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The neonatal Fc receptor (FcRn): From Biology to Therapy

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Antibodies are the adapter molecules that link recognition of foreign antigens or pathogens to effector mechanisms of the immune system. Of the five antibody classes, IgG is the most prevalent in blood where it protects against intruders and toxins. Importantly, IgG is transported from mother to fetus or ...

Antibodies are the adapter molecules that link recognition of foreign antigens or pathogens to effector mechanisms of the immune system. Of the five antibody classes, IgG is the most prevalent in blood where it protects against intruders and toxins. Importantly, IgG is transported from mother to fetus or newborn, and furthermore, has an unusual long half-life of three weeks in humans. Both features are solely due to its interaction with a cellular receptor named the neonatal Fc receptor (FcRn), also known as the Brambell receptor. FcRn resides within endosomal compartments. It directs IgG taken up by pinocytosis back out of cells to the circulation, and thereby rescues IgG from lysosomal degradation. Thus, FcRn serves as a homeostatic regulator of IgG catabolism and directs the biodistribution of IgG.

Recent years have also witnessed an enormous increase in our knowledge of FcRn functions beyond its well-characterized role in half-life regulation, as it transports IgG within and across many different cell types in the body, such as endothelial cells, cells of the placenta, mucosal epithelial cells, kidney cells, liver cells and dendritic cells. In dendritic cells, FcRn is engaged in orchestration and delivery of IgG bound antigens to processing pathways that promote presentation on MHC class II molecules and cross-presentation on MHC class I molecules, while unbound IgG is recycled and rescued, like in endothelial cells lining the blood vessels. Moreover, expression of FcRn has been identified in many other tissues, including the blood-brain barrier, the glomerular filters of the kidneys and the liver. These findings merit further studies on the diverse roles of FcRn at these body sites.

Beside IgG, FcRn binds albumin, which is also protected from intracellular degradation. While IgG combats infections, and is produced by plasma cells, albumin is exclusively produced by hepatocytes and serves as a multi-transporter that fulfils essential roles as a carrier of an array of nutrients,
hormones, drugs and toxins throughout the body. Albumin is the most abundant protein in blood due to the rate of synthesis and its interaction with FcRn.

Importantly, since IgG and albumin are extensively explored as therapeutics or carrier of drugs, there is an intense interest in engineering of novel variants with modulated FcRn binding kinetics tailored for improved pharmacokinetics and therapeutic efficacy. FcRn is a major histocompatibility complex (MHC) class I-related receptor, and knowledge of how FcRn binds both its ligands and ligand variants is of great importance.

In this research topic, we aim to provide a comprehensive state-of the art overview of current research on the versatile functions of FcRn, and encourage submission of research articles, reviews and perspectives. Considering the clinical significance of FcRn, we also aim to provide a range of articles summarizing the current knowledge on how our understanding of FcRn functions that can be translated into development of new therapeutics.


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