Cloning and analysis of the gene encoding the human neonatal Fc receptor

Mikulska, J; Pablo, Lourdes; Canel, Jason; Simister, Neil E.

doi:10.1046/j.1365-2370.2000.00225.x

Cited by 34 publications

(19 citation statements)

References 55 publications

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“…With further advances made in the analysis and cloning of the gene encoding the human neonatal Fc receptor (20,21), the identification of a binding motif for cytokine-inducible transcription factors, NF-IL6 (nuclear factor IL-6), NF1 (nuclear factor 1), and TGF-β upstream of the gene encoding the FcRn α-chain, suggests that raised levels of these cytokines might increase FcRn transcription and hence increase serum IgG concentrations. This process might be of importance during an acute inflammatory response in which IL-6 is known to be operational (22).…”

Section: Discussionmentioning

confidence: 99%

Distribution of the IgG Fc Receptor, FcRn, in the Human Fetal Intestine

Shah¹,

Dickinson²,

Blumberg³

et al. 2003

Pediatric Research

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The intestinal Fc receptor, FcRn, functions in the maternofetal transfer of gamma globulin (IgG) in the neonatal rodent. In humans, most of this transfer is presumed to occur in utero via the placenta. Although the fetus swallows amniotic fluid that contains immunoglobulin, it is unknown whether this transfer also occurs via the fetal intestine. A human FcRn has been identified in the syncytiotrophoblast that mediates the maternofetal transfer of antibody. It has also been identified in human fetal intestine and is postulated to function in IgG transport. We hypothesize that the human fetal intestinal FcRn may play a role in IgG transport from the amniotic fluid into the fetal circulation. The aim of this study was to characterize the distribution of the FcRn along the human fetal intestine. Lysates prepared from human fetal intestine and from a nonmalignant human fetal intestinal epithelial cell line (H4) were subjected to Western blot analysis and probed using anti-FcRn antibodies. A 42-kD band, consistent with the known molecular weight of the FcRn, was detected along the human fetal intestine and in H4 cells. Expression of the human FcRn was confirmed with immunohistochemistry. Our study demonstrates the expression of FcRn along the human fetal intestine and in a human nonmalignant fetal intestinal epithelial cell line (H4), which by location indicates that FcRn could play a role in the uptake and transport of IgG in the human fetus.Humoral immunity acquired via maternofetal transfer of antibody is critical in the prevention of perinatal infections. In rodents, this transfer occurs through the yolk sac and the intestine via a Fc receptor for IgG (FcRn). This receptor has been considered important in the maternofetal transmission of IgG in the yolk sac of mice and rats and also in the human placental syncytiotrophoblast (1). The FcRn is also expressed in the small intestine of suckling mice and rats, where the receptor functions in the uptake of IgG from ingested maternal milk. Although a FcRn has been demonstrated on the human fetal small intestine, a similar function for this receptor in the human fetal intestine has not been demonstrated to date.The acquisition of humoral immunity early in life may have a significant lifelong impact on the prevention of infectious and inflammatory diseases. Because IgG synthesis in the human fetus is reduced, most IgG in the blood of newborns is maternal in origin. Low levels of IgG

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Section: Discussionmentioning

confidence: 99%

Distribution of the IgG Fc Receptor, FcRn, in the Human Fetal Intestine

Shah¹,

Dickinson²,

Blumberg³

et al. 2003

Pediatric Research

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“…FcRn is encoded by FCGRT , a gene located on chromosome 19 [135]. To date, little is known about potential polymorphisms of this gene influencing the pharmacokinetics of mAbs [8].…”

Section: Immunoglobulin-metabolizing Enzymesmentioning

confidence: 99%

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

2016

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Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.

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“…The human FCGRT gene is not associated with either a typical TATA or transcription initiator sequences (Mikulska et al, 2000). Analysis of the 5′-flanking region of the human FCGRT gene initially identified the region from −600 to +300 as containing regulatory activity and identified binding sites for several transcription factors, including a consensus Sp1-element at −640, an Sp1-like sequence at −625, and an additional Sp1 site at +80 (Mikulska et al, 2000). Collectively, these are thought to promote FcRn expression, because Sp1 can induce gene transcription in the absence of a classical TATA box.…”

Section: Regulation Of Fcrn Expressionmentioning

confidence: 99%