Disease relevance of Fcgr3

• In this study, we investigated the relative contribution of FcgammaRIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo [1].
• AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology [2].
• Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice [3].
• Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis [4].
• The low-affinity receptor (FcgammaRIII) has previously been shown to be important in passive heterologous immune complex glomerulonephritis [5].

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

• Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150 [12].
• In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcgammaRIII knock-out mice, as documented by a decrease in hematocrit [13].
• Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcgammaRIII reflects an activation of FcgammaRI that is normally coexpressed with FcgammaRIII on macrophages [13].
• Polymerase chain reaction analysis revealed that the prevalent Fc gamma R isoform at this stage of FL development (day 12 of gestation) was Fc gamma RIII [14].
• Here, we demonstrate that mice deficient for the ligand-binding alpha chain of Fc gamma RIII lack NK cell-mediated antibody-dependent cytotoxicity and phagocytosis of IgG1-coated particles by macrophages [3].

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

• Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin [20].
• These results demonstrate that neutrophil influx after allergen challenge requires prior sensitization, is allergen-specific, is mediated through FcgammaRIII, and is dependent on the presence of Ab [21].
• Role of associated gamma-chain in tyrosine kinase activation via murine Fc gamma RIII [22].
• Northern blot analysis with digoxigenin-labeled oligonucleotide probes demonstrated that NGF induced a marked increase in mRNA synthesis of FcgammaRI and FcgammaRII, but not FcgammaRIII [23].
• These findings indicated that FN induces the costimulatory signal through integrin receptor and enhances the proliferative effect through Fc gamma RIII by a low concentration of IgG [24].

Physical interactions of Fcgr3

• In mice, the beta Fc gamma R gene codes for Fc gamma RII and the alpha Fc gamma R gene codes for the ligand-binding Fc gamma RIII alpha-chain [25].
• The functional results also complement the recently reported evidence that Fc gamma RIII can interact with Fc epsilon RI beta-subunits (J. Exp. Med. 175:447, 1992) [26].

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

• These results indicate a prominent role for Fc gamma RIII in inflammatory and anaphylactic responses, making this receptor a potential target in immunotherapy [3].
• Thus, the three populations of mast cells express different amounts and ratios of the Fc gamma RII and Fc gamma RIII gene products, and maturation of BMMC during coculture with fibroblasts in vitro and in the peritoneal cavity in vivo augments cell-surface expression of the receptors and immune adherence function [35].
• Immunoprecipitation and SDS-PAGE analysis of Fc gamma RII and Fc gamma RIII from BMMC, cocultured mast cells, and SMC that were surface radiolabeled with Na125I revealed predominant native forms of 62, 57, and 56 kDa, respectively, and an additional surface form of 43 kDa in SMC [35].
• Expression of FcgammaRIII is required for development of collagen-induced arthritis [36].
• Moreover, several recent observations in animal models have indicated that MCs may also play a pivotal role in coordinating the early phases of autoimmune diseases through production of TNF-alpha, particularly as a result of FcgammaRIII-mediated activation by autoantibodies [37].

References