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===Fc-gamma receptors=== |
===Fc-gamma receptors=== |
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All FcγRs belong to the [[immunoglobulin superfamily]] and are the most important Fc receptors for inducing [[phagocytosis]] of [[opsonization|opsonized]] (coated) microbes.<ref name=fridman>{{cite journal |author=Fridman W |title=Fc receptors and immunoglobulin binding factors |journal=FASEB J |volume=5 |issue=12 |pages= |
All FcγRs belong to the [[immunoglobulin superfamily]] and are the most important Fc receptors for inducing [[phagocytosis]] of [[opsonization|opsonized]] (coated) microbes.<ref name=fridman>{{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}}</ref> This family includes several members; FcγRI (CD64), FcγRIIA ([[CD32]]), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b); that differ in their antibody [[affinity|affinities]] due to their different [[molecular]] [[structure]].<ref name=indik>{{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}}</ref> For instance, FcγRI binds to IgG more strongly than FcγRII and FcγRIII, and has an [[extracellular]] portion composed of three [[Structural domain|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.<ref name=fridman/> |
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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.<ref>{{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= |
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.<ref>{{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}}</ref> 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]]).<ref>{{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}}</ref><ref>{{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}}</ref> Recently this receptor has been implicated in being involved in homeostasis of IgG serum levels. |
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===Fc-alpha receptors=== |
===Fc-alpha receptors=== |
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Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89).<ref name = otten>{{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= |
Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89).<ref name = otten>{{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}}</ref> FcαRI is found on the surface of [[neutrophil]]s, eosinophils, monocytes, some macrophages (including [[Kupffer cell]]s), and some [[dendritic cell]]s.<ref name=otten/> 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.<ref name=fridman/> It signals by associating with two FcRγ signaling chains.<ref name=otten/> Another receptor can also bind IgA, although it has higher affinity for another antibody called [[IgM]].<ref>{{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}}</ref> 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.<ref>{{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}}</ref> |
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===Fc-epsilon receptors=== |
===Fc-epsilon receptors=== |
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Two types of FcεR are known:<ref name=fridman/> |
Two types of FcεR are known:<ref name=fridman/> |
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* the high-affinity receptor FcεRI is a member of the immunoglobulin superfamily (it has two Ig-like domains). FcεRI is found on epidermal [[Langerhans cell]]s, eosinophils, mast cells and basophils.<ref>{{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= |
* the high-affinity receptor FcεRI is a member of the immunoglobulin superfamily (it has two Ig-like domains). FcεRI is found on epidermal [[Langerhans cell]]s, eosinophils, mast cells and basophils.<ref>{{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}}</ref><ref>{{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}}</ref> As a result of its cellular distribution, this receptor plays a major role in controlling [[allergy|allergic responses]]. FcεRI is also expressed on [[antigen-presenting cell]]s, and controls the production of important immune mediators called [[cytokine]]s that promote [[inflammation]].<ref>{{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}}</ref> |
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* the low-affinity receptor FcεRII ([[CD23]]) is a [[lectin|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.<ref>{{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= |
* the low-affinity receptor FcεRII ([[CD23]]) is a [[lectin|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.<ref>{{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}}</ref> |
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===Summary table=== |
===Summary table=== |
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==Functions of Fc receptors== |
==Functions of Fc receptors== |
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[[Image:2fab fc.png|thumb|170px|left|An antibody has Fab (fragment, antigen-binding) and Fc (fragment, crystalizable) regions. Fc receptors bind to the Fc region.]] |
[[Image:2fab fc.png|thumb|170px|left|An antibody has Fab (fragment, antigen-binding) and Fc (fragment, crystalizable) regions. Fc receptors bind to the Fc region.]] |
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Fc receptors are found on some cells of the immune system. These include [[phagocyte]]s like [[macrophage]]s and [[monocyte]]s, [[granulocyte]]s like [[neutrophil]]s and [[eosinophil]]s, and [[lymphocyte]]s of the [[innate immune system]] ([[natural killer cell]]s) or [[adaptive immune system]] (e.g., [[B cell]]s).<ref>{{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= |
Fc receptors are found on some cells of the immune system. These include [[phagocyte]]s like [[macrophage]]s and [[monocyte]]s, [[granulocyte]]s like [[neutrophil]]s and [[eosinophil]]s, and [[lymphocyte]]s of the [[innate immune system]] ([[natural killer cell]]s) or [[adaptive immune system]] (e.g., [[B cell]]s).<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref> |
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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.<ref>{{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= |
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.<ref>{{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}}</ref> Activation of phagocytes is the most common function attributed to Fc receptors. For example, macrophages begin to [[ingestion|ingest]] and kill an [[IgG]]-coated [[pathogen]] by [[phagocytosis]] following engagement of their Fcγ receptors.<ref name = swanson>{{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}}</ref> 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 [[Granule (cell biology)|granule]]s to kill antibody-covered target cells.<ref>{{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}}</ref> |
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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.<ref name = fridman/> |
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.<ref name = fridman/> |
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==Signaling mechanisms of Fc receptors== |
==Signaling mechanisms of Fc receptors== |
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Fc gamma receptors generate signals within their cells through an important activation motif known as an ''[[Immunoreceptor tyrosine-based activation motif]]'' (ITAM).<ref>{{cite journal |author=Pan L, Pei P |title=Signaling transduction by IgG receptors |journal=Chin Med J (Engl) |volume=116 |issue=4 |pages= |
Fc gamma receptors generate signals within their cells through an important activation motif known as an ''[[Immunoreceptor tyrosine-based activation motif]]'' (ITAM).<ref>{{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}}</ref> An ITAM is a specific sequence of [[amino acid]]s (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 [[enzyme]]s called [[tyrosine kinase]]s, a [[cell signaling|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 [[phosphatase]]s [[SHP-1]] and [[SHIP-1]] inhibit signaling by Fcγ receptors.<ref>{{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}}</ref> |
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==Cellular activation by Fc Receptors== |
==Cellular activation by Fc Receptors== |
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[[Image:Fc receptor response.png|thumb|300px|right|Fc receptors recognize [[microbe]]s that have been bound by [[antibody|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 [[opsonization|opsonized]] microbe.]] |
[[Image:Fc receptor response.png|thumb|300px|right|Fc receptors recognize [[microbe]]s that have been bound by [[antibody|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 [[opsonization|opsonized]] microbe.]] |
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===Fc receptors on phagocytes=== |
===Fc receptors on phagocytes=== |
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When [[IgG]] molecules, specific for a certain antigen or surface component, bind to the pathogen with their [[Fragment antigen binding|Fab region]] (fragment antigen binding region), their Fc regions point outwards, in direct reach of [[phagocyte]]s. Phagocytes bind those Fc regions with their Fc receptors.<ref name = swanson/> 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 (biology)|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.<ref>{{cite journal |author=Joshi T, Butchar J, Tridandapani S |title=Fcgamma receptor signaling in phagocytes |journal=Int J Hematol |volume=84 |issue=3 |pages= |
When [[IgG]] molecules, specific for a certain antigen or surface component, bind to the pathogen with their [[Fragment antigen binding|Fab region]] (fragment antigen binding region), their Fc regions point outwards, in direct reach of [[phagocyte]]s. Phagocytes bind those Fc regions with their Fc receptors.<ref name = swanson/> 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 (biology)|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.<ref>{{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}}</ref> |
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===Fc receptors on NK cells=== |
===Fc receptors on NK cells=== |
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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.<ref>{{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= |
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.<ref>{{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}}</ref> Activation of FcγRIII by IgG causes the release of [[cytokine]]s such as [[interferon#type II IFN|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 cellular cytotoxicity|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.<ref>{{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}}</ref> |
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===Fc receptors on mast cells=== |
===Fc receptors on mast cells=== |
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[[Image:Allergy degranulation processes 01.svg|thumb|300px|right|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)]] |
[[Image:Allergy degranulation processes 01.svg|thumb|300px|right|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)]] |
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[[IgE]] antibodies bind to [[antigen]]s of [[allergen]]s. These allergen-bound IgE molecules interact with Fcε receptors on the surface of [[mast cell]]s. Activation of mast cells following engagement of FcεRI results in a process called [[degranulation]], whereby the mast cell releases preformed molecules from its [[cytoplasm]]ic granules; these are a mixture of compounds including [[histamine]], [[proteoglycan]]s, and [[serine protease]]s.<ref>{{cite journal |author=Yamasaki S, Saito T |title=Regulation of mast cell activation through FcepsilonRI |journal=Chem Immunol Allergy |volume=87 |issue= |pages= |
[[IgE]] antibodies bind to [[antigen]]s of [[allergen]]s. These allergen-bound IgE molecules interact with Fcε receptors on the surface of [[mast cell]]s. Activation of mast cells following engagement of FcεRI results in a process called [[degranulation]], whereby the mast cell releases preformed molecules from its [[cytoplasm]]ic granules; these are a mixture of compounds including [[histamine]], [[proteoglycan]]s, and [[serine protease]]s.<ref>{{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}}</ref> Activated mast cells also synthesize and secrete [[lipid]]-derived mediators (such as [[prostaglandin]]s, [[leukotriene]]s, 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 [[chemokine]]s.<ref>{{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}}</ref><ref>{{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}}</ref> These mediators contribute to [[inflammation]] by attracting other [[leukocyte]]s. |
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===Fc receptors on eosinophils=== |
===Fc receptors on eosinophils=== |
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Large parasites like the [[helminth]] (worm) [[Schistosoma|''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 [[eosinophil]]s. Activated eosinophils release preformed mediators such as [[major basic protein]], and [[enzyme]]s such as [[peroxidase]], against which helminths are not resistant.<ref>{{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= |
Large parasites like the [[helminth]] (worm) [[Schistosoma|''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 [[eosinophil]]s. Activated eosinophils release preformed mediators such as [[major basic protein]], and [[enzyme]]s such as [[peroxidase]], against which helminths are not resistant.<ref>{{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}}</ref><ref>{{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}}</ref> 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.<ref>{{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}}</ref> |
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==See also== |
==See also== |
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Revision as of 12:25, 28 May 2008
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.[1]
Classes of Fc receptor
There are several different types of Fc receptors, which are classified based on the type of antibody that they recognize; 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.[2] 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.[3] 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.[2]
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.[4] 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).[5][6] 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).[7] FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including Kupffer cells), and some dendritic cells.[7] 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.[2] It signals by associating with two FcRγ signaling chains.[7] Another receptor can also bind IgA, although it has higher affinity for another antibody called IgM.[8] 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.[9]
Fc-epsilon receptors
Two types of FcεR are known:[2]
- 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.[10][11] 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.[12]
- 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.[13]
Summary table
| Receptor name | Principal antibody ligand | Affinity for ligand | Cell distribution | Effect following binding to antibody |
| FcγRI (CD64) | IgG1 and IgG3 | High (Kd ~ 10-9 M) | Macrophages Neutrophils Eosinophils Dendritic cells |
Phagocytosis Cell activation Activation of respiratory burst Induction of microbe killing |
| FcγRIIA (CD32) | IgG | Low (Kd > 10-7 M) | Macrophages Neutrophils Eosinophils Platelets Langerhans cells |
Phagocytosis Degranulation (eosinophils) |
| FcγRIIB1 (CD32) | IgG | Low (Kd > 10-7 M) | B Cells Mast cells |
No phagocytosis Inhibition of cell activity |
| FcγRIIB2 (CD32) | IgG | Low (Kd > 10-7 M) | Macrophages Neutrophils Eosinophils |
Phagocytosis Inhibition of cell activity |
| FcγRIIIA (CD16a) | IgG | Low (Kd > 10-6 M) | NK cells | Induction of antibody-dependent cell-mediated cytotoxicity (ADCC) |
| FcγRIIIB (CD16b) | IgG | Low (Kd > 10-6 M) | Eosinophils Macrophages Neutrophils Mast cells Follicular dendritic cells |
Induction of microbe killing |
| FcεRI | IgE | High (Kd ~ 10-10 M) | Mast cells Eosinophils Basophils Langerhans cells |
Degranulation |
| FcεRII (CD23) | IgE | Low (Kd > 10-7 M) | B cells Eosinophils Langerhans cells |
Possible adhesion molecule |
| FcαRI (CD89) | IgA | Low (Kd > 10-6 M) | Monocytes Macrophages Neutrophils Eosinophils |
Phagocytosis Induction of microbe killing |
| Fcα/μR | IgA and IgM | High for IgM, Mid for IgA | B cells Mesangial cells Macrophages |
Endocytosis Induction of microbe killing |
| FcRn | IgG | Monocytes Macrophages Dendritic cells Epithelial cells Endothelial cells Hepatocytes |
Transfers IgG from a mother to fetus through the placenta Transfers IgG from a mother to infant in milk Protects IgG from degradation |
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).[14][15][16] 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.[17] 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.[18] 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.[19] 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.[2]
Signaling 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).[20] 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.[21]
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.[18] 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.[22]
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.[23] 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.[24]
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.[25] 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.[26][27] 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.[28][29] 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.[30]
See also
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
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External links
- Fc+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)