Neonatal Fc receptor

The neonatal Fc receptor (FcRn), also known as the Brambell receptor, is a protein that in humans is encoded by the FCGRT gene. The neonatal Fc receptor (FcRn), also known as the Brambell receptor, is a protein that in humans is encoded by the FCGRT gene. The neonatal Fc receptor is an Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin. Further studies revealed a similar receptor in humans, leading to the naming as a neonatal Fc receptor. In humans, however, it is found in the placenta to help facilitate transport of mother's IgG to the growing fetus. It has also been shown to play a role in monitoring IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ. 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. 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. FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells and bone-marrow derived cells. 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. This mechanism provides an explanation for the greater serum circulation half-life of IgG and serum albumin. FcRn is expressed on antigen-presenting leukocytes like dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria. In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier. 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. Studies have shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium. It has been shown that conjugation of some drugs to the Fc domain of IgG or serum albumin significantly increases their half-life. 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. They include: Amevive (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept). Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α. Several autoimmune disorders are caused by the reaction of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also extend the half-life of these pathogenic antibodies and promote autoimmune disease. New 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. This strategy of blocking the binding of autoantibodies to FcRn by injecting higher affinity antibodies can help prevent inflammation in response to self antigen.