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Neonatal fragment crystallizable receptor

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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] 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.[5][6] In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.[1][7] FcRn has also been shown to play a role in regulating IgG and serum albumin turnover.[8][9][10][11] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[12]

Interactions with IgG and serum albumin

In addition to binding to IgG, FCGRT has been shown to interact with Human serum albumin.[9][13] 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.[5][6][14] 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.[14]

Recycling of IgG and serum albumin

FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells[15] and bone-marrow derived cells.[16][17][18] The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.[8][9] IgG, serum albumin and other serum proteins are continuously internalized through pinocytosis. Generally, serum proteins are transported from the endosomes to the lysosome, where they are degraded. The two most abundant serum proteins, IgG and serum albumin are bound by FcRn at the slightly acidic pH (<6.5), and recycled to the cell surface where they are released at the neutral pH (>7.0) of blood. In this way IgG and serum albumin avoids lysosomal degradation.[19][20][21] This mechanism provides an explanation for the greater serum circulation half-life of IgG and serum albumin.[10][11]

Role in various organs

FcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[12] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.[22][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] For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has recently been approved for the treatment of autoimmunity.[31] It has also been shown that conjugation of some drugs to the Fc region of IgG or serum albumin significantly increases their half-life.[32][33][34]

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.[35]

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.[36] 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.[37][38] 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[39][40] or variable regions.[41][42][43] 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.[44][45][46]

References

  1. ^ a b Story CM, Mikulska JE, Simister NE (December 1994). "A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus". J. Exp. Med. 180 (6): 2377–81. doi:10.1084/jem.180.6.2377. PMC 2191771. PMID 7964511.
  2. ^ Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O (July 1996). "The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3". Cytogenet. Cell Genet. 73 (1–2): 97–8. doi:10.1159/000134316. PMID 8646894.
  3. ^ "Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha".
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  5. ^ a b Rodewald, R; Kraehenbuhl, JP (1984). "Receptor-mediated transport of IgG". Journal of Cell Biology. 99 (1 Pt 2) (1 Pt 2): 159s – 64s. doi:10.1083/jcb.99.1.159s. PMC 2275593. PMID 6235233.
  6. ^ a b Simister, NE; Rees, AR (1985). "Isolation and characterization of an Fc receptor from neonatal rat small intestine". European Journal of Immunology. 15 (7): 733–8. doi:10.1002/eji.1830150718. PMID 2988974. S2CID 42396197.
  7. ^ Firan, M.; Bawdon, R.; Radu, C.; Ober, R. J.; Eaken, D.; Antohe, F.; Ghetie, V.; Ward, E. S. (2001). "The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans". International Immunology. 13 (8): 993–1002. doi:10.1093/intimm/13.8.993. ISSN 0953-8178. PMID 11470769.
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  31. ^ "Ultomiris® (ravulizumab-cwvz) | Alexion". https://alexion.com. Retrieved 2021-10-03. {{cite web}}: External link in |website= (help)
  32. ^ Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, et al. (March 2008). "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clinical Cancer Research. 14 (5): 1487–93. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573.
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Further reading

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