The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Jan Terje Andersen - One of the best experts on this subject based on the ideXlab platform.
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the neonatal Fc Receptor Fcrn a misnomer
Frontiers in Immunology, 2019Co-Authors: Michal Pyzik, Jan Terje Andersen, Inger Sandlie, Richard S Blumberg, Kine Marita Knudsen Sand, Jonathan J HubbardAbstract:Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and Receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) Receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface Receptors as well as atypical intracellular Receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc Receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis Receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune Receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.
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trim21 a cytosolic Fc Receptor with broad antibody isotype specificity
Immunological Reviews, 2015Co-Authors: Stian Foss, Ruth E. Watkinson, Inger Sandlie, Leo C James, Jan Terje AndersenAbstract:Antibodies are key molecules in the fight against infections. Although previously thought to mediate protection solely in the extracellular environment, recent research has revealed that antibody-mediated protection extends to the cytosolic compartment of cells. This postentry viral defense mechanism requires binding of the antibody to a cytosolic Fc Receptor named tripartite motif containing 21 (TRIM21). In contrast to other Fc Receptors, TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG but also IgM and IgA. When viral pathogens coated with these antibody isotypes enter the cytosol, TRIM21 is rapidly recruited and efficient neutralization occurs before the virus has had the time to replicate. In addition, inflammatory signaling is induced. As such, TRIM21 acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment. Here, we summarize our current understanding of how TRIM21 orchestrates humoral immunity in the cytosolic environment.
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Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc Receptor.
Nature Communications, 2012Co-Authors: Jan Terje Andersen, Jason Cameron, Muluneh Bekele Daba, Leslie Evans, Stephan O. Brennan, Kristin Støen Gunnarsen, Bjørn Dalhus, Magnar Bjoras, Andrew Plumridge, Darrell SleepAbstract:Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc Receptor. Andersen et al. investigate the albumin binding site of the neonatal Fc Receptor and find pH sensitive ionic networks at the binding interface.
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Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc Receptor
Nature Communications, 2012Co-Authors: Jan Terje Andersen, Jason Cameron, Muluneh Bekele Daba, Leslie Evans, Stephan O. Brennan, Kristin Støen Gunnarsen, Bjørn Dalhus, Magnar Bjoras, Andrew Plumridge, Darrell SleepAbstract:Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc Receptor. Andersen et al . investigate the albumin binding site of the neonatal Fc Receptor and find pH sensitive ionic networks at the binding interface. Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc Receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn–albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. Molecular details of the FcRn–albumin complex may guide the development of novel albumin variants with altered serum half-life as carriers of drugs.
Richard S Blumberg - One of the best experts on this subject based on the ideXlab platform.
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the neonatal Fc Receptor Fcrn a misnomer
Frontiers in Immunology, 2019Co-Authors: Michal Pyzik, Jan Terje Andersen, Inger Sandlie, Richard S Blumberg, Kine Marita Knudsen Sand, Jonathan J HubbardAbstract:Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and Receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) Receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface Receptors as well as atypical intracellular Receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc Receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis Receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune Receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.
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transepithelial transport of Fc targeted nanoparticles by the neonatal Fc Receptor for oral delivery
Science Translational Medicine, 2013Co-Authors: Eric M Pridgen, Richard S Blumberg, Timothy Kuo, Frank Alexis, Etgar Levynissenbaum, Rohit Karnik, Robert LangerAbstract:Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc Receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration.
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the immunologic functions of the neonatal Fc Receptor for igg
Journal of Clinical Immunology, 2013Co-Authors: Timo Rath, Timothy T Kuo, Derry C Roopenian, Kristi Baker, Masaru Yoshida, Shuowang Qiao, Wayne I Lencer, Kanna Kobayashi, Edda Fiebiger, Richard S BlumbergAbstract:Careful regulation of the body’s immunoglobulin G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. As such, the neonatal Fc Receptor (FcRn), as a single Receptor, is capable of regulating both of these molecules and has become an important focus of investigation. In addition to these essential protection functions, FcRn possesses a number of other functions that are equally as critical and are increasingly coming to attention. During the very first stages of life, FcRn mediates the passive transfer of IgG from mother to offspring both before and after birth. In the adult, FcRn regulates the persistence of both IgG and albumin in the serum as well as the movement of IgG, and any bound cargo, between different compartments of the body via transcytosis across polarized cells. FcRn is also expressed by hematopoietic cells; consistent with this, FcRn regulates MHC class II presentation and MHC class I cross-presentation by dendritic cells. As such, FcRn plays an important role in immune surveillance throughout adult life. The increasing appreciation for FcRn in both homeostatic and pathological conditions is generating an intense interest in the potential for therapeutic modulation of FcRn binding to IgG and albumin.
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neonatal Fc Receptor from immunity to therapeutics
Journal of Clinical Immunology, 2010Co-Authors: Timothy T Kuo, Victoria G. Aveson, Kristi Baker, Masaru Yoshida, Shuowang Qiao, Wayne I Lencer, Richard S BlumbergAbstract:The neonatal Fc Receptor (FcRn), also known as the Brambell Receptor and encoded by Fcgrt, is a MHC class I like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional antigen presenting cells. Its function is evident in early life in the transport of IgG from mother to fetus and neonate for passive immunity and later in the development of adaptive immunity and other functions throughout life. The unique ability of this Receptor to prolong the half-life of IgG and albumin has guided engineering of novel therapeutics. Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn.
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immune and non immune functions of the not so neonatal Fc Receptor Fcrn
Seminars in Immunopathology, 2009Co-Authors: Kristi Baker, Masaru Yoshida, Shuowang Qiao, Wayne I Lencer, Kanna Kobayashi, Timothy Kuo, Richard S BlumbergAbstract:Careful regulation of the body’s immunoglobulin-G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. As such, the neonatal Fc Receptor (FcRn) which, as a single Receptor, is capable of regulating both of these molecules, has become an important focus of investigation. In addition to these essential protection functions, FcRn possesses a host of other functions that are equally as critical. During the very first stages of life, FcRn mediates the passive transfer of IgG from mother to offspring both before and after birth. In the adult, FcRn regulates the persistence of both IgG and albumin in the serum as well as the movement of IgG, and any bound cargo, between different compartments of the body. This shuttling allows for the movement not only of monomeric ligand but also of antigen/antibody complexes from one cell type to another in such a way as to facilitate the efficient initiation of immune responses towards opsonized pathogens. As such, FcRn continues to play the role of an immunological sensor throughout adult life, particularly in regions such as the gut which are exposed to a large number of infectious antigens. Increasing appreciation for the contributions of FcRn to both homeostatic and pathological states is generating an intense interest in the potential for therapeutic modulation of FcRn binding. A greater understanding of FcRn’s pleiotropic roles is thus imperative for a variety of therapeutic purposes.
Mark P Hogarth - One of the best experts on this subject based on the ideXlab platform.
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dimeric Fcγr ectodomains as probes of the Fc Receptor function of anti influenza virus igg
Journal of Immunology, 2016Co-Authors: Bruce Wines, Hillary A Vanderven, Sandra Esparon, Anne B Kristensen, Stephen J Kent, Mark P HogarthAbstract:Ab-dependent cellular cytotoxicity, phagocytosis, and Ag presentation are key mechanisms of action of Abs arising in vaccine or naturally acquired immunity, as well of therapeutic mAbs. Cells expressing the low-affinity FcγRs (FcγRII or CD32 and FcγRIII or CD16) are activated for these functions when Receptors are aggregated following the binding of IgG-opsonized targets. Despite the diversity of the Fc Receptor proteins, IgG ligands, and potential responding cell types, the induction of all FcγR-mediated responses by opsonized targets requires the presentation of multiple Fc regions in close proximity to each other. We demonstrated that such "near-neighbor" Fc regions can be detected using defined recombinant soluble (rs) dimeric low-affinity ectodomains (rsFcγR) that have an absolute binding requirement for the simultaneous engagement of two IgG Fc regions. Like cell surface-expressed FcγRs, the binding of dimeric rsFcγR ectodomains to Ab immune complexes was affected by Ab subclass, presentation, opsonization density, Fc fucosylation, or mutation. The activation of an NK cell line and primary NK cells by human IgG-opsonized influenza A hemagglutinin correlated with dimeric rsFcγRIIIa binding activity but not with Ab titer. Furthermore, the dimeric rsFcγR binding assay sensitively detected greater Fc Receptor activity to pandemic H1N1 hemagglutinin after the swine influenza pandemic of 2009 in pooled human polyclonal IgG. Thus these dimeric rsFcγR ectodomains are validated, defined probes that should prove valuable in measuring the immune-activating capacity of IgG Abs elicited by infection or vaccination or experimentally derived IgG and its variants.
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the igg Fc contains distinct Fc Receptor Fcr binding sites the leukocyte Receptors Fcγri and Fcγriia bind to a region in the Fc distinct from that recognized by neonatal Fcr and protein a
Journal of Immunology, 2000Co-Authors: Bruce D Wines, Paul W H I Parren, Maree S Powell, Nadine Barnes, Mark P HogarthAbstract:The CH2-CH3 interface of the IgG Fc domain contains the binding sites for a number of Fc Receptors including Staphylococcal protein A and the neonatal Fc Receptor (FcRn). It has recently been proposed that the CH2-CH3 interface also contains the principal binding site for an isoform of the low affinity IgG Fc Receptor II (Fc gamma RIIb). The Fc gamma RI and Fc gamma RII binding sites have previously been mapped to the lower hinge and the adjacent surface of the CH2 domain although contributions of the CH2-CH3 interface to binding have been suggested. This study addresses the question whether the CH2-CH3 interface plays a role in the interaction of IgG with Fc gamma RI and Fc gamma RIIa. We demonstrate that recombinant soluble murine Fc gamma RI and human Fc gamma RIIa did not compete with protein A and FcRn for binding to IgG, and that the CH2-CH3 interface therefore appears not to be involved in Fc gamma RI and Fc gamma RIIa binding. The importance of the lower hinge was confirmed by introducing mutations in the proposed binding site (LL234,235AA) which abrogated binding of recombinant soluble Fc gamma RIIa to human IgG1. We conclude that the lower hinge and the adjacent region of the CH2 domain of IgG Fc is critical for the interaction between Fc gamma RIIa and human IgG, whereas contributions of the CH2-CH3 interface appear to be insignificant.
Darrell Sleep - One of the best experts on this subject based on the ideXlab platform.
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Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc Receptor.
Nature Communications, 2012Co-Authors: Jan Terje Andersen, Jason Cameron, Muluneh Bekele Daba, Leslie Evans, Stephan O. Brennan, Kristin Støen Gunnarsen, Bjørn Dalhus, Magnar Bjoras, Andrew Plumridge, Darrell SleepAbstract:Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc Receptor. Andersen et al. investigate the albumin binding site of the neonatal Fc Receptor and find pH sensitive ionic networks at the binding interface.
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Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc Receptor
Nature Communications, 2012Co-Authors: Jan Terje Andersen, Jason Cameron, Muluneh Bekele Daba, Leslie Evans, Stephan O. Brennan, Kristin Støen Gunnarsen, Bjørn Dalhus, Magnar Bjoras, Andrew Plumridge, Darrell SleepAbstract:Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc Receptor. Andersen et al . investigate the albumin binding site of the neonatal Fc Receptor and find pH sensitive ionic networks at the binding interface. Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc Receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn–albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. Molecular details of the FcRn–albumin complex may guide the development of novel albumin variants with altered serum half-life as carriers of drugs.
Pamela J Bjorkman - One of the best experts on this subject based on the ideXlab platform.
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crystal structure and immunoglobulin g binding properties of the human major histocompatibility complex related Fc Receptor
Biochemistry, 2000Co-Authors: And Anthony P West, Pamela J BjorkmanAbstract:The neonatal Fc Receptor (FcRn) performs two distinct but related functions: transport of maternal immunoglobulin G (IgG) to pre- or neonatal mammals, thus providing passive immunity, and protection of IgG from normal serum protein catabolism. FcRn is related to class I MHC proteins but lacks a functional peptide binding groove. The crystal structure of human FcRn has been determined at 2.7 A resolution and compared to the previously described structure of rat FcRn [Burmeister et al. (1994) Nature 372, 336−343] and to the structures of MHC and MHC-related proteins. Human FcRn is structurally similar to the rat Receptor but does not form Receptor dimers in the crystals as observed in crystals of rat FcRn. The interaction between human FcRn and IgG was characterized by determining the binding stoichiometry using equilibrium gel filtration and by deriving binding affinities for the different human IgG subclasses using a surface plasmon resonance assay. Like rat and mouse FcRn, human FcRn interacts with IgG with a 2:1 Receptor:ligand stoichiometry. The binding of human FcRn to the four human IgG subclasses shows subclass and allotype variations but no clear subclass affinity differences that correlate with serum half-lives. The structure of human FcRn and studies of its ligand binding are relevant to current efforts to use FcRn-mediated regulation of IgG half-life in serum to increase the lifetimes of antibody-based therapeutics.
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crystal structure at 2 2 a resolution of the mhc related neonatal Fc Receptor
Nature, 1994Co-Authors: Wilhelm P Burmeister, Louis N Gastinel, Neil E Simister, M Blum, Pamela J BjorkmanAbstract:The three-dimensional structure of the rat neonatal Fc Receptor (FcRn) is similar to the structure of molecules of the major histocompatibility complex (MHC). The counterpart of the MHC peptide-binding site is closed in FcRn, making the FcRn groove incapable of binding peptides. A dimer of FcRn heterodimers seen in the crystals may represent a Receptor dimer that forms when the Fc portion of a single immunoglobulin binds. An alternative use of the MHC fold for immune recognition is indicated by the FcRn and FcRn/Fc co-crystal structures.
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crystal structure of the complex of rat neonatal Fc Receptor with Fc
Nature, 1994Co-Authors: Wilhelm P Burmeister, Andrew H Huber, Pamela J BjorkmanAbstract:The neonatal Fc Receptor (FcRn) transports maternal immunoglobulin G (IgG) to the bloodstream of the newborn. FcRn is structurally similar to class I major histocompatibility complex (MHC) molecules, despite differences in the ligands they bind (the Fc portion of IgG and antigenic peptides, respectively). A low-resolution crystal structure of the complex between FcRn and Fc localizes the binding site for Fc to the side of FcRn, distinct from the tops of the αl and α2 domains which serve as the peptide and T-cell Receptor binding sites in class I molecules. FcRn binds to Fc at the interface between the Fc C_H2 and C_H3 domains, which contains several histidine residues that could account for the sharply pH-dependent FcRn/IgG interaction. A dimer of FcRn heterodimers observed in the co-crystals and in the crystals of FcRn alone could be involved in binding Fc, correlating with the 2:1 binding stoichiometry between FcRn and IgG (ref. 4) and suggesting an unusual orientation of FcRn on the membrane.
