18-607: The neonatal fragment crystallizable (Fc) receptor (also FcRn , IgG receptor FcRn large subunit p51 , or Brambell receptor) is a protein that in humans is encoded by the FCGRT gene . It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin . In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk , leading to its name as
36-500: A Foundation Scholarship and in 1922 he graduated B.A. with Senior Moderatorship and gold medal in natural sciences, and was awarded a postgraduate Fellowship prize. During his first degree he was taught by some distinguished scientists including Professors Henry Horatio Dixon FRS , John Joly FRS , and James Brontë Gatenby . After graduation he worked in cytology under Professor James Brontë Gatenby , gained his BSc (subsequently transformed into MSc) in 1923, and his PhD in 1924 (this
54-481: Is abnormally short in mice that lack functional FcRn. IgG, serum albumin and other serum proteins are continuously internalized into cells through pinocytosis . Generally, internalized serum proteins are transported from early endosomes to lysosomes , where they are degraded. Following entry into cells, the two most abundant serum proteins, IgG and serum albumin, are bound by FcRn at the slightly acidic pH (<6.5) within early (sorting) endosomes, sorted and recycled to
72-496: Is possible because FcRn binds IgG at acidic pH (<6.5) but not at neutral or higher pH. The binding site for FcRn on IgG has been mapped using functional and structural studies, and involves in the interaction of relatively well conserved histidine residues on IgG with acidic residues on FcRn. FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation of these proteins in endothelial cells and bone-marrow derived cells. The clearance rate of IgG and albumin
90-701: The 'Abdeg' technology was recently approved (as 'Vyvgart') for the treatment of generalized myasthenia gravis in December 2021. Francis Brambell Francis William Rogers Brambell (25 February 1901 – 6 June 1970) was an Irish medical scientist who spent all of his professional working life in Britain. Brambell was born in Sandycove , Dublin and was educated (1911–1914) at Aravon School and then privately, specializing in zoology. He entered Trinity College Dublin with an Entrance Prize in natural science. In 1920 Brambell won
108-496: The Fc region of IgG or serum albumin to generate fusion proteins 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-mediated recycling. They include: Amevive ( alefacept ), Arcalyst ( rilonacept ), Enbrel ( etanercept ), Nplate ( romiplostim ), Orencia ( abatacept ) and Nulojix ( belatacept ). Enbrel ( etanercept )
126-474: 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. More recent approaches involve the strategy of blocking
144-460: The binding of IgG to FcRn by delivering antibodies that bind with high affinity to this receptor through their Fc region or variable regions. These engineered Fc fragments or antibodies are being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and skin blistering diseases (pemphigus), and the Fc-based inhibitor, efgartigimod, based on
162-545: The brand name Nulojix , is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4 , which is a molecule crucial in the regulation of T cell costimulation , selectively blocking the process of T-cell activation. It is intended to provide extended graft and transplant survival while limiting the toxicity generated by standard immune suppressing regimens , such as calcineurin inhibitors . It differs from abatacept (Orencia) by only two amino acids. Belatacept
180-417: The cell surface where they are released at the neutral pH (>7.0) of the extracellular environment. In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation. This cellular mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin and transport of these ligands across cellular barriers. In addition, for cell types bathed in an acidic environment such as
198-513: The engineering of IgG-FcRn interactions to increase in vivo persistence of IgG. For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has been approved for the treatment of autoimmunity and a half-life extended antibody cocktail (Evusheld) with 'YTE' mutations is used for the prophylaxis of SARS-CoV2. Engineering of albumin-FcRn interactions has also generated albumin variants with increased in vivo half-lives. It has also been shown that conjugation of some drugs to
SECTION 10
#1732847474954216-476: 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 also shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium. The identification of FcRn as a central regulator of IgG levels led to
234-484: The neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus. FcRn has also been shown to play a role in regulating IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF , and down-regulated by IFN-γ . In addition to binding to IgG, FCGRT has been shown to interact with human serum albumin . FcRn-mediated transcytosis of IgG across epithelial cells
252-465: The slightly acidic intestinal lumen , cell surface FcRn can bind to IgG, transport bound ligand across intestinal epithelial cells followed by release at the near neutral pH at the basolateral surface. FcRn is expressed on antigen-presenting leukocytes such as 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
270-694: Was elected a Fellow of the Royal Society in March, 1949 and won their Royal Medal in 1964 "In recognition of his important contribution to our understanding of the passage of protein from maternal to foetal circulations". In 1965, Brambell lead the UK governmental committee that authored The Five Freedoms , a document asserting the five essential freedom to guarantee quality of life for animals under human control. He died on 6 June 1970. He had married Margaret L. Adgie in 1927. Belatacept Belatacept , sold under
288-418: Was the father of the field of transmission of immunity . As part of his quantitative and temporal studies on transmission, he defined the first Fc receptor system for IgG , and furthermore recognized the link between transmission of passive immunity from mother to young and protection from catabolism via IgG. Brambell wrote Antibodies and Embryos with W. A. Hemmings and M. Henderson in 1951. Brambell
306-673: Was the first PhD of Trinity College Dublin ). In 1924 he was awarded a Science Research Scholarship for the Exhibition of 1851. Owing to the formation of the Irish Free State, Irish graduates had become eligible for the overseas awards of the commission. Brambell was appointed Lloyd Roberts Professor and Head of the Department of Zoology at Bangor University in 1930 at age 29 years. From that time until his retirement 38 years later, he brought great distinction to his Department and College. He
324-405: Was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α. Multiple autoimmune disorders are caused by the binding of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on these pathogenic antibodies and promote autoimmune disease. Therapies seek to disrupt
#953046