Fc receptor

Schematic diagram showing Fc receptor interaction with an antibody-coated microbial pathogen

An 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 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 (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).

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 (coated) microbes.[2] 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.[3] 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.[4]

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.[5] 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).[6][7] 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).[8] FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including Kupffer cells), and some dendritic cells.[8] 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.[8] Another receptor can also bind IgA, although it has higher affinity for another antibody called IgM.[9] 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.[10]

Fc-epsilon receptors

Two types of FcεR are known:[2]

Summary table

Receptor namePrincipal antibody ligandAffinity for ligandCell distributionEffect 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
Macrophages (certain tissues)		 Induction of antibody-dependent cell-mediated cytotoxicity (ADCC)
Induction of cytokine release by macrophages
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
Monocytes		 Degranulation
Phagocytosis
FcεRII (CD23) IgE Low (Kd > 10−7 M) B cells
Eosinophils
Langerhans cells		 Possible adhesion molecule
IgE transport across human intestinal epithelium
Positive-feedback mechanism to enhance allergic sensitization (B cells)
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

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).[15][16][17] 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.[18] 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.[19] 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.[20] 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).[21] 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.[22] 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).[23]

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.:[24] 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+.[25]

Cellular activation by Fc Receptors

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.

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.[19] 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.[26]

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.[27] 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.[28]

Fc receptors 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 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.[29] 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.[30][31] 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.[32][33] 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.[34]

See also

References

  1. ↑ Anderson R (2003). "Manipulation of cell surface macromolecules by flaviviruses". Adv. Virus Res. 59: 229–74. doi:10.1016/S0065-3527(03)59007-8. PMID 14696331.
  2. ↑ 2.0 2.1 2.2 2.3 Fridman W (1991). "Fc receptors and immunoglobulin binding factors". FASEB J 5 (12): 2684–90. PMID 1916092.
  3. ↑ Indik Z, Park J, Hunter S, Schreiber A (1995). "The molecular dissection of Fc gamma receptor mediated phagocytosis". Blood 86 (12): 4389–99. PMID 8541526.
  4. ↑ Harrison, Patrick et al. (1994). "Binding of monomeric immunoglobulin G triggers FcgRI-mediated endocytosis". Journal of Biological Chemistry 39: 24396–24402.
  5. ↑ Zhu X, Meng G, Dickinson B, Li X, Mizoguchi E, Miao L, Wang Y, Robert C, Wu B, Smith P, Lencer W, Blumberg R (2001). "MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells". J Immunol 166 (5): 3266–76. doi:10.4049/jimmunol.166.5.3266. PMC 2827247. PMID 11207281.
  6. ↑ Firan M, Bawdon R, Radu C, Ober R, Eaken D, Antohe F, Ghetie V, Ward E (2001). "The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans". Int Immunol 13 (8): 993–1002. doi:10.1093/intimm/13.8.993. PMID 11470769.
  7. ↑ Simister N, Jacobowitz Israel E, Ahouse J, Story C (1997). "New functions of the MHC class I-related Fc receptor, FcRn". Biochem Soc Trans 25 (2): 481–6. PMID 9191140.
  8. ↑ 8.0 8.1 8.2 Otten M, van Egmond M (2004). "The Fc receptor for IgA (FcalphaRI, CD89)". Immunol Lett 92 (1–2): 23–31. doi:10.1016/j.imlet.2003.11.018. PMID 15081523.
  9. ↑ Shibuya A, Honda S (2006). "Molecular and functional characteristics of the Fcalpha/muR, a novel Fc receptor for IgM and IgA". Springer Semin Immunopathol 28 (4): 377–82. doi:10.1007/s00281-006-0050-3. PMID 17061088.
  10. ↑ Cho Y, Usui K, Honda S, Tahara-Hanaoka S, Shibuya K, Shibuya A (2006). "Molecular characteristics of IgA and IgM Fc binding to the Fcalpha/muR". Biochem Biophys Res Commun 345 (1): 474–8. doi:10.1016/j.bbrc.2006.04.084. PMID 16681999.
  11. ↑ Ochiai K, Wang B, Rieger A, Kilgus O, Maurer D, Födinger D, Kinet J, Stingl G, Tomioka H (1994). "A review on Fc epsilon RI on human epidermal Langerhans cells". Int Arch Allergy Immunol. 104 Suppl 1 (1): 63–4. doi:10.1159/000236756. PMID 8156009.
  12. ↑ Prussin C, Metcalfe D (2006). "5. IgE, mast cells, basophils, and eosinophils". J Allergy Clin Immunol 117 (2 Suppl Mini–Primer): S450–6. doi:10.1016/j.jaci.2005.11.016. PMID 16455345.
  13. ↑ von Bubnoff D, Novak N, Kraft S, Bieber T (2003). "The central role of FcepsilonRI in allergy". Clin Exp Dermatol 28 (2): 184–7. doi:10.1046/j.1365-2230.2003.01209.x. PMID 12653710.
  14. ↑ Kikutani H, Yokota A, Uchibayashi N, Yukawa K, Tanaka T, Sugiyama K, Barsumian E, Suemura M, Kishimoto T (1989). "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". Ciba Found Symp 147: 23–31; discussion 31–5. PMID 2695308.
  15. ↑ Selvaraj P, Fifadara N, Nagarajan S, Cimino A, Wang G (2004). "Functional regulation of human neutrophil Fc gamma receptors". Immunol Res 29 (1–3): 219–30. doi:10.1385/IR:29:1-3:219. PMID 15181284.
  16. ↑ Sulica A, Chambers W, Manciulea M, Metes D, Corey S, Rabinowich H, Whiteside T, Herberman R (1995). "Divergent signal transduction pathways and effects on natural killer cell functions induced by interaction of Fc receptors with physiologic ligands or antireceptor antibodies". Nat Immun 14 (3): 123–33. PMID 8832896.
  17. ↑ Sarfati M, Fournier S, Wu C, Delespesse G (1992). "Expression, regulation and function of human Fc epsilon RII (CD23) antigen". Immunol Res 11 (3–4): 260–72. doi:10.1007/BF02919132. PMID 1287120.
  18. ↑ Raghavan M, Bjorkman P (1996). "Fc receptors and their interactions with immunoglobulins". Annu Rev Cell Dev Biol 12: 181–220. doi:10.1146/annurev.cellbio.12.1.181. PMID 8970726.
  19. ↑ 19.0 19.1 Swanson J, Hoppe A (2004). "The coordination of signaling during Fc receptor-mediated phagocytosis". J Leukoc Biol 76 (6): 1093–103. doi:10.1189/jlb.0804439. PMID 15466916.
  20. ↑ Sun P (2003). "Structure and function of natural-killer-cell receptors". Immunol Res 27 (2–3): 539–48. doi:10.1385/IR:27:2-3:539. PMID 12857997.
  21. ↑ Pan L, Pei P (2003). "Signaling transduction by IgG receptors". Chin Med J (Engl) 116 (4): 487–94. PMID 12875708.
  22. ↑ Huang Z, Hunter S, Kim M, Indik Z, Schreiber A (2003). "The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA". J Leukoc Biol 73 (6): 823–9. doi:10.1189/jlb.0902454. PMID 12773515.
  23. ↑ Cambier, J. C. (June 1997). "Inhibitory receptors abound?". Proc. Natl. Acad. Sci. U.S.A. 94 (12): 5993–5. doi:10.1073/pnas.94.12.5993. PMID 9177155.
  24. ↑ Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV (January 1996). "Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice.". Nature 25 (379): 346–9. doi:10.1038/379346a0. PMID 8552190.
  25. ↑ Coggeshall KM. (June 1998). "Inhibitory signaling by B cell Fc gamma RIIb.". Current Opinion in Immunology 10 (3): 306–12. PMID 9638367.
  26. ↑ Joshi T, Butchar J, Tridandapani S (2006). "Fcgamma receptor signaling in phagocytes". Int J Hematol 84 (3): 210–6. doi:10.1532/IJH97.06140. PMID 17050193.
  27. ↑ Trinchieri G, Valiante N (1993). "Receptors for the Fc fragment of IgG on natural killer cells". Nat Immun 12 (4–5): 218–34. PMID 8257828.
  28. ↑ Sulica A, Galatiuc C, Manciulea M, Bancu A, DeLeo A, Whiteside T, Herberman R (1993). "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". Cell Immunol 147 (2): 397–410. doi:10.1006/cimm.1993.1079. PMID 8453679.
  29. ↑ Yamasaki S, Saito T (2005). "Regulation of mast cell activation through FcepsilonRI". Chem Immunol Allergy 87: 22–31. doi:10.1159/000087568. PMID 16107760.
  30. ↑ Wakahara S, Fujii Y, Nakao T, Tsuritani K, Hara T, Saito H, Ra C (2001). "Gene expression profiles for Fc epsilon RI, cytokines and chemokines upon Fc epsilon RI activation in human cultured mast cells derived from peripheral blood". Cytokine 16 (4): 143–52. doi:10.1006/cyto.2001.0958. PMID 11792124.
  31. ↑ Metcalfe D, Baram D, Mekori Y (1997). "Mast cells". Physiol Rev 77 (4): 1033–79. PMID 9354811.
  32. ↑ David J, Butterworth A, Vadas M (1980). "Mechanism of the interaction mediating killing of Schistosoma mansoni by human eosinophils". Am J Trop Med Hyg 29 (5): 842–8. PMID 7435788.
  33. ↑ Capron M, Soussi Gounni A, Morita M, Truong M, Prin L, Kinet J, Capron A (1995). "Eosinophils: from low- to high-affinity immunoglobulin E receptors". Allergy 50 (25 Suppl): 20–3. doi:10.1111/j.1398-9995.1995.tb04270.x. PMID 7677229.
  34. ↑ Gounni A, Lamkhioued B, Ochiai K, Tanaka Y, Delaporte E, Capron A, Kinet J, Capron M (1994). "High-affinity IgE receptor on eosinophils is involved in defence against parasites". Nature 367 (6459): 183–6. doi:10.1038/367183a0. PMID 8114916.

Further reading

External links