fc receptor fc receptor in immunology, a fc receptor is a protein found on the surface of certain cells – including, among others, b lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. its name is derived from its binding specificity for a part of an antibody known as the fc (fragment crystallizable) region. fc receptors bind to antibodies that are attached to infected cells or invading pathogens. their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. some viruses such as flaviviruses use fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection. immunoglobulin-like receptorschematic diagram showing fc receptor interaction with an antibody-coated microbial pathogenidentifierssymbolfc receptormembranome10 classes there are several different types of fc receptors (abbreviated fcr), which are classified based on the type of antibody that they recognize. the latin letter used to identify a type of antibody is converted into the corresponding greek letter, which is placed after the 'fc' part of the name. for example, those that bind the most common class of antibody, igg, are called fc-gamma receptors (fcγr), those that bind iga are called fc-alpha receptors (fcαr) and those that bind ige are called fc-epsilon receptors (fcεr). the classes of fcr's are also distinguished by the cells that express them (macrophages, granulocytes, natural killer cells, t and b cells) and the signalling properties of each receptor. fc-gamma receptors all of the fcγ receptors (fcγr) belong to the immunoglobulin superfamily and are the most important fc receptors for inducing phagocytosis of opsonized (marked) microbes. this family includes several members, fcγri (cd64), fcγriia (cd32), fcγriib (cd32), fcγriiia (cd16a), fcγriiib (cd16b), which differ in their antibody affinities due to their different molecular structure. for instance, fcγri binds to igg more strongly than fcγrii or fcγriii does. fcγri also has an extracellular portion composed of three immunoglobulin (ig)-like domains, one more domain than fcγrii or fcγriii has. this property allows fcγri to bind a sole igg molecule (or monomer), but all fcγ receptors must bind multiple igg molecules within an immune complex to be activated. the fc-gamma receptors differ in their affinity for igg and likewise the different igg subclasses have unique affinities for each of the fc gamma receptors. these interactions are further tuned by the glycan (oligosaccharide) at position ch2-84.4 of igg. for example, by creating steric hindrance, fucose containing ch2-84.4 glycans reduce igg affinity for fcγriiia. in contrast, g0 glycans, which lack galactose and terminate instead with glcnac moieties, have increased affinity for fcγriiia. neonatal fc receptor another fcr is expressed on multiple cell types and is similar in structure to mhc class i. this receptor also binds igg and is involved in preservation of this antibody. however, since this fc receptor is also involved in transferring igg from a mother either via the placenta to her fetus or in milk to her suckling infant, it is called the neonatal fc receptor (fcrn). recently, research suggested that this receptor plays a role in the homeostasis of igg serum levels. fc-alpha receptors only one fc receptor belongs to the fcαr subgroup, which is called fcαri (or cd89). fcαri is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including kupffer cells), and some dendritic cells. it is composed of two extracellular ig-like domains, and is a member of both the immunoglobulin superfamily and the multi-chain immune recognition receptor (mirr) family. it signals by associating with two fcrγ signaling chains. another receptor can also bind iga, although it has higher affinity for another antibody called igm. this receptor is called the fc-alpha/mu receptor (fcα/μr) and is a type i transmembrane protein. with one ig-like domain in its extracellular portion, this fc receptor is also a member of the immunoglobulin superfamily. fc-epsilon receptors two types of fcεr are known: the high-affinity receptor fcεri is a member of the immunoglobulin superfamily (it has two ig-like domains). fcεri is found on epidermal langerhans cells, eosinophils, mast cells and basophils. as a result of its cellular distribution, this receptor plays a major role in controlling allergic responses. fcεri is also expressed on antigen-presenting cells, and controls the production of important immune mediators called cytokines that promote inflammation. the low-affinity receptor fcεrii (cd23) is a c-type lectin. fcεrii has multiple functions as a membrane-bound or soluble receptor; it controls b cell growth and differentiation and blocks ige-binding of eosinophils, monocytes, and basophils. summary table receptor nameprincipal antibody ligandaffinity for ligandcell distributioneffect following binding to antibody fcγri (cd64) igg1 and igg3 high (kd ~ 10−9 m) macrophagesneutrophilseosinophilsdendritic cells phagocytosiscell activationactivation of respiratory burstinduction of microbe killing fcγriia (cd32) igg low (kd > 10−7 m) macrophagesneutrophilseosinophilsplateletslangerhans cells phagocytosis degranulation (eosinophils) fcγriib1 (cd32) igg low (kd > 10−7 m) b cellsmast cells no phagocytosisinhibition of cell activity fcγriib2 (cd32) igg low (kd > 10−7 m) macrophagesneutrophilseosinophils phagocytosisinhibition of cell activity fcγriiia (cd16a) igg low (kd > 10−6 m) nk cellsmacrophages (certain tissues) induction of antibody-dependent cell-mediated cytotoxicity (adcc)induction of cytokine release by macrophages fcγriiib (cd16b) igg low (kd > 10−6 m) eosinophilsmacrophagesneutrophilsmast cells follicular dendritic cells induction of microbe killing fcεri ige high (kd ~ 10−10 m) mast cellseosinophilsbasophilslangerhans cellsmonocytes degranulationphagocytosis fcεrii (cd23) ige low (kd > 10−7 m) b cellseosinophilslangerhans cells possible adhesion moleculeige transport across human intestinal epitheliumpositive-feedback mechanism to enhance allergic sensitization (b cells) fcαri (cd89) iga low (kd > 10−6 m) monocytesmacrophagesneutrophilseosinophils phagocytosisinduction of microbe killing fcα/μr (cd351) iga and igm high for igm, mid for iga b cellsmesangial cellsmacrophages endocytosisinduction of microbe killing fcμr igm (unknown) human fcμr is predominantly expressed by lymphocytes, but not by phagocytes function has not been fully elucidated / diverse fcrn igg high in acidic cellular endosomeslow in ph neutral extracellular environment monocytesmacrophagesdendritic cellsepithelial cellsendothelial cellshepatocytes transfers igg from a mother to fetus through the placentatransfers igg from a mother to infant in milkprotects igg from degradationtransfers igg across endothelial/epithelial layers functions an antibody has fab (fragment, antigen-binding) and fc (fragment, crystallizable) regions. fc receptors bind to the fc region. fc receptors are found on a number of cells in the immune system including phagocytes like macrophages and monocytes, granulocytes like neutrophils and eosinophils, and lymphocytes of the innate immune system (natural killer cells) or adaptive immune system (e.g., b cells). they allow these cells to bind to antibodies that are attached to the surface of microbes or microbe infected cells, helping these cells to identify and eliminate microbial pathogens. the fc receptors bind the antibodies at their fc region (or tail), an interaction that activates the cell that possesses the fc receptor. activation of phagocytes is the most common function attributed to fc receptors. for example, macrophages begin to ingest and kill an igg-coated pathogen by phagocytosis following engagement of their fcγ receptors. another process involving fc receptors is called antibody-dependent cell-mediated cytotoxicity (adcc). during adcc, fcγriii receptors on the surface of natural killer (nk) cells stimulate the nk cells to release cytotoxic molecules from their granules to kill antibody-covered target cells. fcεri has a different function. fcεri is the fc receptor on granulocytes, that is involved in allergic reactions and defense against parasitic infections. when an appropriate allergic antigen or parasite is present, the cross-linking of at least two ige molecules and their fc receptors on the surface of a granulocyte will trigger the cell to rapidly release preformed mediators from its granules. signaling mechanisms - fc gamma receptors activation fc gamma receptors belong to the group of non-catalytic tyrosine-phosphorylated receptors which share a similar signalling pathway involving phosphorylation of tyrosine residues. the receptors generate signals within their cells through an important activation motif known as an immunoreceptor tyrosine-based activation motif (itam). an itam is a specific sequence of amino acids (yxxl) occurring twice in close succession in the intracellular tail of a receptor. when phosphate groups are added to the tyrosine (y) residue of the itam by membrane-anchored enzymes of the src kinase family, a signaling cascade is generated within the cell. this phosphorylation reaction typically follows interaction of an fc receptor with its ligand. an itam is present in the intracellular tail of fcγriia, and its phosphorylation induces phagocytosis in macrophages. fcγri and fcγriiia do not have an itam but can transmit an activating signal to their phagocytes by interacting with another protein that does. this adaptor protein is called the fcγ subunit and, like fcγriia, contains the two yxxl sequences that are characteristic of an itam. inhibition the presence of only one yxxl motif is not sufficient to activate cells, and represents a motif (i/vxxyxxl) known as an immunoreceptor tyrosine-based inhibitory motif (itim). fcγriib1 and fcγriib2 have an itim sequence and are inhibitory fc receptors; they do not induce phagocytosis. inhibitory actions of these receptors are controlled by enzymes that remove phosphate groups from tyrosine residues; the phosphatases shp-1 and ship-1 inhibit signaling by fcγ receptors. binding of ligand to fcγriib leads to phosphorylation of the tyrosine of the itam motif. this modification generates the binding site for the phosphatase, a sh2 recognition domain. the abrogation of itam activation signaling is caused by inhibition of protein tyrosine kinases of src family, and by hydrolyzing the membrane pip3 interrupting the further downstream signaling by the activating receptors, such as activating fcγrs, tcr, bcr and cytokine receptors (e.g. c-kit). the negative signaling by fcγriib is mainly important for regulation of activated b cells. the positive b cell signaling is initiated by binding of foreign antigen to surface immunoglobulin. the same antigen-specific antibody is secreted and it can feedback-suppress, or promote negative signaling. this negative signaling is being provided by fcγriib.: experiments using b cell deletion mutants and dominant-negative enzymes have firmly established an important role for sh2-domain-containing inositol 5-phosphatase (ship) in negative signaling. negative signaling through ship appears to inhibit the ras pathway through sh2 domain competition with grb2 and shc and may involve consumption of intracellular lipid mediators that act as allosteric enzyme activators or that promote entry of extracellular ca2+. cellular activation fc receptors recognize microbes that have been bound by antibodies. the interaction between the bound antibodies and the cell surface fc receptor activates the immune cell to kill the microbe. this example shows the phagocytosis of an opsonized microbe. on phagocytes when igg molecules, specific for a certain antigen or surface component, bind to the pathogen with their fab region (fragment antigen binding region), their fc regions point outwards, in direct reach of phagocytes. phagocytes bind those fc regions with their fc receptors. many low affinity interactions are formed between receptor and antibody that work together to tightly bind the antibody-coated microbe. the low individual affinity prevents fc receptors from binding antibodies in the absence of antigen, and therefore reduces the chance of immune cell activation in the absence of infection. this also prevents agglutination (clotting) of phagocytes by antibody when there is no antigen. after a pathogen has been bound, interactions between the fc region of the antibody and the fc receptors of the phagocyte results in the initiation of phagocytosis. the pathogen becomes engulfed by the phagocyte by an active process involving the binding and releasing of the fc region/fc receptor complex, until the cell membrane of the phagocyte completely encloses the pathogen. on nk cells the fc receptor on nk cells recognize igg that is bound to the surface of a pathogen-infected target cell and is called cd16 or fcγriii. activation of fcγriii by igg causes the release of cytokines such as ifn-γ that signal to other immune cells, and cytotoxic mediators like perforin and granzyme that enter the target cell and promote cell death by triggering apoptosis. this process is known as antibody-dependent cell-mediated cytotoxicity (adcc). fcγriii on nk cells can also associate with monomeric igg (i.e., igg that is not antigen-bound). when this occurs, the fc receptor inhibits the activity of the nk cell. on mast cells activation of mast cell degranulation by ige interaction with fcεri. 1 = antigen; 2 = ige; 3 = fcεri; 4 = preformed mediators (histamine, proteases, chemokines, heparin); 5 = granules; 6 – mast cell; 7 – newly formed mediators (prostaglandins, leukotrienes, thromboxanes, platelet-activating factor) ige antibodies bind to antigens of allergens. these allergen-bound ige molecules interact with fcε receptors