The goal of our research is to describe in molecular terms
how immunoglobulins are transported from a pregnant or nursing
mammal to her unborn or newborn offspring. Although the
fetus is capable of an immune response, it is normally sheltered
from foreign antigens and does not make antibodies against
them. The mother is not sheltered. Because the antigenic
environment she lives in during pregnancy approximates that
awaiting the neonate, a mother makes the antibodies her
offspring will need. Maternal IgG antibodies are transmitted
to fetal or newborn mammals and provide immunity during
the first weeks of independent life. Rats and mice receive
most maternal IgG as sucklings, from milk, whereas most
evidence suggests that human mothers pass on IgG only before
their child's birth.
Receptors for the Fc region of IgG have been detected
in the intestines of suckling rodents and in human placentae.
In suckling rats, IgG binds an Fc receptor at the surface
of intestinal epithelial cells, and is internalized. IgG
crosses these cells and is released into the plasma. From
here it passes through capillary endothelia into the bloodstream.
We purified the Fc receptor, called FcRn, and found it to
be a dimmer of ß2-microglobulin and a 51 kDa glycoprotein.
We cloned cDNAs encoding the glycoprotein. Its predicted
amino acid sequence revealed homology with the class I molecules
of the major histocompatibility complex. Our current research
uses expression of normal and mutant FcRns in cultured mammalian
cells as an approach to identifying the binding site of
the receptor for IgG, and to locating sorting signals that
direct its transport across the cell.
Most materno-fetal IgG transport occurs after the 22nd
week of human pregnancy. During this time there are two
cellular barriers in the placenta that IgG must cross: the
syncytiotrophoblast and the fetal capillaryendothelium.
IgG has been detected by immunoelectron microscopy in vesicles
in the syncytiotrophoblast and endothelial cells. These
vesicles are presumed to mediate transcytosis of IgG in
placenta. We have recently cloned cDNA encoding a human
homolog of the rat FcRn from a human placental library.
We detect FcRnmRNA and protein in the syncytiotrophoblast
of first trimester and termplacenta. This pattern of expression
is consistent with a role for hFcRn intransport of maternal
IgG to the fetal circulation across the placentalsyncytiotrophoblast,
but not the endothelium.
Selected Publications:
Newton EE, Wu Z, Simister NE. Characterization of basolateral-targeting
signals in the neonatal Fc receptor.J Cell Sci. 2005
Jun 1;118(Pt 11):2461-9. [abstract]
Wernick NL, Haucke V, Simister NE. Recognition of the tryptophan-based
endocytosis signal in the neonatal Fc Receptor by the mu
subunit of adaptor protein-2. J Biol Chem. 2005 Feb
25;280(8):7309-16. [abstract]
Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella
VJ, Stattel JM, Lu Y, Tan CA, Song JJ, Garcia AM, Simister
NE, Spiekermann GM, Lencer WI, Blumberg RS. Pulmonary delivery
of an erythropoietin Fc fusion protein in non-human primates
through an immunoglobulin transport pathway. Proc Natl
Acad Sci U S A. 2004 Jun 29;101(26):9763-8. Epub
2004 Jun 21. [abstract]
Simister NE. Placental transport of immunoglobulin G. (2003)
Vaccine. 21:3365-9. [abstract]
McCarthy, K.M., M. Lam, L. Subramanian, R. Shakya, Z. Wu,
E.E. Newton and N.E. Simister (2001). Effects of mutations
in potential phosphorylation sites on transcytosis of FcRn.
J. Cell Sci. 114:1591-1598. [abstract]
Wu, Z. and N.E. Simister (2001). Tryptophan- and
dileucine-based endocytosis signals in the neonatal Fc receptor.
J. Biol. Chem., 276: 5240-5247. [abstract]
Mikulska, J.E., L. Pablo, J. Canel and N.E. Simister (2000).
Cloning and analysis of the gene encoding the human neonatal
Fc receptor. Eur. J. Immunogenetics 27: 231-240.
[abstract]
Mikulska, J.E. and N.E. Simister (2000). Analysis
of the promoter region of the human FcRn gene. Biochim.
Biophys. Acta, 1492 :180-184. [abstract]
McCarthy, K.M., Y.L. Yoong and N.E. Simister (2000). Bidirectionaltranscytosis
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. 113:1277-1285. [abstract]
Last update: January 26, 2007. E-mail comments
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