Skip to main content
SpringerLink
Log in

Regulation of Immunological Responses by the Neonatal Fc Receptor for IgG, FcRn

  • Chapter
  • First Online:
Molecular and Cellular Mechanisms of Antibody Activity

  • 2009 Accesses

Abstract

Immunoglobulins (Ig) are the hallmark of the humoral immune system and can be found, in varying concentrations, in all tissues of the body as well as throughout the circulatory system. Of the various isotypes, IgG is by far the most abundant in serum due to its extremely long half-life of 7–23 days. Indeed, while other Ig isotypes are known for very specialized roles in allergy (IgE) and pathogen neutralization (IgA), IgG is the main driver of many of the functions originally attributed to humoral immunity including opsonization, complement activation, and antibody-dependent cellular cytotoxicity (ADCC). Increasingly, however, it is being recognized that the functions of IgG extend beyond simply that of a humoral immune system component to that of a potent integrator of the humoral and cellular arms of a coordinated adaptive immune response.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adams RJ, Heazlewood SP, Gilshenan KS, O’Brien M, McGuckin MA, Florin TH (2008) IgG antibodies against common gut bacteria are more diagnostic for Crohn’s disease than IgG against mannan or flagellin. Am J Gastroenterol 103(2):386–396

    PubMed  Google Scholar 

  • Ahouse JJ, Hagerman CL, Mittal P, Gilbert DJ, Copeland NG, Jenkins NA et al (1993) Mouse MHC class I-like Fc receptor encoded outside the MHC. J Immunol 151(11):6076–6088

    PubMed  CAS  Google Scholar 

  • Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (2004) The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 113(9):1328–1333

    PubMed  CAS  Google Scholar 

  • Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB et al (2008) Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc Natl Acad Sci USA 105(3):967–972

    PubMed  CAS  Google Scholar 

  • Andersen JT, Daba MB, Berntzen G, Michaelsen TE, Sandlie I (2010) Cross-species binding analyses of mouse and human neonatal Fc receptor (FcRn) show dramatic differences in immunoglobulin G (IgG) and albumin binding. J Biol Chem 285(7):4826–4836

    PubMed  Google Scholar 

  • Anderson CL, Chaudhury C, Kim J, Bronson CL, Wani MA, Mohanty S (2006) Perspective– FcRn transports albumin: relevance to immunology and medicine. Trends Immunol 27(7):343–348

    PubMed  CAS  Google Scholar 

  • Antohe F, Radulescu L, Gafencu A, Ghetie V, Simionescu M (2001) Expression of functionally active FcRn and the differentiated bidirectional transport of IgG in human placental endothelial cells. Hum Immunol 62(2):93–105

    PubMed  CAS  Google Scholar 

  • Aoyama Y (2010) What’s new in i.v. immunoglobulin therapy and pemphigus: high-dose i.v. immunoglobulin therapy and its mode of action for treatment of pemphigus. J Dermatol 37(3):239–245

    PubMed  CAS  Google Scholar 

  • Bai Y, Ye L, Tesar DB, Song H, Zhao D, Bjorkman PJ et al (2011) Intracellular neutralization of viral infection in polarized epithelial cells mediated by neonatal Fc receptor (FcRn)-mediated IgG transport. Proc Natl Acad Sci USA 108(45):18406–18411

    PubMed  CAS  Google Scholar 

  • Baker K, Qiao S-W, Kuo TT, Aveson VG, Platzer B, Andersen J-T et al (2011) Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b + dendritic cells. Proc Natl Acad Sci USA 108(24):9927–9932

    PubMed  CAS  Google Scholar 

  • Ben Suleiman Y, Yoshida M, Nishiumi S, Tanaka H, Mimura T, Nobutani K et al (2012) Neonatal Fc receptor for IgG (FcRn) expressed in the gastric epithelium regulates bacterial infection in mice. Mucosal Immunol 5(1):87–98

    PubMed  CAS  Google Scholar 

  • Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ et al (2004) Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci USA 101(26):9763–9768

    PubMed  CAS  Google Scholar 

  • Blumberg RS, Koss T, Story CM, Barisani D, Polischuk J, Lipin A et al (1995) A major histocompatibility complex class I-related Fc receptor for IgG on rat hepatocytes. J Clin Invest 95(5):2397–2402

    PubMed  CAS  Google Scholar 

  • Borvak J, Richardson J, Medesan C, Antohe F, Radu C, Simionescu M et al (1998) Functional expression of the MHC class I-related receptor, FcRn, in endothelial cells of mice. Int Immunol 10(9):1289–1298

    PubMed  CAS  Google Scholar 

  • Bossuyt X (2006) Serologic markers in inflammatory bowel disease. Clin Chem 52(2):171–181

    PubMed  CAS  Google Scholar 

  • Brambell FWR (1966) The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet 288(7473):1087–1093

    Google Scholar 

  • Brambell FWR, Halliday R, Morris IG (1958) Interference by human and bovine serum and serum protein fractions with the absorption of antibodies by suckling rats and mice. Proc R Soc Lond B Biol Sci 149(934):1–11

    PubMed  CAS  Google Scholar 

  • Burmeister WP, Gastinel LN, Simister NE, Blum ML, Bjorkman PJ (1994a) Crystal structure at 2.2 A resolution of the MHC-related neonatal Fc receptor. Nature 372(6504):336–343

    PubMed  CAS  Google Scholar 

  • Burmeister WP, Huber AH, Bjorkman PJ (1994b) Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature 372(6504):379–383

    PubMed  CAS  Google Scholar 

  • Catunda Lemos AP, Cervenak J, Bender B, Hoffmann OI, Baranyi M, Kerekes A et al (2012) Characterization of the rabbit neonatal Fc receptor (FcRn) and analyzing the immunophenotype of the transgenic rabbits that overexpresses FcRn. PLoS One 7(1):e28869

    PubMed  Google Scholar 

  • Cervenak J, Bender B, Schneider Z, Magna M, Carstea BV, Liliom K et al (2010) Neonatal FcR overexpression boosts humoral immune response in transgenic mice. J Immunol 186(2):959–968

    PubMed  Google Scholar 

  • Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC et al (2003) The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 197(3):315–322

    PubMed  CAS  Google Scholar 

  • Chaudhury C, Brooks CL, Carter DC, Robinson JM, Anderson CL (2006) Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry 45(15):4983–4990

    PubMed  CAS  Google Scholar 

  • Cianga P, Cianga C, Cozma L, Ward ES, Carasevici E (2003) The MHC class I related Fc receptor, FcRn, is expressed in the epithelial cells of the human mammary gland. Hum Immunol 64(12):1152–1159

    PubMed  CAS  Google Scholar 

  • Claypool SM, Dickinson BL, Yoshida M, Lencer WI, Blumberg RS (2002) Functional reconstitution of human FcRn in Madin-Darby canine kidney cells requires co-expressed human beta 2-microglobulin. J Biol Chem 277(31):28038–28050

    PubMed  CAS  Google Scholar 

  • Claypool SM, Dickinson BL, Wagner JS, Johansen FE, Venu N, Borawski JA et al (2004) Bidirectional transepithelial IgG transport by a strongly polarized basolateral membrane Fc gamma-receptor. Mol Biol Cell 15(4):1746–1759

    PubMed  CAS  Google Scholar 

  • Conroy ME, Shi HN, Walker WA (2009) The long-term health effects of neonatal microbial flora. Curr Opin Allergy Clin Immunol 9(3):197–201

    PubMed  Google Scholar 

  • Crow AR, Suppa SJ, Chen X, Mott PJ, Lazarus AH (2011) The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody-mediated amelioration of murine immune thrombocytopenia. Blood 118(24):6403–6406

    PubMed  CAS  Google Scholar 

  • Csorba K, Sesarman A, Oswald E, Feldrihan V, Fritsch A, Hashimoto T et al (2010) Cross-reactivity of autoantibodies from patients with epidermolysis bullosa acquisita with murine collagen VII. Cell Mol Life Sci 67(8):1343–1351

    PubMed  CAS  Google Scholar 

  • Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H et al (2005) IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood–brain barrier neonatal Fc receptor. J Neurosci 25(50):11495–11503

    PubMed  CAS  Google Scholar 

  • Deane R, Bell RD, Sagare A, Zlokovic BV (2009) Clearance of amyloid-beta peptide across the blood–brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 8(1):16–30

    PubMed  CAS  Google Scholar 

  • Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC et al (2006) Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. J Immunol 176(4):2095–2104

    PubMed  CAS  Google Scholar 

  • Dickinson BL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE et al (1999) Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J Clin Invest 104(7):903–911

    PubMed  CAS  Google Scholar 

  • Dickinson BL, Claypool SM, D’Angelo JA, Aiken ML, Venu N, Yen EH et al (2008) Ca2 + −dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway. Mol Biol Cell 19(1):414–423

    PubMed  CAS  Google Scholar 

  • Dumont JA, Bitonti AJ, Clark D, Evans S, Pickford M, Newman SP (2005) Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J Aerosol Med 18(3):294–303

    PubMed  CAS  Google Scholar 

  • Dumont JA, Liu T, Low SC, Zhang X, Kamphaus G, Sakorafas P et al (2012) Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 119(13):3024–3030

    PubMed  CAS  Google Scholar 

  • Ellinger I, Schwab M, Stefanescu A, Hunziker W, Fuchs R (1999) IgG transport across trophoblast-derived BeWo cells: a model system to study IgG transport in the placenta. Eur J Immunol 29(3):733–744

    PubMed  CAS  Google Scholar 

  • Firan M, Bawdon R, Radu C, Ober RJ, Eaken D, Antohe F et al (2001) The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans. Int Immunol 13(8):993–1002

    PubMed  CAS  Google Scholar 

  • Freiberger T, Ravcuková B, Grodecká L, Kurecová B, Jarkovský J, Bartonková D et al (2010a) No association of FCRN promoter VNTR polymorphism with the rate of maternal-fetal IgG transfer. J Reprod Immunol 85(2):193–197

    PubMed  CAS  Google Scholar 

  • Freiberger T, Grodecka L, Ravcukova B, Kurecova B, Postranecka V, Vlcek J et al (2010b) Association of FcRn expression with lung abnormalities and IVIG catabolism in patients with common variable immunodeficiency. Clin Immunol 136(3):419–425

    PubMed  CAS  Google Scholar 

  • Furrie E, Macfarlane S, Cummings JH, Macfarlane GT (2004) Systemic antibodies towards mucosal bacteria in ulcerative colitis and Crohn’s disease differentially activate the innate immune response. Gut 53(1):91–98

    PubMed  CAS  Google Scholar 

  • Gafencu A, Heltianu C, Burlacu A, Hunziker W, Simionescu M (2003) Investigation of IgG receptors expressed on the surface of human placental endothelial cells. Placenta 24(6):664–676

    PubMed  CAS  Google Scholar 

  • Hansen RJ, Balthasar JP (2002) Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost 88(6):898–899

    PubMed  CAS  Google Scholar 

  • Hattori R, Otani H, Moriguchi Y, Matsubara H, Yamamura T, Nakao Y et al (2001) NHE and ICAM-1 expression in hypoxic/reoxygenated coronary microvascular endothelial cells. Am J Physiol Heart Circ Physiol 280(6):H2796–H2803

    PubMed  CAS  Google Scholar 

  • He Y, Bjorkman PJ (2011) Structure of FcRY, an avian immunoglobulin receptor related to mammalian mannose receptors, and its complex with IgY. Proc Natl Acad Sci USA 108(30):12431–12436

    PubMed  CAS  Google Scholar 

  • He W, Ladinsky MS, Huey-Tubman KE, Jensen GJ, McIntosh JR, Bjorkman PJ (2008) FcRn-mediated antibody transport across epithelial cells revealed by electron tomography. Nature 455(7212):542–546

    PubMed  CAS  Google Scholar 

  • Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C et al (2004) Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem 279(8):6213–6216

    PubMed  CAS  Google Scholar 

  • Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N (2006) An engineered human IgG1 antibody with longer serum half-life. J Immunol 176(1):346–356

    PubMed  CAS  Google Scholar 

  • Ishii-Watabe A, Saito Y, Suzuki T, Tada M, Ukaji M, Maekawa K et al (2010) Genetic polymorphisms of FCGRT encoding FcRn in a Japanese population and their functional analysis. Drug Metab Pharmacokinet 25(6):578–587

    PubMed  CAS  Google Scholar 

  • Israel EJ, Taylor S, Wu Z, Mizoguchi E, Blumberg RS, Bhan A et al (1997) Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology 92(1):69–74

    PubMed  CAS  Google Scholar 

  • Jerdeva GV, Tesar DB, Huey-Tubman KE, Ladinsky MS, Fraser SE, Bjorkman PJ (2010) Comparison of FcRn- and pIgR-mediated transport in MDCK cells by fluorescence confocal microscopy. Traffic 11(9):1205–1220

    PubMed  CAS  Google Scholar 

  • Jin-Kyoo K, May-Fang T, Victor G, Ward ES (1994) Localization of the site of the murine IgG1 molecule that is involved in binding to the murine intestinal Fc receptor. Eur J Immunol 24(10):2429–2434

    Google Scholar 

  • Jones EA, Waldmann TA (1972) The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat. J Clin Invest 51(11):2916–2927

    PubMed  CAS  Google Scholar 

  • Kacskovics I (2004) Fc receptors in livestock species. Vet Immunol Immunopathol 102(4):351–362

    PubMed  CAS  Google Scholar 

  • Kacskovics I, Wu Z, Simister NE, Frenyo LV, Hammarstrom L (2000) Cloning and characterization of the bovine MHC class I-like Fc receptor. J Immunol 164(4):1889–1897

    PubMed  CAS  Google Scholar 

  • Kacskovics I, Kis Z, Mayer B, West AP Jr, Tiangco NE, Tilahun M et al (2006a) FcRn mediates elongated serum half-life of human IgG in cattle. Int Immunol 18(4):525–536

    PubMed  CAS  Google Scholar 

  • Kacskovics I, Mayer B, Kis Z, Frenyo LV, Zhao Y, Muyldermans S et al (2006b) Cloning and characterization of the dromedary (Camelus dromedarius) neonatal Fc receptor (drFcRn). Dev Comp Immunol 30(12):1203–1215

    PubMed  CAS  Google Scholar 

  • Kelly D, King T, Aminov R (2007) Importance of microbial colonization of the gut in early life to the development of immunity. Mutat Res 622(1–2):58–69

    PubMed  CAS  Google Scholar 

  • Kim JK, Firan M, Radu CG, Kim CH, Ghetie V, Ward ES (1999) Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn. Eur J Immunol 29(9):2819–2825

    PubMed  CAS  Google Scholar 

  • Kim J, Bronson CL, Wani MA, Oberyszyn TM, Mohanty S, Chaudhury C et al (2008) Beta 2-microglobulin deficient mice catabolize IgG more rapidly than FcRn- alpha-chain deficient mice. Exp Biol Med (Maywood) 233(5):603–609

    CAS  Google Scholar 

  • Kim J, Mohanty S, Ganesan LP, Hua K, Jarjoura D, Hayton WL et al (2009) FcRn in the yolk sac endoderm of mouse is required for IgG transport to fetus. J Immunol 182(5):2583–2589

    PubMed  CAS  Google Scholar 

  • Kobayashi N, Suzuki Y, Tsuge T, Okumura K, Ra C, Tomino Y (2002) FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells. Am J Physiol Renal Physiol 282(2):F358–F365

    PubMed  Google Scholar 

  • Kobayashi K, Qiao SW, Yoshida M, Baker K, Lencer WI, Blumberg RS (2009) An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice. Gastroenterology 137(5):1746–1756, e1

    PubMed  CAS  Google Scholar 

  • Kozlowski PA, Cu-Uvin S, Neutra MR, Flanigan TP (1997) Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect Immun 65(4):1387–1394

    PubMed  CAS  Google Scholar 

  • Kuo TT, Aveson VG (2011) Neonatal Fc receptor and IgG-based therapeutics. MAbs 3(5):422–430

    PubMed  Google Scholar 

  • Kuo TT, de Muinck EJ, Claypool SM, Yoshida M, Nagaishi T, Aveson VG et al (2009) N-glycan moieties in neonatal Fc receptor determine steady-state membrane distribution and directional transport of IgG. J Biol Chem 284(13):8292–8300

    PubMed  CAS  Google Scholar 

  • Kuo T, Baker K, Yoshida M, Qiao S-W, Aveson V, Lencer W et al (2010) Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol 30(6):777–789

    Google Scholar 

  • Leach JL, Sedmak DD, Osborne JM, Rahill B, Lairmore MD, Anderson CL (1996) Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport. J Immunol 157(8):3317–3322

    PubMed  CAS  Google Scholar 

  • Lencer WI, Blumberg RS (2005) A passionate kiss, then run: exocytosis and recycling of IgG by FcRn. Trends Cell Biol 15(1):5–9

    PubMed  CAS  Google Scholar 

  • Li N, Zhao M, Hilario-Vargas J, Prisayanh P, Warren S, Diaz LA et al (2005) Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest 115(12):3440–3450

    PubMed  CAS  Google Scholar 

  • Li Z, Palaniyandi S, Zeng R, Tuo W, Roopenian DC, Zhu X (2011) Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection. Proc Natl Acad Sci USA 108(11):4388–4393

    PubMed  CAS  Google Scholar 

  • Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, Dumont J et al (2007) Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol 178(8):5390–5398

    PubMed  CAS  Google Scholar 

  • Liu X, Lu L, Yang Z, Palaniyandi S, Zeng R, Gao L-Y et al (2011) The neonatal FcR-mediated presentation of immune-complexed antigen is associated with endosomal and phagosomal pH and antigen stability in macrophages and dendritic cells. J Immunol 186(8):4674–4686

    PubMed  CAS  Google Scholar 

  • Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR et al (2004) Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 113(9):1296–1306

    PubMed  CAS  Google Scholar 

  • Low SC, Mezo AR (2009) Inhibitors of the FcRn: IgG protein-protein interaction. AAPS J 11(3):432–434

    PubMed  CAS  Google Scholar 

  • Lu W, Zhao Z, Zhao Y, Yu S, Zhao Y, Fan B et al (2007) Over-expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice. Immunology 122(3):401–408

    PubMed  CAS  Google Scholar 

  • Lu L, Palaniyandi S, Zeng R, Bai Y, Liu X, Wang Y et al (2011) An FcRn-targeted mucosal vaccine strategy effectively induces HIV-1 antigen-specific immunity to genital infection. J Virol 85(20):10542–10553

    PubMed  CAS  Google Scholar 

  • Martin WL, Bjorkman PJ (1999) Characterization of the 2:1 complex between the class I MHC-related Fc receptor and its Fc ligand in solution. Biochemistry 38(39):12639–12647

    PubMed  CAS  Google Scholar 

  • Martin WL, West AP Jr, Gan L, Bjorkman PJ (2001) Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 7(4):867–877

    PubMed  CAS  Google Scholar 

  • Matson AP, Thrall RS, Rafti E, Lingenheld EG, Puddington L (2010) IgG transmitted from allergic mothers decreases allergic sensitization in breastfed offspring. Clin Mol Allergy 8:9

    PubMed  Google Scholar 

  • Mayer B, Zolnai A, Frenyo LV, Jancsik V, Szentirmay Z, Hammarstrom L et al (2002) Redistribution of the sheep neonatal Fc receptor in the mammary gland around the time of parturition in ewes and its localization in the small intestine of neonatal lambs. Immunology 107(3):288–296

    PubMed  CAS  Google Scholar 

  • Mayer B, Kis Z, Kajan G, Frenyo LV, Hammarstrom L, Kacskovics I (2004) The neonatal Fc receptor (FcRn) is expressed in the bovine lung. Vet Immunol Immunopathol 98(1–2):85–89

    PubMed  CAS  Google Scholar 

  • McCarthy KM, Yoong Y, Simister NE (2000) Bidirectional transcytosis of IgG by the rat neonatal Fc receptor expressed in a rat kidney cell line: a system to study protein transport across epithelia. J Cell Sci 113(Pt 7):1277–1285

    PubMed  CAS  Google Scholar 

  • McCarthy KM, Lam M, Subramanian L, Shakya R, Wu Z, Newton EE et al (2001) Effects of mutations in potential phosphorylation sites on transcytosis of FcRn. J Cell Sci 114(Pt 8):1591–1598

    PubMed  CAS  Google Scholar 

  • Medesan C, Matesoi D, Radu C, Ghetie V, Ward ES (1997) Delineation of the amino acid residues involved in transcytosis and catabolism of mouse IgG1. J Immunol 158(5):2211–2217

    PubMed  CAS  Google Scholar 

  • Mestecky J (1987) The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol 7(4):265–276

    PubMed  CAS  Google Scholar 

  • Mezo AR, McDonnell KA, Hehir CA, Low SC, Palombella VJ, Stattel JM et al (2008a) Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci USA 105(7):2337–2342

    PubMed  CAS  Google Scholar 

  • Mezo AR, McDonnell KA, Castro A, Fraley C (2008b) Structure-activity relationships of a peptide inhibitor of the human FcRn: human IgG interaction. Bioorg Med Chem 16(12):6394–6405

    PubMed  CAS  Google Scholar 

  • Mezo AR, Low SC, Hoehn T, Palmieri H (2011) PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn. Bioorg Med Chem Lett 21(21):6332–6335

    PubMed  CAS  Google Scholar 

  • Mi W, Wanjie S, Lo ST, Gan Z, Pickl-Herk B, Ober RJ et al (2008) Targeting the neonatal fc receptor for antigen delivery using engineered fc fragments. J Immunol 181(11):7550–7561

    PubMed  CAS  Google Scholar 

  • Mohanty S, Kim J, Ganesan LP, Phillips GS, Hua K, Jarjoura D et al (2010) IgG is transported across the mouse yolk sac independently of Fc[gamma]RIIb. J Reprod Immunol 84(2):133–144

    PubMed  CAS  Google Scholar 

  • Montoyo HP, Vaccaro C, Hafner M, Ober RJ, Mueller W, Ward ES (2009) Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice. Proc Natl Acad Sci USA 106(8):2788–2793

    PubMed  CAS  Google Scholar 

  • Morell A, Terry WD, Waldmann TA (1970) Metabolic properties of IgG subclasses in man. J Clin Invest 49(4):673–680

    PubMed  CAS  Google Scholar 

  • Mosconi E, Rekima A, Seitz-Polski B, Kanda A, Fleury S, Tissandie E et al (2010) Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol 3(5):461–474

    PubMed  CAS  Google Scholar 

  • Nimmerjahn F, Ravetch JV (2010) Antibody-mediated modulation of immune responses. Immunol Rev 236(1):265–275

    PubMed  CAS  Google Scholar 

  • Ober RJ, Radu CG, Ghetie V, Ward ES (2001) Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int Immunol 13(12):1551–1559

    PubMed  CAS  Google Scholar 

  • Ober RJ, Martinez C, Vaccaro C, Zhou J, Ward ES (2004a) Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn. J Immunol 172(4):2021–2029

    PubMed  CAS  Google Scholar 

  • Ober RJ, Martinez C, Lai X, Zhou J, Ward ES (2004b) Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level. Proc Natl Acad Sci USA 101(30):11076–11081

    PubMed  CAS  Google Scholar 

  • Patel DA, Puig-Canto A, Challa DK, Montoyo HP, Ober RJ, Ward ES (2011) Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol 187(2):1015–1022

    PubMed  CAS  Google Scholar 

  • Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q et al (2010) Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 115(10):2057–2064

    PubMed  CAS  Google Scholar 

  • Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC et al (2006) Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18(12):1759–1769

    PubMed  CAS  Google Scholar 

  • Cianga P, Medesan C, Richardson JA, Ghetie V, Ward ES (1999) Identification and function of neonatal Fc receptor in mammary gland of lactating mice. Eur J Immunol 29(8):2515–2523

    PubMed  CAS  Google Scholar 

  • Popivanova BK, Kitamura K, Yu W, Kondo T, Kagaya T, Kaneko S et al (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118(2):560–570

    PubMed  CAS  Google Scholar 

  • Porollo A, Meller J (2007) Versatile annotation and publication quality visualization of protein complexes using POLYVIEW-3D. BMC Bioinformatics 8:316

    PubMed  Google Scholar 

  • Praetor A, Hunziker W (2002) beta(2)-Microglobulin is important for cell surface expression and pH-dependent IgG binding of human FcRn. J Cell Sci 115(Pt 11):2389–2397

    PubMed  CAS  Google Scholar 

  • Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E et al (2008) Dependence of antibody-mediated presentation of antigen on FcRn. Proc Natl Acad Sci USA 105(27):9337–9342

    PubMed  CAS  Google Scholar 

  • Raghavan M, Gastinel LN, Bjorkman PJ (1993) The class I major histocompatibility complex related Fc receptor shows pH-dependent stability differences correlating with immunoglobulin binding and release. Biochemistry 32(33):8654–8660

    PubMed  CAS  Google Scholar 

  • Raghavan M, Bonagura VR, Morrison SL, Bjorkman PJ (1995) Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants. Biochemistry 34(45):14649–14657

    PubMed  CAS  Google Scholar 

  • Rodewald R (1976) pH-dependent binding of immunoglobulins to intestinal cells of the neonatal rat. J Cell Biol 71(2):666–669

    PubMed  CAS  Google Scholar 

  • Roopenian D, Sun V (2010) Clinical ramifications of the MHC family Fc receptor FcRn. J Clin Immunol 30(6):790–797

    PubMed  CAS  Google Scholar 

  • Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N et al (2003) The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 170(7):3528–3533

    PubMed  CAS  Google Scholar 

  • Roopenian DC, Christianson GJ, Sproule TJ (2010) Human FcRn transgenic mice for pharmacokinetic evaluation of therapeutic antibodies. Methods Mol Biol 602:93–104

    PubMed  CAS  Google Scholar 

  • Russell DG (2007) New ways to arrest phagosome maturation. Nat Cell Biol 9(4):357–359

    PubMed  CAS  Google Scholar 

  • Sakagami M, Omidi Y, Campbell L, Kandalaft LE, Morris CJ, Barar J et al (2006) Expression and transport functionality of FcRn within rat alveolar epithelium: a study in primary cell culture and in the isolated perfused lung. Pharm Res 23(2):270–279

    PubMed  CAS  Google Scholar 

  • Sarav M, Wang Y, Hack BK, Chang A, Jensen M, Bao L et al (2009) Renal FcRn reclaims albumin but facilitates elimination of IgG. J Am Soc Nephrol 20(9):1941–1952

    PubMed  CAS  Google Scholar 

  • Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC et al (2006) NOX2 controls phagosomal pH to regulate antigen processing during cross-presentation by dendritic cells. Cell 126(1):205–218

    PubMed  CAS  Google Scholar 

  • Sayed-Ahmed A, Kassab M, Abd-Elmaksoud A, Elnasharty M, El-Kirdasy A (2010) Expression and immunohistochemical localization of the neonatal Fc receptor (FcRn) in the mammary glands of the Egyptian water buffalo. Acta Histochem 112(4):383–391

    PubMed  CAS  Google Scholar 

  • Schlachetzki F, Zhu C, Pardridge WM (2002) Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier. J Neurochem 81(1):203–206

    PubMed  CAS  Google Scholar 

  • Schnulle PM, Hurley WL (2003) Sequence and expression of the FcRn in the porcine mammary gland. Vet Immunol Immunopathol 91(3–4):227–231

    PubMed  CAS  Google Scholar 

  • Schroeder HW Jr, Cavacini L (2010) Structure and function of immunoglobulins. J Allergy Clin Immunol 125(Suppl 2):S41–S52

    PubMed  Google Scholar 

  • Sesarman A, Sitaru AG, Olaru F, Zillikens D, Sitaru C (2008) Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita. J Mol Med 86(8):951–959

    PubMed  CAS  Google Scholar 

  • Sesarman A, Vidarsson G, Sitaru C (2010) The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases. Cell Mol Life Sci 67(15):2533–2550

    PubMed  CAS  Google Scholar 

  • Shah U, Dickinson BL, Blumberg RS, Simister NE, Lencer WI, Walker WA (2003) Distribution of the IgG Fc receptor, FcRn, in the human fetal intestine. Pediatr Res 53(2):295–301

    PubMed  CAS  Google Scholar 

  • Shiomi H, Masuda A, Nishiumi S, Nishida M, Takagawa T, Shiomi Y et al (2010) Gamma interferon produced by antigen-specific CD4+ T cells regulates the mucosal immune responses to Citrobacter rodentium infection. Infect Immun 78(6):2653–2666

    PubMed  CAS  Google Scholar 

  • Simister NE (2003) Placental transport of immunoglobulin G. Vaccine 21(24):3365–3369

    PubMed  CAS  Google Scholar 

  • Simister NE, Ahouse JC (1996) The structure and evolution of FcRn. Res Immunol 147(5):333–337

    PubMed  CAS  Google Scholar 

  • Simister NE, Mostov KE (1989a) An Fc receptor structurally related to MHC class I antigens. Nature 337(6203):184–187

    PubMed  CAS  Google Scholar 

  • Simister NE, Mostov KE (1989b) Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog. Cold Spring Harb Symp Quant Biol 54(Pt 1):571–580

    PubMed  CAS  Google Scholar 

  • Simister NE, Rees AR (1985) Isolation and characterization of an Fc receptor from neonatal rat small intestine. Eur J Immunol 15(7):733–738

    PubMed  CAS  Google Scholar 

  • Spiegelberg HL (1989) Biological role of different antibody classes. Int Arch Allergy Appl Immunol 90(Suppl 1):22–27

    PubMed  CAS  Google Scholar 

  • Spiegelberg HL, Weigle WO (1965) Studies on the catabolism of gamma- G subunits and chains. J Immunol 95(6):1034–1040

    PubMed  CAS  Google Scholar 

  • Spiegelberg HL, Fishkin BG, Grey HM (1968) Catabolism of human gammaG-immunoglobulins of different heavy chain subclasses. I. Catabolism of gammaG-myeloma proteins in man. J Clin Invest 47(10):2323–2330

    PubMed  CAS  Google Scholar 

  • Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS et al (2002) Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung. J Exp Med 196(3):303–310

    PubMed  CAS  Google Scholar 

  • Stirling CM, Charleston B, Takamatsu H, Claypool S, Lencer W, Blumberg RS et al (2005) Characterization of the porcine neonatal Fc receptor–potential use for trans-epithelial protein delivery. Immunology 114(4):542–553

    PubMed  CAS  Google Scholar 

  • Story CM, Mikulska JE, Simister NE (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):2377–2381

    PubMed  CAS  Google Scholar 

  • Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T et al (2010) Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol 184(4):1968–1976

    PubMed  CAS  Google Scholar 

  • Szlauer R, Ellinger I, Haider S, Saleh L, Busch BL, Knofler M et al (2009) Functional expression of the human neonatal Fc-receptor, hFcRn, in isolated cultured human syncytiotrophoblasts. Placenta 30(6):507–515

    PubMed  CAS  Google Scholar 

  • Tesar DB, Björkman PJ (2010) An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin G. Curr Opin Struct Biol 20(2):226–233

    PubMed  CAS  Google Scholar 

  • Tesar DB, Cheung EJ, Bjorkman PJ (2008) The chicken yolk sac IgY receptor, a mammalian mannose receptor family member, transcytoses IgY across polarized epithelial cells. Mol Biol Cell 19(4):1587–1593

    PubMed  CAS  Google Scholar 

  • Tiwari B, Junghans RP (2005) Functional analysis of the mouse Fcgrt 5′ proximal promoter. Biochim Biophys Acta 1681(2–3):88–98

    PubMed  CAS  Google Scholar 

  • Tzaban S, Massol RH, Yen E, Hamman W, Frank SR, Lapierre LA et al (2009) The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J Cell Biol 185(4):673–684

    PubMed  CAS  Google Scholar 

  • Vaccaro C, Zhou J, Ober RJ, Ward ES (2005) Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23(10):1283–1288

    PubMed  CAS  Google Scholar 

  • Vaccaro C, Bawdon R, Wanjie S, Ober RJ, Ward ES (2006) Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies. Proc Natl Acad Sci USA 103(49):18709–18714

    PubMed  CAS  Google Scholar 

  • Vaughn DE, Bjorkman PJ (1998) Structural basis of pH-dependent antibody binding by the neonatal Fc receptor. Structure 6(1):63–73

    PubMed  CAS  Google Scholar 

  • Verhasselt V, Milcent V, Cazareth J, Kanda A, Fleury S, Dombrowicz D et al (2008) Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 14(2):170–175

    PubMed  CAS  Google Scholar 

  • Waldmann TA, Terry WD (1990) Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin. J Clin Invest 86(6):2093–2098

    PubMed  CAS  Google Scholar 

  • Wang Y, Geer LY, Chappey C, Kans JA, Bryant SH (2000) Cn3D: sequence and structure views for Entrez. Trends Biochem Sci 25(6):300–302

    PubMed  CAS  Google Scholar 

  • Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S et al (2006) Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci USA 103(13):5084–5089

    PubMed  CAS  Google Scholar 

  • Ward ES, Ober RJ, Frederick WA (2009) Chapter 4 Multitasking by exploitation of intracellular transport functions: the many faces of FcRn. Adv Immunol 103:77–115, Academic Press

    PubMed  CAS  Google Scholar 

  • Wernick NL, Haucke V, Simister NE (2005) Recognition of the tryptophan-based endocytosis signal in the neonatal Fc receptor by the mu subunit of adaptor protein-2. J Biol Chem 280(8):7309–7316

    PubMed  CAS  Google Scholar 

  • West AP Jr, Bjorkman PJ (2000) Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor. Biochemistry 39(32):9698–9708

    PubMed  CAS  Google Scholar 

  • West AP Jr, Herr AB, Bjorkman PJ (2004) The chicken yolk sac IgY receptor, a functional equivalent of the mammalian MHC-related Fc receptor, is a phospholipase A2 receptor homolog. Immunity 20(5):601–610

    PubMed  CAS  Google Scholar 

  • Wu Z, Simister NE (2001) Tryptophan- and dileucine-based endocytosis signals in the neonatal Fc receptor. J Biol Chem 276(7):5240–5247

    PubMed  CAS  Google Scholar 

  • Ye L, Liu X, Rout SN, Li Z, Yan Y, Lu L et al (2008) The MHC class II-associated invariant chain interacts with the neonatal Fc gamma receptor and modulates its trafficking to endosomal/lysosomal compartments. J Immunol 181(4):2572–2585

    PubMed  CAS  Google Scholar 

  • Ye L, Zeng R, Bai Y, Roopenian DC, Zhu X (2011) Efficient mucosal vaccination mediated by the neonatal Fc receptor. Nat Biotech 29(2):158–163

    CAS  Google Scholar 

  • Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S et al (2009) Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol 182(12):7663–7671

    PubMed  CAS  Google Scholar 

  • Yeung YA, Wu X, Reyes AE 2nd, Vernes JM, Lien S, Lowe J et al (2010) A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Res 70(8):3269–3277

    PubMed  CAS  Google Scholar 

  • Yoshida M, Claypool SM, Wagner JS, Mizoguchi E, Mizoguchi A, Roopenian DC et al (2004) Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20(6):769–783

    PubMed  CAS  Google Scholar 

  • Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, Claypool SM et al (2006) Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 116(8):2142–2151

    PubMed  CAS  Google Scholar 

  • Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IWL, Sproule TJ et al (2010) Enhanced antibody half-life improves in vivo activity. Nat Biotech 28(2):157–159

    CAS  Google Scholar 

  • Zheng Y, Scheerens H, Davis JC Jr, Deng R, Fischer SK, Woods C et al (2011) Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study. Clin Pharmacol Ther 89(2):283–290

    PubMed  CAS  Google Scholar 

  • Zhou J, Mateos F, Ober RJ, Ward ES (2005a) Conferring the binding properties of the mouse MHC class I-related receptor, FcRn, onto the human ortholog by sequential rounds of site-directed mutagenesis. J Mol Biol 345(5):1071–1081

    PubMed  CAS  Google Scholar 

  • Zhou J, Pop LM, Ghetie V (2005b) Hypercatabolism of IgG in mice with lupus-like syndrome. Lupus 14(6):458–466

    PubMed  CAS  Google Scholar 

  • Zhou XJ, Yu L, Zhu L, Hou P, Lv JC, Yu F et al (2009) Association between polymorphisms in the FCGRT gene and lupus nephritis in Chinese patients. Clin Exp Rheumatol 27(4):609–614

    PubMed  CAS  Google Scholar 

  • Zhu X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L et al (2001) MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells. J Immunol 166(5):3266–3276

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Canadian Institutes of Health Research, the Deutsche Forschungsgemeinschaft (RA 2040/1–1), the High Pointe Foundation, the National Institutes of Health Research (DK53056, DK053162, DK088199, and DK044319), and the Harvard Digestive Diseases Center (NIH P30DK034854).

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Thorn 1415, 02115, Boston, MA, USA

    Kristi Baker Ph.D. & Timo Rath M.D.

  2. Division of Gastroenterology, Hepatology and Endoscopy, Harvard Medical School and Brigham and Women’s Hospital, 75 Francis Street, Thorn 1415, 02115, Boston, MA, USA

    Richard S. Blumberg MD

Authors
  1. Kristi Baker Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timo Rath M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard S. Blumberg MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristi Baker Ph.D. .

Editor information

Editors and Affiliations

  1. Lab Experimental Immunology, Glueckstr 6, 91054 ERLANGEN, 91001, Germany

    Falk Nimmerjahn

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Baker, K., Rath, T., Blumberg, R.S. (2013). Regulation of Immunological Responses by the Neonatal Fc Receptor for IgG, FcRn. In: Nimmerjahn, F. (eds) Molecular and Cellular Mechanisms of Antibody Activity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7107-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation