The acquisition of maternal antibodies is critical for immunologic defense of the newborn. In humans, maternal IgG is actively transported across the placenta. The receptor responsible for this transport has not been identified definitively. We report the isolation from a placental cDNA library of clones encoding the alpha-chain of an immunoglobulin G (IgG)-Fc receptor (hFcRn) that resembles a class I major histocompatibility complex antigen. The DNA and predicted amino acid sequences are very similar to those of the neonatal rat and mouse intestinal Fc receptors, rFcRn and mFcRn. These receptors mediate transport of maternal IgG from milk to the blood-stream of the suckling rat or mouse. Like rat and mouse FcRn, hFcRn binds IgG preferentially at low pH, which may imply that IgG binds hFcRn in an acidic intracellular compartment during transport across the placenta.

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A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus.

During normal human pregnancy, maternal IgG crosses the placenta and provides passive immunity for the fetus. In so doing, IgG passes through two cellular barriers: the syncytiotrophoblast and the fetal capillary endothelium. The Fc region of IgG is required for its transport across the placenta, but the Fc receptors responsible have not been identified definitively. We recently reported the isolation from a placental cDNA library of clones encoding the alpha chain of a human homologue of the major histocompatibility complex class I-related Fc receptor, the neonatal Fc receptor (FcRn). In mice, FcRn is essential for the transport of maternal IgG to the fetus and the neonate. We report here the localization of human FcRn mRNA within the placenta by in situ hybridization, and of human FcRn protein by immunohistochemistry. Both methods show that human FcRn is expressed in syncytiotrophoblast, and is, thus, appropriately located to transport maternal IgG across the first barrier. We confirm previous findings that specific binding of IgG to placental membranes is greater at pH 6.0 than pH 7.5. This corresponds with the pH dependence of IgG binding to FcRn and is consistent with the presence of FcRn in syncytiotrophoblast. We propose a transport model in which maternal IgG binds FcRn at low pH in endosomes within the syncytiotrophoblast. FcRn is not expressed in fetal capillary endothelia, and the mechanism of IgG transport across the second barrier remains unknown.

An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta.

Transplacental transport of maternal immunoglobulin G (IgG) to the developing fetus is extremely important in the protection of the newborn from infection. Although the exact mechanisms of the selective and active transfer of IgG across the placental barrier are not fully understood, receptors for the Fc part of IgG (FcγRs) in the placenta are believed to play a key role. Several known Fc receptors, FcγRI, FcγRII, FcγRIII and FcRn (neonatal FcR), demonstrate heterogeneous expression patterns in placenta. Immunohistochemical analysis shows the expression of FcγRI on Hofbauer cells in stromal tissue, FcγRII on Hofbauer cells and fetal blood endothelium, FcγRIII on Hofbauer cells and trophoblasts, and FcRn on syncytiotrophoblasts and endothelial cells. Recent studies provide evidence for important associations among these receptors and transcytosis of IgG, as well as scavenger mechanisms for clearing immune complexes in the placenta during pregnancy.

Dynamics of immunoglobulins at the feto-maternal interface.

Human placental Fc receptors and the transmission of antibodies from mother to fetus

Oxidative Stress in Patients with Hepatitis, Cirrhosis, and Hepatoma Evaluated by Plasma Antioxidants

1. To investigate the relative degree to which human IgG and other plasma proteins bind to cell membranes of the full-term human placenta, suspensions of membranes mixed with radio-iodinated proteins were incubated at pH 6·5 and subjected to Sepharose 2B column chromatography. The amount of labelled protein associated with membrane protein in membrane-containing fractions of the eluate was then determined. 2. Binding of IgG and each of the four subclasses of IgG was appreciable. Binding of IgG was markedly reduced if membranes were incubated at pH 8·0 rather than 6·5. Binding of labelled IgG was inhibited by excess of unlabelled IgG but not by excess of unlabelled albumin. Placental membranes bound much more IgG than did erythrocyte membranes. 3. Binding of insulin was relatively greater than that of IgG, whereas binding of IgE, IgM, IgA, albumin, transferrin and polyvinylpyrrolidone was much less than that of IgG and each of its subclasses. 4. The relative binding of IgG and fragments of the IgG molecule was, in decreasing order of magnitude: light chains, IgG, Fc, heavy chains and F(ab′) 2 . 5. The results are consistent with Brambell9s hypothesis for the mechanism of the transmission of passive immunity from mother to young. In particular the data are consistent with the existence of a limited number of IgG specific receptors on the microvillus membrane of the syncytial trophoblast. Such receptors could protect IgG molecules from degradation during their transplacental transport. The submolecular region of the IgG molecule involved in specific membrane binding appears to be common to all four subclasses and to include the Fc region.

The binding of plasma proteins to human placental cell membranes.

1. The kinetics of unconjugated [ 14 C]-bilirubin metabolism have been investigated and analysed in terms of a three-pool model in a group of seven normal subjects and in a group of eight cirrhotic patients who had appreciable impairment of liver cell function. 2. In the patients with cirrhosis, the plasma unconjugated bilirubin was either normal or only slightly increased but the metabolism of unconjugated bilirubin was deranged. 3. The mean volume of distribution, the mean 4 h retention, and the mean mass of the rapidly mixing pool were all significantly greater than in the normal subjects. In contrast, mean fractional clearance rate and mean estimated erythrocyte life-span were significantly less than in the normal subjects. 4. The mean fractional transfer rates and fluxes from pool 1 (rapidly mixing pool—‘plasma’) to pool 3 (‘extravascular’) and vice versa were significantly greater than the corresponding values in the normal subjects. 5. The results indicate that, in patients with compensated cirrhosis, the efficiency of the liver in extracting unconjugated bilirubin from plasma against a concentration gradient is impaired, even though the liver9s capacity to conjugate bilirubin may be normal. As a consequence of the increased volume of distribution, the absolute hepatic clearance of unconjugated bilirubin is relatively well maintained.

E. A. Jones

Papers

The binding of plasma proteins to human placental cell membranes.

Studies on the Kinetics of Unconjugated [14C]Bilirubin Metabolism in Normal Subjects and Patients with Compensated Cirrhosis