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Gene Review

Fcgr3  -  Fc receptor, IgG, low affinity III

Mus musculus

Synonyms: CD16, Fc-gamma RIII, FcRIII, Fcg receptor III, FcgammaRIII, ...
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Disease relevance of Fcgr3


High impact information on Fcgr3

  • The gamma subunit of immunoglobulin Fc receptors is an essential component of the high-affinity receptor for IgG (Fc gamma RIII) and is associated with the high-affinity receptor for IgG (Fc gamma RI) and the T cell receptor-CD3 complex [6].
  • Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential [7].
  • Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a) [8].
  • FcRgamma signaling is also defective, resulting in a loss of collagen-induced platelet aggregation, mast cell FcepsilonR function, and NK cell FcgammaRIII and 2B4 function [9].
  • FcRbeta is a subunit common to the high-affinity IgE (FcepsilonRI) and low-affinity IgG (FcgammaRIII) receptors, both of which contribute to the initiation of allergic reactions [10].

Chemical compound and disease context of Fcgr3

  • In contrast, neither mast cells nor platelets appeared important for antigen-induced anaphylaxis, which was FcgammaRIII and macrophage dependent and mediated predominantly by PAF [11].
  • BACKGROUND: Although anaphylaxis is classically mediated by IgE, FcepsilonRI, mast cells, and histamine, several rodent studies suggest that an alternative pathway involving IgG, FcgammaRIII, macrophages and platelets, and platelet-activating factor (PAF) may be more important in the anaphylactic response to antigen challenge [11].

Biological context of Fcgr3


Anatomical context of Fcgr3

  • IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcgammaRIII [15].
  • The IC-mediated slow leukocyte rolling velocity and subsequent adhesion and emigration are dependent on Fcgamma receptors (FcgammaRs), particularly FcgammaRIII, with complement C3 and C5 having no detectable role [16].
  • An unexpected critical role of the low-affinity FcgammaRIII was revealed by the use of two different IgG2a anti-red blood cell autoantibodies, which displayed a striking preferential utilization of FcgammaRIII, compared with the high-affinity FcgammaRI [17].
  • We confirmed that IC inflammation of skin can be mediated largely by mast cells expressing C5aR and FcgammaRIII [18].
  • Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher) [19].

Associations of Fcgr3 with chemical compounds


Physical interactions of Fcgr3


Regulatory relationships of Fcgr3

  • These data suggest that in immune complex alveolitis, the activation of FcgammaRIII may induce divergent downstream effector pathways with TNF-alpha acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice [1].
  • Taken together, our results define a novel regulatory pathway with opposite regulation of FcgammaRII (suppressed) and FcgammaRIII (induced) by IFN-gamma on MCs in vitro and anti-GBM IgG in vivo [27].
  • However, mice lacking either the FcgammaRII or the FcgammaRIII were fully capable of upregulating IL-10 production, implicating FcgammaRI in this process [28].
  • We fine that day 14.5 CD4-CD8- double-negative (DN) fetal thymocytes of Fc epsilon RI gamma-/- mice express mRNA of both Fc gamma RIIb1 and Fc gamma RIII [29].
  • IL-4 selectively enhances FcgammaRIII expression and signaling on mouse mast cells [30].

Other interactions of Fcgr3

  • The high-affinity receptor for IgG, FcgammaRI, shares its capacity to bind IgG2a immune complexes (IgG2a-IC) with the low-affinity receptor FcgammaRIII and complement factors, hampering the definition of its biological role [31].
  • IgG Fc receptors (FcgammaRs, especially FcgammaRIII) and complement (in particular, C5a anaphylatoxin) are critical effectors of the acute inflammatory response to immune complexes (ICs) [32].
  • Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas [19].
  • Enhancement was in the same order of magnitude in Fc gamma RIII-/- mice (</=177-fold of controls administered Ag alone), whereas it was abrogated in FcR gamma-/- mice and augmented in Fc gamma RII-/- mice (</=5147-fold of controls) [33].
  • Depending on antibody isotype, mouse B cell depletion is regulated by FcgammaRI-, FcgammaRII-, FcgammaRIII-, and FcgammaRIV-dependent pathways [34].

Analytical, diagnostic and therapeutic context of Fcgr3


  1. Fc gamma RIII-mediated production of TNF-alpha induces immune complex alveolitis independently of CXC chemokine generation. Chouchakova, N., Skokowa, J., Baumann, U., Tschernig, T., Philippens, K.M., Nieswandt, B., Schmidt, R.E., Gessner, J.E. J. Immunol. (2001) [Pubmed]
  2. Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation. Skokowa, J., Ali, S.R., Felda, O., Kumar, V., Konrad, S., Shushakova, N., Schmidt, R.E., Piekorz, R.P., Nürnberg, B., Spicher, K., Birnbaumer, L., Zwirner, J., Claassens, J.W., Verbeek, J.S., van Rooijen, N., Köhl, J., Gessner, J.E. J. Immunol. (2005) [Pubmed]
  3. Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice. Hazenbos, W.L., Gessner, J.E., Hofhuis, F.M., Kuipers, H., Meyer, D., Heijnen, I.A., Schmidt, R.E., Sandor, M., Capel, P.J., Daëron, M., van de Winkel, J.G., Verbeek, J.S. Immunity (1996) [Pubmed]
  4. Mast cells induce autoantibody-mediated vasculitis syndrome through tumor necrosis factor production upon triggering Fcgamma receptors. Watanabe, N., Akikusa, B., Park, S.Y., Ohno, H., Fossati, L., Vecchietti, G., Gessner, J.E., Schmidt, R.E., Verbeek, J.S., Ryffel, B., Iwamoto, I., Izui, S., Saito, T. Blood (1999) [Pubmed]
  5. Both Fcgamma receptor I and Fcgamma receptor III mediate disease in accelerated nephrotoxic nephritis. Tarzi, R.M., Davies, K.A., Claassens, J.W., Verbeek, J.S., Walport, M.J., Cook, H.T. Am. J. Pathol. (2003) [Pubmed]
  6. FcR gamma chain deletion results in pleiotrophic effector cell defects. Takai, T., Li, M., Sylvestre, D., Clynes, R., Ravetch, J.V. Cell (1994) [Pubmed]
  7. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Clynes, R.A., Towers, T.L., Presta, L.G., Ravetch, J.V. Nat. Med. (2000) [Pubmed]
  8. Arthritis critically dependent on innate immune system players. Ji, H., Ohmura, K., Mahmood, U., Lee, D.M., Hofhuis, F.M., Boackle, S.A., Takahashi, K., Holers, V.M., Walport, M., Gerard, C., Ezekowitz, A., Carroll, M.C., Brenner, M., Weissleder, R., Verbeek, J.S., Duchatelle, V., Degott, C., Benoist, C., Mathis, D. Immunity (2002) [Pubmed]
  9. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Wang, D., Feng, J., Wen, R., Marine, J.C., Sangster, M.Y., Parganas, E., Hoffmeyer, A., Jackson, C.W., Cleveland, J.L., Murray, P.J., Ihle, J.N. Immunity (2000) [Pubmed]
  10. Allergy-associated FcRbeta is a molecular amplifier of IgE- and IgG-mediated in vivo responses. Dombrowicz, D., Lin, S., Flamand, V., Brini, A.T., Koller, B.H., Kinet, J.P. Immunity (1998) [Pubmed]
  11. Pathways of anaphylaxis in the mouse. Strait, R.T., Morris, S.C., Yang, M., Qu, X.W., Finkelman, F.D. J. Allergy Clin. Immunol. (2002) [Pubmed]
  12. Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene. Ferraro, T.N., Golden, G.T., Smith, G.G., Martin, J.F., Lohoff, F.W., Gieringer, T.A., Zamboni, D., Schwebel, C.L., Press, D.M., Kratzer, S.O., Zhao, H., Berrettini, W.H., Buono, R.J. Mamm. Genome (2004) [Pubmed]
  13. FcgammaRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia. Meyer, D., Schiller, C., Westermann, J., Izui, S., Hazenbos, W.L., Verbeek, J.S., Schmidt, R.E., Gessner, J.E. Blood (1998) [Pubmed]
  14. Expression of Fc gamma RIII defines distinct subpopulations of fetal liver B cell and myeloid precursors. Carlsson, L., Candéias, S., Staerz, U., Keller, G. Eur. J. Immunol. (1995) [Pubmed]
  15. Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy. Hamaguchi, Y., Xiu, Y., Komura, K., Nimmerjahn, F., Tedder, T.F. J. Exp. Med. (2006) [Pubmed]
  16. C1q governs deposition of circulating immune complexes and leukocyte Fcgamma receptors mediate subsequent neutrophil recruitment. Stokol, T., O'Donnell, P., Xiao, L., Knight, S., Stavrakis, G., Botto, M., von Andrian, U.H., Mayadas, T.N. J. Exp. Med. (2004) [Pubmed]
  17. Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcgamma receptor III. Fossati-Jimack, L., Ioan-Facsinay, A., Reininger, L., Chicheportiche, Y., Watanabe, N., Saito, T., Hofhuis, F.M., Gessner, J.E., Schiller, C., Schmidt, R.E., Honjo, T., Verbeek, J.S., Izui, S. J. Exp. Med. (2000) [Pubmed]
  18. Distinct tissue site-specific requirements of mast cells and complement components C3/C5a receptor in IgG immune complex-induced injury of skin and lung. Baumann, U., Chouchakova, N., Gewecke, B., Köhl, J., Carroll, M.C., Schmidt, R.E., Gessner, J.E. J. Immunol. (2001) [Pubmed]
  19. Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis. Nabbe, K.C., Blom, A.B., Holthuysen, A.E., Boross, P., Roth, J., Verbeek, S., van Lent, P.L., van den Berg, W.B. Arthritis Rheum. (2003) [Pubmed]
  20. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc gamma RII and Fc gamma RIII. Takizawa, F., Adamczewski, M., Kinet, J.P. J. Exp. Med. (1992) [Pubmed]
  21. Transient neutrophil infiltration after allergen challenge is dependent on specific antibodies and Fc gamma III receptors. Taube, C., Dakhama, A., Rha, Y.H., Takeda, K., Joetham, A., Park, J.W., Balhorn, A., Takai, T., Poch, K.R., Nick, J.A., Gelfand, E.W. J. Immunol. (2003) [Pubmed]
  22. Role of associated gamma-chain in tyrosine kinase activation via murine Fc gamma RIII. Bonnerot, C., Amigorena, S., Choquet, D., Pavlovich, R., Choukroun, V., Fridman, W.H. EMBO J. (1992) [Pubmed]
  23. Nerve growth factor modulates Fc gamma receptor expression on murine macrophage J774A.1 cells. Susaki, Y., Tanaka, A., Honda, E., Matsuda, H. J. Vet. Med. Sci. (1998) [Pubmed]
  24. Costimulation of fibronectin receptor promotes Fc gamma R-mediated rescue of IL-3-dependent bone marrow-derived cells from apoptosis. Yoshikawa, H., Sakihama, T., Nakajima, Y., Tasaka, K. J. Immunol. (1996) [Pubmed]
  25. Two distinct regions of the mouse beta Fc gamma R gene control its transcription. Bonnerot, C., Choukroun, V., Marloie, M.A., Fridman, W.H. Immunobiology (1992) [Pubmed]
  26. Functional comparison of Fc epsilon RI, Fc gamma RII, and Fc gamma RIII in mast cells. Alber, G., Kent, U.M., Metzger, H. J. Immunol. (1992) [Pubmed]
  27. Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis. Radeke, H.H., Janssen-Graalfs, I., Sowa, E.N., Chouchakova, N., Skokowa, J., Löscher, F., Schmidt, R.E., Heeringa, P., Gessner, J.E. J. Biol. Chem. (2002) [Pubmed]
  28. Reversal of proinflammatory responses by ligating the macrophage Fcgamma receptor type I. Sutterwala, F.S., Noel, G.J., Salgame, P., Mosser, D.M. J. Exp. Med. (1998) [Pubmed]
  29. T lymphocyte development in the absence of Fc epsilon receptor I gamma subunit: analysis of thymic-dependent and independent alpha beta and gamma delta pathways. Heiken, H., Schulz, R.J., Ravetch, J.V., Reinherz, E.L., Koyasu, S. Eur. J. Immunol. (1996) [Pubmed]
  30. IL-4 selectively enhances FcgammaRIII expression and signaling on mouse mast cells. Chong, H.J., Andrew Bouton, L., Bailey, D.P., Wright, H., Ramirez, C., Gharse, A., Oskeritzian, C., Xia, H.Z., Zhu, J., Paul, W.E., Kepley, C., Schwartz, L.B., Ryan, J.J. Cell. Immunol. (2003) [Pubmed]
  31. FcgammaRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Ioan-Facsinay, A., de Kimpe, S.J., Hellwig, S.M., van Lent, P.L., Hofhuis, F.M., van Ojik, H.H., Sedlik, C., da Silveira, S.A., Gerber, J., de Jong, Y.F., Roozendaal, R., Aarden, L.A., van den Berg, W.B., Saito, T., Mosser, D., Amigorena, S., Izui, S., van Ommen, G.J., van Vugt, M., van de Winkel, J.G., Verbeek, J.S. Immunity (2002) [Pubmed]
  32. C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. Shushakova, N., Skokowa, J., Schulman, J., Baumann, U., Zwirner, J., Schmidt, R.E., Gessner, J.E. J. Clin. Invest. (2002) [Pubmed]
  33. IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain-deficient mice and increased in Fc gamma RII-deficient mice. Wernersson, S., Karlsson, M.C., Dahlström, J., Mattsson, R., Verbeek, J.S., Heyman, B. J. Immunol. (1999) [Pubmed]
  34. Fcgamma receptor-dependent effector mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity. Tedder, T.F., Baras, A., Xiu, Y. Springer Semin. Immunopathol. (2006) [Pubmed]
  35. Maturation-related changes in the expression of Fc gamma RII and Fc gamma RIII on mouse mast cells derived in vitro and in vivo. Katz, H.R., Arm, J.P., Benson, A.C., Austen, K.F. J. Immunol. (1990) [Pubmed]
  36. Expression of FcgammaRIII is required for development of collagen-induced arthritis. Díaz de Ståhl, T., Andrén, M., Martinsson, P., Verbeek, J.S., Kleinau, S. Eur. J. Immunol. (2002) [Pubmed]
  37. Mast cell-derived cytokine expression induced via Fc receptors and Toll-like receptors. Okayama, Y. Chemical immunology and allergy (2005) [Pubmed]
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