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The '''neonatal Fc receptor''', 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 | author = 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 | author = 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''', 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 | author = 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 | author = 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''' is an [[Fc receptor]] which is similar in structure to [[MHC class I]] molecules. 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>Jones EA and Waldman TA (1972) The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat. J Clin Invest, 51, 2916.</ref> Further studies revealed a similar receptor in humans. 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. FcRn binds IgG at acidic pH (<6.5) but not at neutral or higher pH. Therefore, FcRn can bind IgG from the intestinal lumen (the inside of the gut that is at a slightly acidic pH) and ensure efficient unidirectional transport to the basolateral side (inside the body) where the pH is neutral to basic (pH 7.0–7.5).
The '''neonatal Fc receptor''' is an [[Fc receptor]] which is similar in structure to [[MHC class I]] molecules. 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>Jones EA and Waldman TA (1972) The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat. J Clin Invest, 51, 2916.</ref> Further studies revealed a similar receptor in humans. 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.


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 intestinal lumen (the inside of the gut that is at a slightly acidic pH) and ensure efficient unidirectional transport to the basolateral side (inside the body) where the pH is neutral to basic (pH 7.0–7.5). 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|url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836734/|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}}</ref>
⚫
This receptor also plays a role in salvage of [[IgG]] in adults through its role in the process of [[endocytosis]] in [[endothelial cells]]. Fc receptors in the 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 isotypes (3 weeks).<ref name="pmid18843053">{{cite journal | author = 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, possibly through this mechanism.<ref name="pmid18316573">{{cite journal | author = 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> There are several drugs on the market that have Fc portions fused to the effector proteins in order to increase their halflives. They include: Amevive ([[alefacept]]), Arcalyst ([[rilonacept]]), Enbrel ([[etanercept]]), Nplate ([[romiplostim]]), Orencia ([[abatacept]]) and Nulojix ([[belatacept]]).

⚫
This receptor also plays a role in salvage of [[IgG]] in adults through its role in the process of [[endocytosis]] in [[endothelial cells]]. Fc receptors in the 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 isotypes (3 weeks).<ref name="pmid18843053">{{cite journal | author = 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, possibly through this mechanism.<ref name="pmid18316573">{{cite journal | author = 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> There are several drugs on the market that have Fc portions fused to the effector proteins in order to increase their half-lives. They include: Amevive ([[alefacept]]), Arcalyst ([[rilonacept]]), Enbrel ([[etanercept]]), Nplate ([[romiplostim]]), Orencia ([[abatacept]]) and Nulojix ([[belatacept]]).

FcRn is expressed on antigen-presenting lymphocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.<ref name=":02">Kuo, Timothy T., Kristi Baker, Masaru Yoshida, Shuo-Wang Qiao, Victoria G. Aveson, Wayne I. Lencer, and Richard S. Blumberg. 2010. Neonatal Fc receptor: from immunity to therapeutics. Journal of Clinical Immunology 30(6): 777-789.</ref> In the kidneys, FcRn is expressed on epithelial cells called [[Podocyte|podocytes]] 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|url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306297/|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> 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=":0">Kuo, Timothy T., Kristi Baker, Masaru Yoshida, Shuo-Wang Qiao, Victoria G. Aveson, Wayne I. Lencer, and Richard S. Blumberg. 2010. Neonatal Fc receptor: from immunity to therapeutics. Journal of Clinical Immunology 30(6): 777-789.</ref>

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 = http://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>


==References==
==References==

Revision as of 05:36, 16 February 2016

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 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 MHC class I molecules. 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.[3] Further studies revealed a similar receptor in humans. 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.

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 intestinal lumen (the inside of the gut that is at a slightly acidic pH) and ensure efficient unidirectional transport to the basolateral side (inside the body) where the pH is neutral to basic (pH 7.0–7.5). Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[4]

This receptor also plays a role in salvage of IgG in adults through its role in the process of endocytosis in endothelial cells. Fc receptors in the 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 isotypes (3 weeks).[5] It has been shown that conjugation of some drugs to the Fc domain of IgG significantly increases their half-life, possibly through this mechanism.[6] There are several drugs on the market that have Fc portions fused to the effector proteins in order to increase their half-lives. They include: Amevive (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept).

FcRn is expressed on antigen-presenting lymphocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[7] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG from clogging the glomeruli and albumin from being excreted.[8] Current studies are investigating FcRn in the liver because there are relatively low concentrations of both IgG and albumin in liver bile despite high concentrations in the blood.[9] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[10]

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

References

  1. ^ Story CM, Mikulska JE, Simister NE (December 1994). "A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus". J. Exp. Med. 180 (6): 2377–81. doi:10.1084/jem.180.6.2377. PMC 2191771. PMID 7964511.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O (1996). "The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3". Cytogenet. Cell Genet. 73 (1–2): 97–8. doi:10.1159/000134316. PMID 8646894.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Jones EA and Waldman TA (1972) The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat. J Clin Invest, 51, 2916.
  4. ^ Gupta, Sandeep; Gach, Johannes S.; Becerra, Juan C.; Phan, Tran B.; Pudney, Jeffrey; Moldoveanu, Zina; Joseph, Sarah B.; Landucci, Gary; Supnet, Medalyn Jude (2013-11-01). "The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells". PLoS Pathogens. 9 (11). doi:10.1371/journal.ppat.1003776. ISSN 1553-7366. PMC 3836734. PMID 24278022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Goebl NA, Babbey CM, Datta-Mannan A, Witcher DR, Wroblewski VJ, Dunn KW (December 2008). "Neonatal Fc Receptor Mediates Internalization of Fc in Transfected Human Endothelial Cells". Mol. Biol. Cell. 19 (12): 5490–505. doi:10.1091/mbc.E07-02-0101. PMC 2592658. PMID 18843053.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K (March 2008). "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clin. Cancer Res. 14 (5): 1487–93. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Kuo, Timothy T., Kristi Baker, Masaru Yoshida, Shuo-Wang Qiao, Victoria G. Aveson, Wayne I. Lencer, and Richard S. Blumberg. 2010. Neonatal Fc receptor: from immunity to therapeutics. Journal of Clinical Immunology 30(6): 777-789.
  8. ^ Bern, Malin; Sand, Kine Marita Knudsen; Nilsen, Jeannette; Sandlie, Inger; Andersen, Jan Terje (2015-08-10). "The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery". Journal of Controlled Release. 211: 144–162. doi:10.1016/j.jconrel.2015.06.006.
  9. ^ Sand, Kine Marita Knudsen; Bern, Malin; Nilsen, Jeannette; Noordzij, Hanna Theodora; Sandlie, Inger; Andersen, Jan Terje (2015-01-26). "Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00682. ISSN 1664-3224. PMC 4306297. PMID 25674083.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Kuo, Timothy T., Kristi Baker, Masaru Yoshida, Shuo-Wang Qiao, Victoria G. Aveson, Wayne I. Lencer, and Richard S. Blumberg. 2010. Neonatal Fc receptor: from immunity to therapeutics. Journal of Clinical Immunology 30(6): 777-789.
  11. ^ Sockolosky, Jonathan T.; Szoka, Francis C. (2015-08-30). "The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy". Advanced Drug Delivery Reviews. Editor's Collection 2015. 91: 109–124. doi:10.1016/j.addr.2015.02.005. PMC 4544678. PMID 25703189.
  12. ^ Nimmerjahn, Falk; Ravetch, Jeffrey V. (2008-01-01). "Anti-Inflammatory Actions of Intravenous Immunoglobulin". Annual Review of Immunology. 26 (1): 513–533. doi:10.1146/annurev.immunol.26.021607.090232. PMID 18370923.

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