Radu|first4=C.|last5=Matesoi|first5=D.|last6=Medesan|first6=C.|last7=Ober|first7=R. J.|last8=Ward|first8=E. S.|date=1997|title=Increasing the serum persistence of an IgG fragment by random mutagenesis|url=https://pubmed.ncbi.nlm.nih.gov/9219265/|journal=Nature Biotechnology|volume=15|issue=7|pages=637–640|doi=10.1038/nbt0797-637|issn=1087-0156|pmid=9219265|s2cid=39836528}}</ref><ref>{{Cite journal|last1=Dall'Acqua|first1=WF|last2=Kiener|first2=PA|last3=Wu|first3=H|date=2006|title=Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn)|journal=The Journal of Biological Chemistry|volume=281|issue=33|pages=23514–23524|doi=10.1074/jbc.M604292200|issn=0021-9258|pmid=16793771|doi-access=free}}</ref><ref>{{Cite journal|last1=Zalevsky|first1=J|last2=Chamberlain|first2=AK|last3=Horton|first3=HM|last4=Karki|first4=S|last5=Leung|first5=IWL|last6=Sproule|first6=TJ|last7=Lazar|first7=GA|last8=Roopenian|first8=DC|last9=Desjarlais|first9=JR|date=2010|title=Enhanced antibody half-life improves in vivo activity|journal=Nature Biotechnology|volume=28|issue=2|pages=157–159|doi=10.1038/nbt.1601|issn=1546-1696|pmc=2855492|pmid=20081867}}</ref><ref>{{Cite journal|last1=Ward|first1=ES|last2=Ober|first2=RJ|date=2018|title=Targeting FcRn to Generate Antibody-Based Therapeutics|journal=Trends in Pharmacological Sciences|volume=39|issue=10|pages=892–904|doi=10.1016/j.tips.2018.07.007|issn=1873-3735|pmc=6169532|pmid=30143244}}</ref> For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has recently been approved for the treatment of autoimmunity.<ref>{{Cite web|title=Ultomiris® (ravulizumab-cwvz) {{!}} Alexion|url=https://alexion.com/|access-date=2021-10-03|website=https://alexion.com|language=en}}</ref> It has also been shown that conjugation of some drugs to the Fc region 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 | display-authors = 6 | 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 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Poznansky MJ, Halford J, Taylor D | title = Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance | journal = FEBS Letters | volume = 239 | issue = 1 | pages = 18–22 | date = October 1988 | pmid = 3181423 | doi = 10.1016/0014-5793(88)80537-4 | s2cid = 38592689 }}</ref><ref>{{Cite journal|last=Strohl|first=WR|date=2015|title=Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters|journal=BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy|volume=29|issue=4|pages=215–239|doi=10.1007/s40259-015-0133-6|issn=1179-190X|pmc=4562006|pmid=26177629}}</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-mediated recycling. 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 }}</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-mediated recycling. 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 }}</ref>
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== Therapeutic potential ==
== Therapeutic potential ==


Several autoimmune disorders are caused by the binding of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on 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 }}</ref> 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 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 | series = Editor's Collection 2015 }}</ref><ref>{{cite journal|vauthors=Nimmerjahn F, Ravetch JV|date=2008-01-01|title=Anti-inflammatory actions of intravenous immunoglobulin|journal=Annual Review of Immunology|volume=26|issue=1|pages=513–33|doi=10.1146/annurev.immunol.26.021607.090232|pmid=18370923}}</ref> More recent approaches involve the strategy of blocking the binding of IgG to FcRn by injecting antibodies that bind with high affinity to this receptor through their Fc region<ref>{{Cite journal|last=Vaccaro|first=C|last2=Zhou|first2=J|last3=Ober|first3=RJ|last4=Ward|first4=ES|date=2005|title=Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels|url=https://pubmed.ncbi.nlm.nih.gov/16186811/|journal=Nature Biotechnology|volume=23|issue=10|pages=1283–1288|doi=10.1038/nbt1143|issn=1087-0156|pmid=16186811}}</ref><ref>{{Cite journal|last=Ulrichts|first=P|last2=Guglietta|first2=A|last3=Dreier|first3=T|last4=van Bragt|first4=T|last5=Hanssens|first5=V|last6=Hofman|first6=E|last7=Vankerckhoven|first7=B|last8=Verheesen|first8=P|last9=Ongenae|first9=N|last10=Lykhopiy|first10=V|last11=Enriquez|first11=FJ|date=2018|title=Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans|url=https://pubmed.ncbi.nlm.nih.gov/30040076/|journal=The Journal of Clinical Investigation|volume=128|issue=10|pages=4372–4386|doi=10.1172/JCI97911|issn=1558-8238|pmc=6159959|pmid=30040076}}</ref> or variable regions.<ref>{{Cite journal|last=Nixon|first=AE|last2=Chen|first2=J|last3=Sexton|first3=DJ|last4=Muruganandam|first4=A|last5=Bitonti|first5=AJ|last6=Dumont|first6=J|last7=Viswanathan|first7=M|last8=Martik|first8=D|last9=Wassaf|first9=D|last10=Mezo|first10=A|last11=Wood|first11=CR|date=2015|title=Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates|url=https://pubmed.ncbi.nlm.nih.gov/25954273/|journal=Frontiers in Immunology|volume=6|pages=176|doi=10.3389/fimmu.2015.00176|issn=1664-3224|pmc=4407741|pmid=25954273}}</ref><ref>{{Cite journal|last=Kiessling|first=P|last2=Lledo-Garcia|first2=R|last3=Watanabe|first3=S|last4=Langdon|first4=G|last5=Tran|first5=D|last6=Bari|first6=M|last7=Christodoulou|first7=L|last8=Jones|first8=E|last9=Price|first9=G|last10=Smith|first10=B|last11=Brennan|first11=F|date=2017|title=The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study|url=https://pubmed.ncbi.nlm.nih.gov/29093180/|journal=Science Translational Medicine|volume=9|issue=414|pages=eaan1208|doi=10.1126/scitranslmed.aan1208|issn=1946-6242|pmid=29093180}}</ref><ref>{{Cite journal|last=Blumberg|first=LJ|last2=Humphries|first2=JE|last3=Jones|first3=SD|last4=Pearce|first4=LB|last5=Holgate|first5=R|last6=Hearn|first6=A|last7=Cheung|first7=J|last8=Mahmood|first8=A|last9=Del Tito|first9=B|last10=Graydon|first10=JS|last11=Stolz|first11=LE|date=2019|title=Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses|url=https://pubmed.ncbi.nlm.nih.gov/31897428/|journal=Science Advances|volume=5|issue=12|pages=eaax9586|doi=10.1126/sciadv.aax9586|issn=2375-2548|pmc=6920022|pmid=31897428}}</ref> These engineered Fc fragments or antibodies are currently being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and myasthenia gravis.<ref>{{Cite journal|last=Newland|first=AC|last2=Sánchez-González|first2=B|last3=Rejtő|first3=L|last4=Egyed|first4=M|last5=Romanyuk|first5=N|last6=Godar|first6=M|last7=Verschueren|first7=K|last8=Gandini|first8=D|last9=Ulrichts|first9=P|last10=Beauchamp|first10=J|last11=Dreier|first11=T|date=2020|title=Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia|url=https://pubmed.ncbi.nlm.nih.gov/31821591/|journal=American Journal of Hematology|volume=95|issue=2|pages=178–187|doi=10.1002/ajh.25680|issn=1096-8652|pmc=7004056|pmid=31821591}}</ref><ref>{{Cite journal|last=Robak|first=T|last2=Kaźmierczak|first2=M|last3=Jarque|first3=I|last4=Musteata|first4=V|last5=Treliński|first5=J|last6=Cooper|first6=N|last7=Kiessling|first7=P|last8=Massow|first8=U|last9=Woltering|first9=F|last10=Snipes|first10=R|last11=Ke|first11=J|date=2020|title=Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia|url=https://pubmed.ncbi.nlm.nih.gov/32886753/|journal=Blood Advances|volume=4|issue=17|pages=4136–4146|doi=10.1182/bloodadvances.2020002003|issn=2473-9537|pmc=7479959|pmid=32886753}}</ref><ref>{{Cite journal|last=Wolfe|first=GI|last2=Ward|first2=ES|last3=de Haard|first3=H|last4=Ulrichts|first4=P|last5=Mozaffar|first5=T|last6=Pasnoor|first6=M|last7=Vidarsson|first7=G|date=2021|title=IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis|url=https://pubmed.ncbi.nlm.nih.gov/34563918/|journal=Journal of the Neurological Sciences|volume=430|pages=118074|doi=10.1016/j.jns.2021.118074|issn=1878-5883|pmid=34563918}}</ref>
Several autoimmune disorders are caused by the binding of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on 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 }}</ref> 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 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 | series = Editor's Collection 2015 }}</ref><ref>{{cite journal|vauthors=Nimmerjahn F, Ravetch JV|date=2008-01-01|title=Anti-inflammatory actions of intravenous immunoglobulin|journal=Annual Review of Immunology|volume=26|issue=1|pages=513–33|doi=10.1146/annurev.immunol.26.021607.090232|pmid=18370923}}</ref> More recent approaches involve the strategy of blocking the binding of IgG to FcRn by injecting antibodies that bind with high affinity to this receptor through their Fc region<ref>{{Cite journal|last1=Vaccaro|first1=C|last2=Zhou|first2=J|last3=Ober|first3=RJ|last4=Ward|first4=ES|date=2005|title=Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels|url=https://pubmed.ncbi.nlm.nih.gov/16186811/|journal=Nature Biotechnology|volume=23|issue=10|pages=1283–1288|doi=10.1038/nbt1143|issn=1087-0156|pmid=16186811|s2cid=13526188}}</ref><ref>{{Cite journal|last1=Ulrichts|first1=P|last2=Guglietta|first2=A|last3=Dreier|first3=T|last4=van Bragt|first4=T|last5=Hanssens|first5=V|last6=Hofman|first6=E|last7=Vankerckhoven|first7=B|last8=Verheesen|first8=P|last9=Ongenae|first9=N|last10=Lykhopiy|first10=V|last11=Enriquez|first11=FJ|date=2018|title=Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans|journal=The Journal of Clinical Investigation|volume=128|issue=10|pages=4372–4386|doi=10.1172/JCI97911|issn=1558-8238|pmc=6159959|pmid=30040076}}</ref> or variable regions.<ref>{{Cite journal|last1=Nixon|first1=AE|last2=Chen|first2=J|last3=Sexton|first3=DJ|last4=Muruganandam|first4=A|last5=Bitonti|first5=AJ|last6=Dumont|first6=J|last7=Viswanathan|first7=M|last8=Martik|first8=D|last9=Wassaf|first9=D|last10=Mezo|first10=A|last11=Wood|first11=CR|date=2015|title=Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates|journal=Frontiers in Immunology|volume=6|pages=176|doi=10.3389/fimmu.2015.00176|issn=1664-3224|pmc=4407741|pmid=25954273|doi-access=free}}</ref><ref>{{Cite journal|last1=Kiessling|first1=P|last2=Lledo-Garcia|first2=R|last3=Watanabe|first3=S|last4=Langdon|first4=G|last5=Tran|first5=D|last6=Bari|first6=M|last7=Christodoulou|first7=L|last8=Jones|first8=E|last9=Price|first9=G|last10=Smith|first10=B|last11=Brennan|first11=F|date=2017|title=The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study|url=https://pubmed.ncbi.nlm.nih.gov/29093180/|journal=Science Translational Medicine|volume=9|issue=414|pages=eaan1208|doi=10.1126/scitranslmed.aan1208|issn=1946-6242|pmid=29093180|s2cid=206694327}}</ref><ref>{{Cite journal|last1=Blumberg|first1=LJ|last2=Humphries|first2=JE|last3=Jones|first3=SD|last4=Pearce|first4=LB|last5=Holgate|first5=R|last6=Hearn|first6=A|last7=Cheung|first7=J|last8=Mahmood|first8=A|last9=Del Tito|first9=B|last10=Graydon|first10=JS|last11=Stolz|first11=LE|date=2019|title=Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses|journal=Science Advances|volume=5|issue=12|pages=eaax9586|doi=10.1126/sciadv.aax9586|issn=2375-2548|pmc=6920022|pmid=31897428|bibcode=2019SciA....5.9586B}}</ref> These engineered Fc fragments or antibodies are currently being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and myasthenia gravis.<ref>{{Cite journal|last1=Newland|first1=AC|last2=Sánchez-González|first2=B|last3=Rejtő|first3=L|last4=Egyed|first4=M|last5=Romanyuk|first5=N|last6=Godar|first6=M|last7=Verschueren|first7=K|last8=Gandini|first8=D|last9=Ulrichts|first9=P|last10=Beauchamp|first10=J|last11=Dreier|first11=T|date=2020|title=Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia|journal=American Journal of Hematology|volume=95|issue=2|pages=178–187|doi=10.1002/ajh.25680|issn=1096-8652|pmc=7004056|pmid=31821591}}</ref><ref>{{Cite journal|last1=Robak|first1=T|last2=Kaźmierczak|first2=M|last3=Jarque|first3=I|last4=Musteata|first4=V|last5=Treliński|first5=J|last6=Cooper|first6=N|last7=Kiessling|first7=P|last8=Massow|first8=U|last9=Woltering|first9=F|last10=Snipes|first10=R|last11=Ke|first11=J|date=2020|title=Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia|journal=Blood Advances|volume=4|issue=17|pages=4136–4146|doi=10.1182/bloodadvances.2020002003|issn=2473-9537|pmc=7479959|pmid=32886753}}</ref><ref>{{Cite journal|last1=Wolfe|first1=GI|last2=Ward|first2=ES|last3=de Haard|first3=H|last4=Ulrichts|first4=P|last5=Mozaffar|first5=T|last6=Pasnoor|first6=M|last7=Vidarsson|first7=G|date=2021|title=IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis|url=https://pubmed.ncbi.nlm.nih.gov/34563918/|journal=Journal of the Neurological Sciences|volume=430|pages=118074|doi=10.1016/j.jns.2021.118074|issn=1878-5883|pmid=34563918|s2cid=237488156}}</ref>


== References ==
== References ==

Revision as of 22:49, 22 October 2021

Fc fragment of IgG, receptor, transporter, alpha
Identifiers
SymbolFCGRT
NCBI gene2217
HGNC3621
OMIM601437
RefSeqNM_004107
UniProtP55899
Other data
LocusChr. 19 q13.3
Search for
StructuresSwiss-model
DomainsInterPro

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][5] In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor.[6][7] In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.[1][8] FcRn has also been shown to play a role in regulating IgG and serum albumin turnover.[9][10][11][12] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[13]

Interactions with IgG and serum albumin

In addition to binding to IgG, FCGRT has been shown to interact with Human serum albumin.[10][14] 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.[6][7][15] 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.[15]

Recycling of IgG and serum albumin

FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells[16] and bone-marrow derived cells.[17][18][19] The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.[9][10] 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.[20][21] In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.[20][21][22] This mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin.[11][12]

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.[13] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.[23][24] 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.[25][26] Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[27]

Half-life extension of therapeutic proteins

The engineering of IgG and albumin to increase their in vivo persistence has been achieved to generate half-life extended therapeutics.[28][29][30][31] For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has recently been approved for the treatment of autoimmunity.[32] It has also been shown that conjugation of some drugs to the Fc region of IgG or serum albumin significantly increases their half-life.[33][34][35]

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-mediated recycling. 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.[36]

Therapeutic potential

Several autoimmune disorders are caused by the binding of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on these pathogenic antibodies and promote autoimmune disease.[37] 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.[38][39] More recent approaches involve the strategy of blocking the binding of IgG to FcRn by injecting antibodies that bind with high affinity to this receptor through their Fc region[40][41] or variable regions.[42][43][44] These engineered Fc fragments or antibodies are currently being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and myasthenia gravis.[45][46][47]

References

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  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".
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Further reading

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