Fc receptor

An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, 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".cite journal |author=Anderson R |title=Manipulation of cell surface macromolecules by flaviviruses |journal=Adv. Virus Res. |volume=59 |issue= |pages=229–74 |year=2003 |pmid=14696331 |doi=]

Classes of Fc receptor

There are several different types of Fc receptors, 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).

Fc-gamma receptors

All FcγRs belong to the immunoglobulin superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized (coated) microbes.cite journal |author=Fridman W |title=Fc receptors and immunoglobulin binding factors |journal=FASEB J |volume=5 |issue=12 |pages=2684–90 |year=1991 |pmid=1916092] This family includes several members; FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b); that differ in their antibody affinities due to their different molecular structure.cite journal |author=Indik Z, Park J, Hunter S, Schreiber A |title=The molecular dissection of Fc gamma receptor mediated phagocytosis |journal=Blood |volume=86 |issue=12 |pages=4389–99 |year=1995 |pmid=8541526] For instance, FcγRI binds to IgG more strongly than FcγRII and FcγRIII, and has an extracellular portion composed of three immunoglobulin (Ig)-like domains, one more domain than FcγRII and FcγRIII. These properties allow activation of FcγRI by a sole IgG molecule (or monomer), while the latter two Fcγ receptors must bind multiple IgG molecules within an immune complex to be activated.

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. [cite journal |author=Zhu X, Meng G, Dickinson B, Li X, Mizoguchi E, Miao L, Wang Y, Robert C, Wu B, Smith P, Lencer W, Blumberg R |title=MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells |journal=J Immunol |volume=166 |issue=5 |pages=3266–76 |year=2001 |pmid=11207281] 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). [cite journal |author=Firan M, Bawdon R, Radu C, Ober R, Eaken D, Antohe F, Ghetie V, Ward E |title=The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans |journal=Int Immunol |volume=13 |issue=8 |pages=993–1002 |year=2001 |pmid=11470769 |doi=10.1093/intimm/13.8.993] [cite journal |author=Simister N, Jacobowitz Israel E, Ahouse J, Story C |title=New functions of the MHC class I-related Fc receptor, FcRn |journal=Biochem Soc Trans |volume=25 |issue=2 |pages=481–6 |year=1997 |pmid=9191140] Recently this receptor has been implicated in being involved in homeostasis of IgG serum levels.

Fc-alpha receptors

Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89).cite journal |author=Otten M, van Egmond M |title=The Fc receptor for IgA (FcalphaRI, CD89) |journal=Immunol Lett |volume=92 |issue=1-2 |pages=23–31 |year=2004 |pmid=15081523 |doi=10.1016/j.imlet.2003.11.018] 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. [cite journal |author=Shibuya A, Honda S |title=Molecular and functional characteristics of the Fcalpha/muR, a novel Fc receptor for IgM and IgA |journal=Springer Semin Immunopathol |volume=28 |issue=4 |pages=377–82 |year=2006 |pmid=17061088 |doi=10.1007/s00281-006-0050-3] 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. [cite journal |author=Cho Y, Usui K, Honda S, Tahara-Hanaoka S, Shibuya K, Shibuya A |title=Molecular characteristics of IgA and IgM Fc binding to the Fcalpha/muR |journal=Biochem Biophys Res Commun |volume=345 |issue=1 |pages=474–8 |year=2006 |pmid=16681999 |doi=10.1016/j.bbrc.2006.04.084]

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. [cite journal |author=Ochiai K, Wang B, Rieger A, Kilgus O, Maurer D, Födinger D, Kinet J, Stingl G, Tomioka H |title=A review on Fc epsilon RI on human epidermal Langerhans cells |journal=Int Arch Allergy Immunol |volume=104 Suppl 1 |issue=1 |pages=63–4 |year=1994 |pmid=8156009] [cite journal |author=Prussin C, Metcalfe D |title=5. IgE, mast cells, basophils, and eosinophils |journal=J Allergy Clin Immunol |volume=117 |issue=2 Suppl Mini-Primer |pages=S450–6 |year=2006 |pmid=16455345 |doi=10.1016/j.jaci.2005.11.016] 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. [cite journal |author=von Bubnoff D, Novak N, Kraft S, Bieber T |title=The central role of FcepsilonRI in allergy |journal=Clin Exp Dermatol |volume=28 |issue=2 |pages=184–7 |year=2003 |pmid=12653710 |doi=10.1046/j.1365-2230.2003.01209.x]

* 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. [cite journal |author=Kikutani H, Yokota A, Uchibayashi N, Yukawa K, Tanaka T, Sugiyama K, Barsumian E, Suemura M, Kishimoto T |title=Structure and function of Fc epsilon receptor II (Fc epsilon RII/CD23): a point of contact between the effector phase of allergy and B cell differentiation |journal=Ciba Found Symp |volume=147 |issue= |pages=23–31; discussion 31–5 |year= |pmid=2695308]

ummary table

Functions of Fc receptors

Fc receptors are found on some cells of the immune system. These include 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). [cite journal |author=Selvaraj P, Fifadara N, Nagarajan S, Cimino A, Wang G |title=Functional regulation of human neutrophil Fc gamma receptors |journal=Immunol Res |volume=29 |issue=1-3 |pages=219–30 |year=2004 |pmid=15181284 |doi=10.1385/IR:29:1-3:219] [cite journal |author=Sulica A, Chambers W, Manciulea M, Metes D, Corey S, Rabinowich H, Whiteside T, Herberman R |title=Divergent signal transduction pathways and effects on natural killer cell functions induced by interaction of Fc receptors with physiologic ligands or antireceptor antibodies |journal=Nat Immun |volume=14 |issue=3 |pages=123–33 |year=1995 |pmid=8832896] [cite journal |author=Sarfati M, Fournier S, Wu C, Delespesse G |title=Expression, regulation and function of human Fc epsilon RII (CD23) antigen |journal=Immunol Res |volume=11 |issue=3-4 |pages=260–72 |year=1992 |pmid=1287120 |doi=10.1007/BF02919132] 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. [cite journal |author=Raghavan M, Bjorkman P |title=Fc receptors and their interactions with immunoglobulins |journal=Annu Rev Cell Dev Biol |volume=12 |issue= |pages=181–220 |year= |pmid=8970726 |doi=10.1146/annurev.cellbio.12.1.181] 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.cite journal |author=Swanson J, Hoppe A |title=The coordination of signaling during Fc receptor-mediated phagocytosis |journal=J Leukoc Biol |volume=76 |issue=6 |pages=1093–103 |year=2004 |pmid=15466916 |doi=10.1189/jlb.0804439] 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. [cite journal |author=Sun P |title=Structure and function of natural-killer-cell receptors |journal=Immunol Res |volume=27 |issue=2-3 |pages=539–48 |year=2003 |pmid=12857997 |doi=10.1385/IR:27:2-3:539] 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 a least two of IgE molecules and their Fc receptors on the surface of a granulocyte will trigger the cell to rapidly release preformed mediators from its granules.

ignaling mechanisms of Fc receptors

Fc gamma receptors generate signals within their cells through an important activation motif known as an "Immunoreceptor tyrosine-based activation motif" (ITAM). [cite journal |author=Pan L, Pei P |title=Signaling transduction by IgG receptors |journal=Chin Med J (Engl) |volume=116 |issue=4 |pages=487–94 |year=2003 |pmid=12875708] 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 enzymes called tyrosine kinases, 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. 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. [cite journal |author=Huang Z, Hunter S, Kim M, Indik Z, Schreiber A |title=The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA |journal=J Leukoc Biol |volume=73 |issue=6 |pages=823–9 |year=2003 |pmid=12773515 |doi=10.1189/jlb.0902454]

Cellular activation by Fc Receptors

Fc receptors 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. [cite journal |author=Joshi T, Butchar J, Tridandapani S |title=Fcgamma receptor signaling in phagocytes |journal=Int J Hematol |volume=84 |issue=3 |pages=210–6 |year=2006 |pmid=17050193 |doi=10.1532/IJH97.06140]

Fc receptors 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. [cite journal |author=Trinchieri G, Valiante N |title=Receptors for the Fc fragment of IgG on natural killer cells |journal=Nat Immun |volume=12 |issue=4-5 |pages=218–34 |year= |pmid=8257828] 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. [cite journal |author=Sulica A, Galatiuc C, Manciulea M, Bancu A, DeLeo A, Whiteside T, Herberman R |title=Regulation of human natural cytotoxicity by IgG. IV. Association between binding of monomeric IgG to the Fc receptors on large granular lymphocytes and inhibition of natural killer (NK) cell activity |journal=Cell Immunol |volume=147 |issue=2 |pages=397–410 |year=1993 |pmid=8453679 |doi=10.1006/cimm.1993.1079]

Fc receptors on mast cells

IgE antibodies bind to antigens of allergens. These allergen-bound IgE molecules interact with Fcε receptors on the surface of mast cells. Activation of mast cells following engagement of FcεRI results in a process called degranulation, whereby the mast cell releases preformed molecules from its cytoplasmic granules; these are a mixture of compounds including histamine, proteoglycans, and serine proteases. [cite journal |author=Yamasaki S, Saito T |title=Regulation of mast cell activation through FcepsilonRI |journal=Chem Immunol Allergy |volume=87 |issue= |pages=22–31 |year= |pmid=16107760] Activated mast cells also synthesize and secrete lipid-derived mediators (such as prostaglandins, leukotrienes, and platelet-activating factor) and cytokines (such as interleukin 1, interleukin 3, interleukin 4, interleukin 5, interleukin 6, interleukin 13, tumor necrosis factor-alpha, GM-CSF, and several chemokines. [cite journal |author=Wakahara S, Fujii Y, Nakao T, Tsuritani K, Hara T, Saito H, Ra C |title=Gene expression profiles for Fc epsilon RI, cytokines and chemokines upon Fc epsilon RI activation in human cultured mast cells derived from peripheral blood |journal=Cytokine |volume=16 |issue=4 |pages=143–52 |year=2001 |pmid=11792124 |doi=10.1006/cyto.2001.0958] [cite journal |author=Metcalfe D, Baram D, Mekori Y |title=Mast cells |journal=Physiol Rev |volume=77 |issue=4 |pages=1033–79 |year=1997 |pmid=9354811] These mediators contribute to inflammation by attracting other leukocytes.

Fc receptors on eosinophils

Large parasites like the helminth (worm) "Schistosoma mansoni" are too large for ingestion by phagocytes. They also have an external structure called an integument that is resistant to attack by substances released by macrophages and mast cells. However, these parasites can become coated with IgE and recognized by FcεRI on the surface of eosinophils. Activated eosinophils release preformed mediators such as major basic protein, and enzymes such as peroxidase, against which helminths are not resistant. [cite journal |author=David J, Butterworth A, Vadas M |title=Mechanism of the interaction mediating killing of Schistosoma mansoni by human eosinophils |journal=Am J Trop Med Hyg |volume=29 |issue=5 |pages=842–8 |year=1980 |pmid=7435788] [cite journal |author=Capron M, Soussi Gounni A, Morita M, Truong M, Prin L, Kinet J, Capron A |title=Eosinophils: from low- to high-affinity immunoglobulin E receptors |journal=Allergy |volume=50 |issue=25 Suppl |pages=20–3 |year=1995 |pmid=7677229 |doi=10.1111/j.1398-9995.1995.tb04270.x] The interaction of the FcεRI receptor with the Fc portion of helminth bound IgE causes the eosinophil to release these molecules in a mechanism similar to that of the NK cell during ADCC. [cite journal |author=Gounni A, Lamkhioued B, Ochiai K, Tanaka Y, Delaporte E, Capron A, Kinet J, Capron M |title=High-affinity IgE receptor on eosinophils is involved in defence against parasites |journal=Nature |volume=367 |issue=6459 |pages=183–6 |year=1994 |pmid=8114916 |doi=10.1038/367183a0]

ee also

* Fc receptor-like molecule

Further reading

* Immunobiology. 5th ed. Janeway, Charles A.; Travers, Paul; Walport, Mark; Shlomchik, Mark. New York and London: Garland Publishing; c2001.

* Cellular and molecular immunology / Abul K. Abbas, Andrew H. Lichtman ; illustrations by David L. Baker, Alexandra Baker. Philadelphia, PA : Elsevier Saunders, c2005

* Stimulatory and inhibitory signals originating from the macrophage Fcγ receptors. Jeffrey S. Gerber and David M. Mosser. Microbes Infect. 2001 Feb;3(2):131-9.

References

External links

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