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Indik, ZK, JG Park, S. Hunter, and AD Schreiber. "The molecular dissection of Fc gamma receptor mediated phagocytosis." Blood 86, no. 12 (December 15, 1995): 4389–99. http://dx.doi.org/10.1182/blood.v86.12.4389.bloodjournal86124389.
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Because hematopoietic cells express multiple Fc gamma receptor isoforms, the role of the individual Fc gamma receptors in phagocytosis has been difficult to define. Transfection of Fc gamma receptors into COS-1 cells, which lack endogeneous Fc gamma receptors but have phagocytic potential, has proved valuable for the study of individual Fc gamma receptor function. Using this model system, we have established that a single class of human Fc gamma receptor mediates phagocytosis in the absence of other Fc receptors and that isoforms from each Fc gamma receptor class mediate phagocytosis, although the requirements for phagocytosis differ. In investigating the relationship between structure and function for Fc gamma receptor mediated phagocytosis, the importance of the cytoplasmic tyrosines of the receptor or its associated gamma chain has been established. For example, two cytoplasmic YXXL sequences, in a configuration similar to the conserved tyrosine-containing motif found in Ig gene family receptors, are important for phagocytosis by the human Fc gamma receptor, Fc gamma RIIA. Fc gamma RI and Fc gamma RIIIA do not possess cytoplasmic tyrosines but transmit a phagocytic signal through interaction with an associated gamma subunit that contains two YXXL sequences in a conserved motif required for phagocytosis. The human Fc gamma RII isoforms Fc gamma RIIB1 and Fc gamma RIIB2 do not induce phagocytosis and have only a single YXXL sequence. Cross-linking the phagocytic Fc gamma receptors induces tyrosine phosphorylation of either Fc gamma RIIA or the gamma chain, and treatment with tyrosine kinase inhibitors reduces both phagocytosis and phosphorylation of the receptor tyrosine residues. Activation of protein tyrosine kinases follows Fc gamma receptor engagement of IgG-coated cells. The data indicate that coexpression of the protein tyrosine kinase Syk, which is associated with the gamma chain in monocytes/macrophages, is important for phagocytosis mediated by Fc gamma RI and Fc gamma RIIIA. Furthermore, phosphatidylinositol-3 kinase is required for phagocytosis mediated by Fc gamma RIIA as well as for phagocytosis mediated by Fc gamma RI/gamma and Rc gamma RIIIA/gamma.
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Weng, Wen-Kai, Jeffrey Stavenhagen, Scott Koenig, and Ronald Levy. "Rituximab Variants with Re-Engineered Fc with Higher Affinity to Activating Fcγ R Eliminate the Functional Difference between Fcγ R Genotypes." Blood 106, no. 11 (November 16, 2005): 347. http://dx.doi.org/10.1182/blood.v106.11.347.347.
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Abstract We and others have found that IgG Fc receptor, Fcγ RIIIa Valine/Valine (V/V) and Fcγ RIIa Histidine/Histidine (H/H) genotypes predicted the response to rituximab in follicular lymphoma patients probably due to their higher affinity to the constant region (Fc) of rituximab during antibody-dependent cellular cytotoxicity (ADCC). Patients with low affinity Fcγ RIIIa Phenylalanine (F) carrier (V/F and F/F) and Fcγ RIIa Arginine (R) carrier (H/R and R/R) have much lower chance to respond to rituximab and have a brief remission when they responded. This observation implicates the interaction between the Fc of rituximab and Fcγ R on effectors (NK cells and macrophages) as a determinant for clinical response. Therefore, it may be possible to re-engineer the Fc of rituximab to increase its affinity to Fcγ R and thereby to enhance the antibody’s ability to mediate ADCC and to improve its clinical efficacy. Rituximab variants with re-engineered Fc were generated by MacroGenics. Single amino acid substitutions with increased affinity to different Fcγ R alleles were identified by screening a yeast library containing randomly mutated Fc. Further re-engineering was accomplished by combining multiple amino acid substitutions within both the Fcγ R-binding CH2 and the conformational CH3 domains of the Fc to further improve their affinity. We have tested 12 such variants for their ability to mediate ADCC against primary follicular lymphoma targets. Three variants (4, 10, 12) showed significant enhancement in ADCC compared to rituximab, using effector cells of V/V genotype. We then tested whether the enhancement of ADCC applies to effectors of different Fcγ RIIIa genotypes. In one experiment, at a 30:1 effector/target ratio, specific ADCC lysis for rituximab, Variant 6 (a modest enhancer) and Variant 10 (a strong enhancer) were 37%, 50% and 66%, respectively, with V/V effectors and 23%, 36% and 65%, respectively, with F/F effectors. Thus, enhancement of ADCC by these variants applied to effectors of both high (V/V) and low (F/F) affinity Fcγ Rs. In one case, Variant 10, enhancement of ADCC with effctors of low affinity Fcγ R, brought its activity up to that of effectors with the high affinity Fcγ R. We further examined the ability of these variants to engage and internalize the Fcγ R on NK cells as a measure of primary engagement of Fcγ R. Rituximab-coated tumor cells reduced the surface Fcγ RIIIa on NK cells of V/V genotype by 78% determined by flow cytometric analysis. By comparison, Variant 6 down-regulated surface Fcγ RIIIa by 84% and Variant 10 by 88%. For NK cells of F/F genotype, rituximab down-regulated surface Fcγ RIIIa by 32%, Variant 6 by 64% and Variant 10 by 68%. This result confirmed that two rituximab variants were more effective in interacting with effectors of both high and low affinity Fcγ Rs. This study has demonstrated that several rituximab variants with re-engineered Fc showed increased interaction with Fcγ R on effectors and mediated ADCC more effectively than rituximab even with effectors of low affinity Fcγ R genotypes. These rituximab variants may prove to be more effective therapeutic anti-CD20 antibodies than rituximab, especially for patients with low affinity Fcγ Rs. Figure Figure
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Meisel, P., LE Carlsson, H. Sawaf, J. Fanghaenel, A. Greinacher, and T. Kocher. "Polymorphisms of Fcγ-receptors RIIa, RIIIa, and RIIIb in patients with adult periodontal diseases." Genes & Immunity 2, no. 5 (August 2001): 258–62. http://dx.doi.org/10.1038/sj.gene.6363777.
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Ahlgrimm, Manfred, Evi Regitz, Klaus-Dieter Preuss, Sandra Grass, Viola Poeschel, Markus Kreuz, and Michael Pfreundschuh. "Single Nucleotide Polymorphisms (SNPs) of FCγRIIA and FCγRIIIA in Patients with Diffuse Large B-Cell Lymphoma Have No Impact On Treatment Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with CHOP with and without Rituximab: Results From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymhoma Study Group (DSHNHL)." Blood 114, no. 22 (November 20, 2009): 3956. http://dx.doi.org/10.1182/blood.v114.22.3956.3956.
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Abstract Abstract 3956 Poster Board III-892 BACKGROUND During the last decade the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has significantly improved by the addition of rituximab (R) to the standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Despite this improvement in response rates, event- progression and overall survival, about one third of the patients with DLBCL will eventually fail. The main therapeutic efficacy of rituximab is not fully elucidated. One major effector mechanism is by antibody dependent cellular cytotoxicity (ADCC) mediated by cell-bound rituximab via its FCg part that activates effector cells by binding to their Fcg receptor (FCγR). Three classes and eight subclasses of FCγR have been described. SNPs have been detected for FcgRIIA at amino acid position (AA) 131 where histidin is substituted by arginin (131 R/H) and for FCγRIIIA at position 158, where phenylalanine is substituted by valine (158 V/F). These SNPs have an increased affinity to Fcg and induce a stronger ADCC which explains better responses to rituximab treatment in follicular lymphoma. The aim of this study was to determine the impact of FCγRIIA and FCγRIIIA SNPs on the outcome R-CHOP chemotherapy in elderly patients with newly diagnosed DLBCL. PATIENTS AND METHODS In the RICOVER-60 therapy study 1222 elderly patients (aged 61-80 years) were randomly assigned to 6 or 8 cycles of CHOP, both with or without rituximab (Pfreundschuh et al., Lancet Oncology 2008). The control group (n=100) consisted of anonymous healthy blood donors of Saarland University Institute of Transfusion Medicine. Available for this study were peripheral blood samples from 570 patients who were representative for the entire RICOVER-60 population. The 2 FCgR SNPs FCγ-RIIa AA 131 R/H and FCγ-RIIIa 158 V/F were determined and univariate and multivariate analyses adjusting for the IPI-relevant risk factors (LDH, ECOG performance status, advanced stage and >1 extranodal involvement) were performed for the entire study population and separately for patients receiving or not receiving rituximab. RESULTS Frequencies of FCγ-RIIa and FCγ-RIIIa polymorphisms were not different in healthy controls compared to DLBCL patients. In our statistical analyses finaly 512 patients were included. The characteristic for the groups were for group 1 (6x CHOP-14) 127 patients (24.8%), for group 2 (8x CHOP-14) 122 patients (23.83%), for group 3 (6x CHOP-14+8x rituximab) 124 patients (24.22%) and for group 4 (8x CHOP-14 + 8x rituximab) 139 patients (27.15%) [fisher test (included vs excluded): p=0.4691]. The median age at admission was the same for included and excluded patients. The gender characteristics for the included patients were well balanced [fisher test (included vs excluded): p=1.0000]. The median observation time for the included vs. excluded patients was 40.25 months vs. 34.50 months. This verification shows that the collective of included patients represents the whole RICOVER-60 population. Statistical analyses of overall survival, 3 year event-free survival and 3 year overall-survival were done for the complete RICOVER-60 population. 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In summary, event-free, progression free, overall survival and complete remission rates were not different among patients with FCγ-RIIa (AA 131R/H) and FCγ-RIIIa (AA 158 V/F) SNPs, irrespective of whether the entire RICOVER-60 population was analysed or when patients treated with and without rituximab were analysed separately. CONCLUSIONS FCγ-RIIa and FCγ-RIIIa SNPs have no influence on the outcome of patients treated with CHOP-14 with or without rituximab. Therefore, modifications of schedule and dose of rituximab according to the underlying FCγ-R SNPs are not justified. Supported by a HOMFOR grant of Saarland University Medical School, Homburg, Germany Disclosures: Pfreundschuh: Roche MabThera Advisory Board: Consultancy, Honoraria.
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Matsuda, M., J. G. Park, D. C. Wang, S. Hunter, P. Chien, and A. D. Schreiber. "Abrogation of the Fc gamma receptor IIA-mediated phagocytic signal by stem-loop Syk antisense oligonucleotides." Molecular Biology of the Cell 7, no. 7 (July 1996): 1095–106. http://dx.doi.org/10.1091/mbc.7.7.1095.
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The role of Syk kinase in Fc gamma receptor (Fc gamma R) IIA-mediated phagocytosis was examined with two forms of antisense oligodeoxynucleotides (ODNs) designed to hybridize to human Syk mRNA. Monocytes were incubated with linear and stem-loop antisense ODNs targeted to Syk mRNA. When complexed with cationic liposomes, stem-loop Syk antisense ODN with phosphorothioate modification exhibited stability in fetal bovine and human serum. The stem-loop Syk antisense ODN at a concentration of 0.2 microM inhibited Fc gamma RIIA-mediated phagocytosis by 90% and completely eliminated Syk mRNA and protein in monocytes, whereas scrambled-control ODNs had no effect. The Syk antisense ODNs did not change beta-actin mRNA levels and Fc gamma RII cell-surface expression. In addition, stem-loop Syk antisense ODN inhibited Fc gamma RI and Fc gamma RIIIA-mediated phagocytosis. These data indicate the efficacy of stem-loop Syk antisense ODN for targeting and degrading Syk mRNA and protein and the importance of Syk kinase in Fc gamma receptor-mediated phagocytosis. Immunoblotting assay demonstrated that Fc gamma RII tyrosine phosphorylation after Fc gamma RII cross-linking did not change in the absence of Syk protein. These results indicate that Syk kinase is required for Fc gamma RIIA-mediated phagocytic signaling and that Fc gamma RII cross-linking leads to tyrosine phosphorylation of Fc gamma RII independent of Syk kinase.
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Hernandez, A., E. Bandres, J. Rodriguez, N. Bitarte, N. Ramirez, R. Zarate, A. Abajo, A. Chopitea, A. Viudez, and J. Garcia-Foncillas. "Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14531-e14531. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14531.
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e14531 Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts. No significant financial relationships to disclose.
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Edberg, J. C., and R. P. Kimberly. "Cell type-specific glycoforms of Fc gamma RIIIa (CD16): differential ligand binding." Journal of Immunology 159, no. 8 (October 15, 1997): 3849–57. http://dx.doi.org/10.4049/jimmunol.159.8.3849.
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Abstract Fc gamma RIIIa, considered an intermediate affinity receptor, can variably bind monomeric IgG and appears to have a higher affinity for IgG than the lower affinity Fc gamma Rs, Fc gamma RII and Fc gamma RIIIb. We explored this property for both NK cell and monocyte Fc gamma RIIIa and found higher affinity ligand binding by Fc gamma RIIIa expressed on NK cells compared with Fc gamma RIIIa on monocytes. In normal whole blood or plasma (containing 8-11 mg/ml IgG), NK cell Fc gamma RIIIa was fully blocked, but in monocytes Fc gamma RIIIa showed approximately 60% blockade of the binding of mAb 3G8, which binds in or near the ligand binding site. The ligand binding site of NK cell Fc gamma RIIIa was blocked with as little as 2 mg/ml of human IgG, while monocyte Fc gamma RIIIa was only partially (30%) blocked by 2 mg/ml of human IgG. In contrast, plasma containing approximately 26 mg/ml of IgG (obtained from patients receiving therapeutic gamma-globulin) showed complete saturation of monocyte Fc gamma RIIIa with blockade of mAb 3G8 binding. These binding differences are not due to allelic polymorphisms or primary sequence differences between donors. Although NK cell and monocyte Fc gamma RIIIa have identical protein cores, they each undergo differential cell type-specific glycosylation. NK cell Fc gamma RIIIa is glycosylated with high mannose- and complex-type oligosaccharides, while monocyte Fc gamma RIIIa has no high mannose-type oligosaccharides. These results indicate that natural glycoforms of Fc gamma RIIIa (cell type-specific glycosylation variants) bind ligand differently, conferring a lower affinity on monocyte/macrophage Fc gamma RIIIa, which makes the receptor ideal for initial immune complex capture and sensitive to moderate changes in serum IgG levels.
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Indik, ZK, JG Park, XQ Pan, and AD Schreiber. "Induction of phagocytosis by a protein tyrosine kinase." Blood 85, no. 5 (March 1, 1995): 1175–80. http://dx.doi.org/10.1182/blood.v85.5.1175.bloodjournal8551175.
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The transmission of extracellular signals to cellular targets by many noncatalytic surface receptors is dependent on interaction between cytoplasmic protein tyrosine kinases (PTKs) and tyrosine-containing sequences in the cytoplasmic domain of the receptor or an associated subunit. Isoforms of each of the three classes of the noncatalytic Fc gamma receptors, Fc gamma RI, Fc gamma RII, and Fc gamma RIII, are able to transmit a phagocytic signal in transfected COS-1 cells. Both Fc gamma RI and Fc gamma RIIIA require the gamma subunit for this signaling event. The protein tyrosine kinase Syk dramatically enhances phagocytosis mediated by both these receptors and increases the number of cells able to mediate phagocytosis. Two gamma chain cytoplasmic YXXL sequences are required for this effect. The action of Syk is less pronounced on the phagocytic Fc gamma RII receptor, Fc gamma RIIA, which does not require the gamma chain for phagocytosis. However, Syk allows phagocytosis by the nonphagocytic Fc gamma RII receptor Fc gamma RIIB2, which contains only a single YXXL sequence, when an additional tyrosine-containing sequence, YMTL, is introduced. These studies indicate that the efficiency of phagocytosis is markedly enhanced by the presence of a specific protein tyrosine kinase.
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de Haas, M., H. R. Koene, M. Kleijer, E. de Vries, S. Simsek, M. J. van Tol, D. Roos, and A. E. von dem Borne. "A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa." Journal of Immunology 156, no. 8 (April 15, 1996): 2948–55. http://dx.doi.org/10.4049/jimmunol.156.8.2948.
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Abstract A donor-dependent difference in electrophoretic mobility of deglycosylated released Fc gamma RIIIa derived from NK cells and macrophages was observed. We investigated whether this was based on a polymorphism of the Fc gamma RIIIA gene. Cloning and sequencing of Fc gamma RIIIa-encoding cDNA derived from an apparently heterozygous donor showed one single nucleotide substitution at position 230 (T-->G), which was responsible for a leucine (L)-->arginine (R) substitution at position 48 in the first extracellular Ig-like domain (EC1) of Fc-gamma RIIIa and caused a higher electrophoretic mobility of Fc gamma RIIIa. An allele-specific primer annealing PCR assay was developed to amplify specifically an Fc gamma RIIIA gene-derived fragment, which was digested with AciI (recognizing G230) or MnlI (recognizing T230). MnlI restriction analysis revealed the presence of a third Fc gamma RIIIa allele with a T230-->A substitution, which predicts a change of 48-leucine into 48-histidine (H). A gene frequency of 86% for the T230 (48-L) allele, 6% for G230 (48-R), and 8% for A230 (48-H) was found. A significantly different genotype distribution was found among 12 unrelated Caucasian Fc gamma RIIIB gene-deficient donors. Fc gamma RIIIa-48R and Fc gamma RIIIa-48H showed a higher binding capacity of human (h)IgG1, hIgG3, and hIgG4 compared with Fc gamma RIIIa-48L. Finally, the CD16 mAbs 1D3 and MEM154 bound more strongly and Leu11c (B73.1) bound less to the newly identified Fc gamma RIIIa isoforms.
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Garcia-Foncillas, Jesus, Javier Rodriguez, Valentina Boni, Iosu Sola, Beatriz Honorato, Ruth Zarate, and Eva Bandres. "Role of polymorphic fc gamma receptor II/III in the efficacy of cetuximab in KRAS-NRAS-BRAF-PI3K mutated." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 477. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.477.
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477 Background: The immunoglobulin G1 (IgG1) monoclonal antibody (MoAb) cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumors. IgG1 may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by FcγR polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus cetuximab. Methods: Tumor tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester. UK). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumors (61% vs 39%, p=0.049). In EGFR downstream-mutated mCRC patients, those harbouring a FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% vs 33%, p=0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p=0.008). Conclusions: FcγR polymorphisms may play a role in the clinical efficacy of cetuximab in EGFR downstream mutated mCRC patients. Further research into cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.
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Boettcher, Sebastian, Matthias Ritgen, Christiane Pott, Andreas Humpe, and Michael Kneba. "Development and Evaluation of a Novel Flow Cytometric Assay for Determination of Fcγ Receptor IIIa-158 V/F Dimorphism." Blood 104, no. 11 (November 16, 2004): 1366. http://dx.doi.org/10.1182/blood.v104.11.1366.1366.
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Abstract A recently described dimorphism at position 559 of FCGR3A gene results in two allotypes of Fcγ receptor IIIa (Fcγ RIIIa) with phenylalanine (F) or valine (V) at amino acid position 158. It has been shown that Fcγ RIIIa-VV homozygous patients with follicular lymphoma respond better to Rituximab as a single agent than F carriers. However, there is evidence that this disadvantage in F carriers can be overcome by higher Rituximab concentrations or by the use of defucosylated therapeutic antibodies. Therefore rapid, widely applicable, and cost-effective methods for the determination of this Fcγ RIIIa dimorphism are necessary. Currently available methods to determine this dimorphism are based on PCR techniques. To simplify the determination of Fcγ RIIIa-V/F dimorphism we developed a novel flow cytometric approach using known differences in epitope recognition of monoclonal antibodies (moabs) to Fcγ RIIIa. The moab MEM-154 recognizes Fcγ RIIIa-V only, whereas moab 3G8 recognizes Fcγ RIIIa irrespective of the dimorphism. We determined the expression level of epitopes recognized by 3G8 and MEM-154 in NK cells of 35 healthy donors (FF 14; V/F 17; VV 4) by three color flow cytometry and secondary immunofluorescence. Results were compared to genotypes determined by a TaqMan assay using allele specific fluorochrome labelled probes. Donors genotyped as Fcγ RIIIa FF, V/F, and VV demonstrated overlapping immunofluorescence levels detected by both 3G8 and MEM-154. However, the ratio of fluorescence measured using MEM-154 divided by the immunofluorescence measured using 3G8 was 100% accurate for predicting genotypes. Ratios below 0.05 were measured in Fcγ RIIIa FF individuals, ratios between 0.1 and 0.5 were measured in heterozygotes, whereas ratios higher than 0.6 were found in Fcγ RIIIa VV individuals only. Quantitative flow cytometry demonstrated a great variation in Fcγ RIIIa expression on NK cells between individuals with identical Fcγ R IIIa genotype explaining the failure to predict the genotype by a single Fcγ R IIIa moab only. This novel flow cytometric assay is cost-efficient, easy to implement, reliable and uses standard flow cytometric techniques. Compared to known methods to determine the dimorphism it is faster and applicable in laboratories without sophisticated PCR technology.
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de Haas, M., M. Kleijer, R. M. Minchinton, D. Roos, and A. E. von dem Borne. "Soluble Fc gamma RIIIa is present in plasma and is derived from natural killer cells." Journal of Immunology 152, no. 2 (January 15, 1994): 900–907. http://dx.doi.org/10.4049/jimmunol.152.2.900.
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Abstract Fc gamma RIII (CD16), a receptor for complexed IgG, is encoded by two very homologous genes: Fc gamma RIIIA and Fc gamma RIIIB. NK cells and macrophages express Fc gamma RIIIa, whereas only neutrophils constitutively express Fc gamma RIIIb. In a previous study we found that soluble (s)Fc gamma RIII in plasma seemed to originate only from neutrophils. However, CD16 mAb, directed against different epitopes of Fc gamma RIII, precipitated a glycoprotein from plasma of homozygous Fc gamma RIIIB gene-deficient donors. This glycoprotein migrated in a similar way as did released Fc gamma RIIIa derived from NK cells, whereas Fc gamma RIIIa released by cultured monocytes migrated differently and appeared to be more heavily glycosylated on SDS-PAGE. After deglycosylation, the M(r) of the plasma sFc gamma RIIIa was similar to that of released Fc gamma RIIIa. Moreover, V8-protease maps were identical. Therefore, we conclude that sFc gamma RIIIa is also present in plasma and is derived from NK cells. Because sFc gamma RIII levels are hardly detectable in the plasma of most homozygous Fc gamma RIIIB gene-deficient donors, we suspect that the sFc gamma RIIIa level is negligible compared with the level of sFc gamma RIIIb in plasma of healthy donors. Two patients with an NK cell lymphocytosis had a high plasma level of sFc gamma RIIIaNK. Furthermore, high levels of sFc gamma RIIIaNK were found in plasma of two patients with rheumatoid arthritis. Thus, the level of sFc gamma RIIIaNK might reflect either an increase in circulating NK cells or an enhanced release of Fc gamma RIIIaNK in certain diseases. This study shows that an assay that discriminates between sFc gamma RIIIa and sFc gamma RIIIb is necessary for the interpretation of sFc gamma RIII levels in patients.
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Daegelen, P., and E. Brody. "The rIIA gene of bacteriophage T4. I. Its DNA sequence and discovery of a new open reading frame between genes 60 and rIIA." Genetics 125, no. 2 (June 1, 1990): 237–48. http://dx.doi.org/10.1093/genetics/125.2.237.
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Abstract We have determined the DNA sequence of the rIIA gene and have discovered a small open reading frame, rIIA.1, between genes 60 and rIIA. The predicted molecular weights of these proteins are 82,840 for rIIA and 8,124 for rIIA.1. The rIIA protein has a repeated motif which suggests that the gene has evolved by duplication. It also has a motif which suggests that it belongs to a group of ompR-like proteins that control regulation of gene expression in response to changes in the external environment. We have sequenced three different missense mutants whose mutations lie in the Ala segment of the rIIA genetic map. All three changes are found within the first 35 bp of the rIIA coding sequence. The region of control of protein synthesis is identical in the rIIA gene and in gene 44 of T4. We relate this finding to the high sensitivity of both RNAs to translational repression by the T4 regA gene product.
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Mares, Rizia Mendes. "Rizia Mendes Mares." Geografia em Atos (Online) 8, no. 15 (December 31, 2019): 1. http://dx.doi.org/10.35416/geoatos.v8i15.7084.
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Mares, Rizia Mendes. "Rizia Mendes Mares." Geografia em Atos (Online) 4, no. 19 (December 19, 2020): V. http://dx.doi.org/10.35416/geoatos.v4i19.8285.
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Salcedo, T. W., T. Kurosaki, P. Kanakaraj, J. V. Ravetch, and B. Perussia. "Physical and functional association of p56lck with Fc gamma RIIIA (CD16) in natural killer cells." Journal of Experimental Medicine 177, no. 5 (May 1, 1993): 1475–80. http://dx.doi.org/10.1084/jem.177.5.1475.
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The transmembrane receptor for immunoglobulin G immune complexes on natural killer (NK) cells and macrophages, Fc gamma RIIIA (CD16), mediates cellular activation through a tyrosine kinase-dependent pathway. We show that Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells and demonstrate a physical association of p56lck with Fc gamma RIIIA in immunoprecipitates from NK cells obtained using anti-Fc gamma RIII antibodies or immune complexes. Our studies show that the zeta chain, the signal transducing subunit of Fc gamma RIIIA and of T cell receptor, associates with p56lck and, in NK cells, is a substrate for this kinase. Such direct association of p56lck with the zeta subunit as confirmed by demonstrating the interaction in heterologous cells transfected with cDNA expressing p56lck and zeta. Our findings demonstrate both functional and physical association of p56lck with Fc gamma RIIIA, through direct interaction of the kinase with the zeta and/or the gamma signal transducer subunits of the receptor. These data suggest a possible mechanism by which activation via Fc gamma RIIIA occurs.
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Azzoni, L., M. Kamoun, T. W. Salcedo, P. Kanakaraj, and B. Perussia. "Stimulation of Fc gamma RIIIA results in phospholipase C-gamma 1 tyrosine phosphorylation and p56lck activation." Journal of Experimental Medicine 176, no. 6 (December 1, 1992): 1745–50. http://dx.doi.org/10.1084/jem.176.6.1745.
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Binding of ligand to the alpha subunit of Fc gamma RIIIA(CD16), expressed at the natural killer (NK) cell membrane in association with homo or heterodimers of proteins of the zeta family, results in phosphorylation of several proteins on tyrosine residues. We have analyzed the role of protein tyrosine phosphorylation in the regulation of molecular events induced upon stimulation of Fc gamma RIIIA in NK cells and in T cells expressing the Fc gamma RIII alpha chain in association with endogenous zeta 2 homodimers and devoid of other (CD3, CD2) transducing molecules. Our data indicate that treatment of these cells with protein tyrosine kinase inhibitors prevents not only Fc gamma RIIIA-induced protein tyrosine phosphorylation but also phosphatidylinositol 4,5 diphosphate hydrolysis and increased intracellular Ca2+ concentration, indicating a primary role of tyrosine kinase(s) in the induction of these early activation events. Occupancy of Fc gamma RIIIA by ligand results in phospholipase C (PLC)-gamma 1 tyrosine phosphorylation in NK cells and in Fc gamma RIIIA-transfected CD3-/CD2- T cells, and induces functional activation of p56lck in Fc gamma RIIIA alpha/zeta 2-transfected T cells, suggesting the possibility that the receptor-induced PLC-gamma 1 activation occurs upon phosphorylation of its tyrosine residues mediated by this kinase and is, at least in part, responsible for the signal transduction mediated via CD16 upon ligand binding.
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Mitrovic, Z., I. Aurer, I. Radman, R. Ajdukovic, J. Sertic, and B. Labar. "FC RIIIA and FC RIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma." Haematologica 92, no. 7 (July 1, 2007): 998–99. http://dx.doi.org/10.3324/haematol.10327.
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Carlotti, E., G. A. Palumbo, E. Oldani, D. Tibullo, S. Salmoiraghi, A. Rossi, J. Golay, A. Pulsoni, R. Foa, and A. Rambaldi. "Fc RIIIA and Fc RIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab." Haematologica 92, no. 8 (August 1, 2007): 1127–30. http://dx.doi.org/10.3324/haematol.11288.
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Masuda, M., A. J. Verhoeven, and D. Roos. "Tyrosine phosphorylation of a gamma-chain homodimer associated with Fc gamma RIII (CD16) in cultured human monocytes." Journal of Immunology 151, no. 11 (December 1, 1993): 6382–88. http://dx.doi.org/10.4049/jimmunol.151.11.6382.
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Abstract The efficient expression of transmembrane-anchored Fc gamma RIIIa requires the presence of other peptides, such as the gamma-chain of the IgE receptor I or the zeta-chain of the TCR. We found that Fc gamma RIIIa in cultured human monocytes is specifically associated with the gamma-chain homodimer, and that the gamma-chains in this complex are phosphorylated on tyrosine residues. Anti-Fc gamma RIII immunoprecipitates, which were prepared from 1% digitonin lysates of cultured human monocytes, incorporated phosphate into a homodimer consisting of two 14-kDa polypeptides when incubated with [gamma-32P]ATP. Identity of this co-associated structure of Fc gamma RIIIa as the gamma-chain dimer was confirmed by elution of the protein from the anti-Fc gamma RIII immunoabsorbent with 1% Nonidet P-40 detergent and reimmunoprecipitation with anti-gamma-chain antibody. Phosphoamino acid analysis showed that the gamma-chain exclusively contained phosphotyrosine. The gamma-chain was also phosphorylated when electropermeabilized cells were activated by cross-linking Fc gamma RIIIa. The gamma-chain may play an important role in signal transduction via Fc gamma RIIIa in human macrophages.
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Yanaga, F., A. Poole, J. Asselin, R. Blake, G. L. Schieven, E. A. Clark, C. L. Law, and S. P. Watson. "Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc γ-IIA receptor." Biochemical Journal 311, no. 2 (October 15, 1995): 471–78. http://dx.doi.org/10.1042/bj3110471.
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Activation of human platelets by cross-linking of the platelet low-affinity IgG receptor, the Fc gamma receptor IIA (Fc gamma-RIIA), or by collagen is associated with rapid phosphorylation on tyrosine of the non-receptor tyrosine kinase syk. Phosphorylation is still observed, albeit sometimes reduced, in the presence of a combination of a protein kinase C inhibitor, Ro 31-8220, and the intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase C (PLC) activity. In contrast, the combination of Ro 31-8220 and BAPTA-AM completely inhibits phosphorylation of syk in thrombin-stimulated platelets. Phosphorylation of syk increases its autophosphorylation activity measured in a kinase assay performed on syk immunoprecipitates. Fc gamma-RIIA also undergoes phosphorylation in syk immunoprecipitates from platelets activated by cross-linking of Fc gamma-RIIA but not by collagen, suggesting that it associates with the kinase. Consistent with this, tyrosine-phosphorylated Fc gamma-RIIA is precipitated by a glutathione S-transferase (GST) fusion protein containing the tandem src homology (SH2) domains of syk from Fc gamma-RIIA- but not collagen-activated cells. Two uncharacterized tyrosine-phosphorylated proteins of 40 and 65 kDa are uniquely precipitated by a GST fusion protein containing the tandem syk-SH2 domains in collagen-stimulated platelets. A peptide based on the antigen recognition activation motif (ARAM) of Fc gamma-RIIA, and phosphorylated on the two tyrosine residues found within this region, selectively binds syk from lysates of resting platelets; this interaction is not seen with a non-phosphorylated peptide. Kinase assays on Fc gamma-RIIA immunoprecipitates reveal the constitutive association of an unidentified kinase activity in resting cells which phosphorylates a 67 kDa protein. Syk is not detected in Fc gamma-RIIA immunoprecipitates from resting cells but associates with the receptor following activation and, together with Fc gamma-RIIA, is phosphorylated in the kinase assay in vitro. These results demonstrate that syk is activated by Fc gamma-RIIA cross-linking and collagen, independent of PLC, suggesting that it may have an important role in the early events associated with platelet activation. The association of syk with Fc gamma-RIIA appears to be mediated through the tandem SH2 domains in syk and the ARAM motif of Fc gamma-RIIA. A similar interaction may underlie the response to collagen, suggesting that its signalling receptor contains an ARAM motif.
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Endeman, Henrik, Marie Claire A. Cornips, Jan C. Grutters, Jules M. van den Bosch, Hendrik J. T. Ruven, Heleen van Velzen-Blad, Ger T. Rijkers, and Douwe H. Biesma. "The Fcγ Receptor IIA-R/R131 Genotype Is Associated with Severe Sepsis in Community-Acquired Pneumonia." Clinical and Vaccine Immunology 16, no. 7 (June 3, 2009): 1087–90. http://dx.doi.org/10.1128/cvi.00037-09.
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ABSTRACT Community-acquired pneumonia (CAP) can be caused by a variety of microorganisms but is most frequently associated with Streptococcus pneumoniae and gram-negative bacteria like Haemophilus influenzae. Encapsulated bacteria are able to escape phagocytosis, unless they are bound by immunoglobulin G2 subclass antibodies. These antibodies interact with Fcγ receptor IIa (Fcγ-RIIa), thereby facilitating opsonophagocytosis of the encapsulated bacteria. We studied the relationship between the Fcγ-RIIa-R/H131 polymorphism and the clinical course of CAP and pathogen-specific susceptibility. Regarding methodology, the Fcγ-RIIa genotype R/H131 was determined in 200 patients with CAP and in 313 healthy controls and was correlated with the clinical course, laboratory parameters, and causative microorganism. The Fcγ-RIIa-R/R131 genotype was found more frequently in patients with severe sepsis (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.30 to 5.00; P < 0.01). The majority of patients in this group suffered from invasive pneumococcal disease. The duration of hospital stay was longer for patients with the Fcγ-RIIa-R/R131 genotype. Fcγ-RIIa genotypes were not associated with an increased risk of CAP in general; however, the Fcγ-RIIa-R/R131 genotype was found more frequently in patients with CAP caused by H. influenzae than in controls (OR, 3.03; CI, 1.04 to 9.09; P < 0.05). In conclusion, the Fcγ-RIIa-R/R131 genotype is associated with severity of CAP and is more frequent in CAP caused by H. influenzae.
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Daegelen, P., and E. Brody. "The rIIA gene of bacteriophage T4. II. Regulation of its messenger RNA synthesis." Genetics 125, no. 2 (June 1, 1990): 249–60. http://dx.doi.org/10.1093/genetics/125.2.249.
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Abstract When the rII genes are first introduced into cells which had been previously infected by T4 phage deleted for these genes, the kinetics of synthesis of rIIA and rIIB RNA are rapid and identical. We show that this rapid synthesis depends on a functional motA gene for rIIB, but not for rIIA, RNA synthesis. By primer-extension mapping of T4 messenger RNA, we find three promoters close to the rIIA gene. One of them is an early promoter just before the rIIA.1 gene; it is used under all conditions tested. Another is in the coding portion of the rIIA.1 gene; it is weak, primarily because of a 19-bp spacing between the -10 and -35 elements, and its use is stimulated by T4 functions. The third is a motA-dependent (middle) promoter which has an unusual CCCGCTT box at -33. We present results which suggest that none of these promoters is likely to be the site at which the motB and motC gene products exercise their major influence on rIIA RNA synthesis.
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Astier, A., H. de la Salle, C. de la Salle, T. Bieber, M. E. Esposito-Farese, M. Freund, J. P. Cazenave, W. H. Fridman, J. L. Teillaud, and D. Hanau. "Human epidermal Langerhans cells secrete a soluble receptor for IgG (Fc gamma RII/CD32) that inhibits the binding of immune complexes to Fc gamma R+ cells." Journal of Immunology 152, no. 1 (January 1, 1994): 201–12. http://dx.doi.org/10.4049/jimmunol.152.1.201.
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Abstract Langerhans cells (LC) express Fc gamma RII on their cell surface. In this paper, we demonstrate that these cells also release soluble Fc gamma RII (sFc gamma RII) molecules. LC express transcripts encoding a membrane-associated receptor and a transmembrane-deleted Fc gamma RIIA. The latter form was identified in LC culture supernatants using specific antibodies. CHO cells, transfected with LC-derived cDNA encoding the transmembrane-deleted Fc gamma RIIA, secrete sFc gamma RIIA that include the intracellular domain and exhibit the same backbone as the protein identified in LC supernatants. Secreted sFc gamma RIIA exhibits the same pattern of binding to human and mouse IgG subclasses as do membrane Fc gamma RII and inhibits the binding of immune complexes to Fc gamma RII+ cells. In addition, CHO cells expressing the membrane-associated Fc gamma RIIA release truncated and unstable Fc gamma RIIA molecules that lack the intracellular domain. Thus, sFc gamma RII can result from shedding of membrane molecules and/or from secretion of soluble receptors lacking the transmembrane domain.
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Warmerdam, P. A., J. G. van de Winkel, A. Vlug, N. A. Westerdaal, and P. J. Capel. "A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding." Journal of Immunology 147, no. 4 (August 15, 1991): 1338–43. http://dx.doi.org/10.4049/jimmunol.147.4.1338.
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Abstract The low-affinity human Fc gamma RIIa is encoded by a single gene with allelic variation, defined by low-responder and high-responder alleles (LR and HR). The HR Fc gamma RIIa transcript interacts strongly with murine (m) IgG1 complexes, in contrast to the LR Fc gamma RIIa. Furthermore, the transcripts can be discriminated by mAb 41H16, which recognizes an epitope expressed on the HR Fc gamma RIIa molecule. We report that this receptor is also polymorphic in its reactivity with human (h) IgG2. Binding studies using well-defined hIgG dimers revealed that LR Fc gamma RIIa molecules can efficiently bind hIgG2, in contrast to HR Fc gamma RIIa. Previous work of others showed one amino acid difference between the allelic forms of Fc gamma RII. We, however, found a second amino acid difference between both allelic forms. In this study, hybrid Fc gamma RIIa molecules were constructed to determine the epitope for mAb 41H16 and the binding domain for mIgG1 and hIgG2 complexes. Our data point to the importance of the amino acid at position 131, located in the second Ig-like domain of Fc gamma RIIa. When an arginine residue is present at amino acid position 131, the receptor is recognized by mAb 41H16. Furthermore, the receptor can bind mIgG1-sensitized indicator E, but binds hIgG2 dimers only weakly. When a histidine residue is present at this amino acid position, hIgG2 dimers do bind efficiently to Fc gamma RII, whereas mIgG1-sensitized E and mAb 41H16 exhibit a strongly diminished binding.
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Darby, C., R. L. Geahlen, and A. D. Schreiber. "Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein." Journal of Immunology 152, no. 11 (June 1, 1994): 5429–37. http://dx.doi.org/10.4049/jimmunol.152.11.5429.
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Abstract The role of tyrosine phosphorylation during signal transduction by the phagocytic macrophage (Mphi) FcR Fc gamma RIIIA was investigated. Cross-linking Fc gamma RIIIA on pulmonary Mphi or cultured monocytes used as in vitro model for differentiated Mphi induced rapid and transient phosphorylation of multiple protein substrates. The lymphocyte/mast cell 72-kDa protein tyrosine kinase (PTK) designated PTK72 or Syk, whose expression in Mphi was previously unknown, was identified as a major substrate by immunoprecipitation and phosphopeptide mapping. Activation of Fc gamma RIIIA stimulated a fourfold increase in Syk kinase activity assessed by autophosphorylation. Under mild lysis conditions several specific proteins were co-precipitated with the gamma subunit of Fc gamma RIIIA. Tyrosine kinase activity was also co-precipitated with gamma, as shown by in vitro phosphorylation of gamma. One of these kinases was identified as Syk by phosphopeptide mapping, suggesting a physical association between this PTK and the receptor. Two additional phosphoproteins induced by Fc gamma RIIIA cross-linking were identified: the hematopoietic proto-oncogene product p95Vav, previously implicated in B lymphocyte and mast cell signaling; and p62, a protein associated with p21Ras-GAP. Our results also establish that there are important functional similarities in signal transduction between a phagocytic Mphi FcR and other multi-subunit Ig gene family receptors in diverse cell lineages.
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Liao, F., H. S. Shin, and S. G. Rhee. "Cross-linking of Fc gamma RIIIA on natural killer cells results in tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2." Journal of Immunology 150, no. 7 (April 1, 1993): 2668–74. http://dx.doi.org/10.4049/jimmunol.150.7.2668.
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Abstract The Fc gamma RIIIA, which is composed of a transmembrane IgG-binding glycoprotein and either a disulfide-linked homodimer (zeta zeta, gamma gamma) or heterodimer (zeta gamma), mediates the antibody-dependent cellular cytotoxicity in NK cells. The role of phospholipase C (PLC) isozymes in Fc gamma RIIIA-mediated signal transduction was investigated. The NK cell line NK3.3 was found to contain PLC-gamma 1 and an especially high concentration of PLC-gamma 2, but PLC-beta 1 and PLC-delta 1 were not detected. Cross-linking of Fc gamma RIIIA on NK3.3 cells induced a rapid phosphorylation of PLC-gamma 1 and PLC-gamma 2 on tyrosine residues. Pretreatment of NK3.3 cells with a tyrosine kinase inhibitor, herbimycin A, prevented the tyrosine phosphorylation of both PLC-gamma 1 and PLC-gamma 2. These results indicate that activation of Fc gamma RIIIA on NK3.3 cells is coupled either directly or indirectly to a nonreceptor tyrosine kinase, which phosphorylates, and thereby activates PLC-gamma 1 and PLC-gamma 2.
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Van den Herik-Oudijk, IE, MW Ter Bekke, MJ Tempelman, PJ Capel, and JG Van de Winkel. "Functional differences between two Fc receptor ITAM signaling motifs." Blood 86, no. 9 (November 1, 1995): 3302–7. http://dx.doi.org/10.1182/blood.v86.9.3302.bloodjournal8693302.
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Most Ig receptors exist as multi-subunit complexes with a unique ligand binding alpha chain and a common signaling FcR gamma-chain. The myeloid Fc gamma RIIa (CD32) appears unique among FcR because both ligand- binding and signaling capacity are found in the alpha chain. Within the cytoplasmic tails of Fc gamma RIIa and FcR gamma-chain similar, but not identical, activatory motifs (ITAMs) have been defined, in which tyrosines play an important role. Previously, Fc gamma RIIa-ITAM was shown to be critical for both proximal and distal activatory functions in IIA1.6 B-cell transfectants. Triggering of interleukin-2 (IL-2) release and antigen presentation was absent in Fc gamma RIIa, but not in FcR gamma-chain receptor complexes. We now assessed the capacity of Fc gamma RIIa wild-type and Fc gamma RIIa/gamma chimeric molecules to trigger IL-2 production and antigen presentation by B cells. Both of these functions could solely be triggered by receptors containing the FcRIIa was capable of functional interaction with FcR gamma-chain, thus reconstituting the capacity to trigger IL-2 release and antigen presentation. These data document qualitative differences between Fc receptor ITAMs.
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Sivadas, Priyanka, Jennifer M. Dienes, Martin St. Maurice, William D. Meek, and Pinfen Yang. "A flagellar A-kinase anchoring protein with two amphipathic helices forms a structural scaffold in the radial spoke complex." Journal of Cell Biology 199, no. 4 (November 12, 2012): 639–51. http://dx.doi.org/10.1083/jcb.201111042.
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A-kinase anchoring proteins (AKAPs) contain an amphipathic helix (AH) that binds the dimerization and docking (D/D) domain, RIIa, in cAMP-dependent protein kinase A (PKA). Many AKAPs were discovered solely based on the AH–RIIa interaction in vitro. An RIIa or a similar Dpy-30 domain is also present in numerous diverged molecules that are implicated in critical processes as diverse as flagellar beating, membrane trafficking, histone methylation, and stem cell differentiation, yet these molecules remain poorly characterized. Here we demonstrate that an AKAP, RSP3, forms a dimeric structural scaffold in the flagellar radial spoke complex, anchoring through two distinct AHs, the RIIa and Dpy-30 domains, in four non-PKA spoke proteins involved in the assembly and modulation of the complex. Interestingly, one AH can bind both RIIa and Dpy-30 domains in vitro. Thus, AHs and D/D domains constitute a versatile yet potentially promiscuous system for localizing various effector mechanisms. These results greatly expand the current concept about anchoring mechanisms and AKAPs.
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O'Leary, Michael E. "Characterization of the isoform-specific differences in the gating of neuronal and muscle sodium channels." Canadian Journal of Physiology and Pharmacology 76, no. 10-11 (October 1, 1998): 1041–50. http://dx.doi.org/10.1139/y98-137.
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Human heart (hH1), human skeletal muscle (hSkM1), and rat brain (rIIA) Na channels were expressed in cultured cells and the activation and inactivation of the whole-cell Na currents measured using the patch clamp technique. hH1 Na channels were found to activate and inactivate at more hyperpolarized voltages than hSkM1 and rIIA. The conductance versus voltage and steady state inactivation relationships have midpoints of -48 and -92 mV (hH1), -28 and -72 mV (hSkM1), and -22 and -61 mV (rIIA). At depolarized voltages, where Na channels predominately inactivate from the open state, the inactivation of hH1 is 2-fold slower than that of hSkM1 and rIIA. The recovery from fast inactivation of all three isoforms is well described by a single rapid component with time constants at -100 mV of 44 ms (hH1), 4.7 ms (hSkM1), and 7.6 ms (rIIA). After accounting for differences in voltage dependence, the kinetics of activation, inactivation, and recovery of hH1 were found to be generally slower than those of hSkM1 and rIIA. Modeling of Na channel gating at hyperpolarized voltages where the channel does not open suggests that the slow rate of recovery from inactivation of hH1 accounts for most of the differences in the steady-state inactivation of these Na channels.Key words: cardiac, neuronal, skeletal muscle, sodium channel.
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Kanakaraj, P., B. Duckworth, L. Azzoni, M. Kamoun, L. C. Cantley, and B. Perussia. "Phosphatidylinositol-3 kinase activation induced upon Fc gamma RIIIA-ligand interaction." Journal of Experimental Medicine 179, no. 2 (February 1, 1994): 551–58. http://dx.doi.org/10.1084/jem.179.2.551.
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Induced activation of protein tyrosine kinase(s) is a central event in signal transduction mediated via the low affinity receptor for IgG (Fc gamma RIIIA, CD16) in natural killer (NK) cells. Tyrosine phosphorylation may affect the function of several protein directly, or indirectly by inducing their association with other tyrosine phosphorylated proteins. Here, we report that Fc gamma RIII stimulation induces activation of phosphatidylinositol (PI)-3 kinase in NK cells. Phosphotyrosine immunoprecipitates from Fc gamma RIII-stimulated NK cells contain PI-kinase activity and PI-3 kinase can be directly precipitated from them. Conversely, a series of tyrosine-phosphorylated proteins is coprecipitated with PI-3 kinase from the stimulated, but not from control cells. Analogous results obtained using Jurkat T cells expressing transfected Fc gamma RIIIA alpha ligand binding chain in association with gamma 2 or zeta 2 homodimers indicate that both complexes transduce this effect, although the Fc gamma RIIIA-zeta 2 complexes do so with greater efficiency. Accumulation of phosphoinositide D3 phosphorylated products in stimulated cells confirms PI-3 kinase activation, indicating the participation of this enzyme in Fc gamma RIIIA-mediated signal transduction.
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Mitchell, MA, MM Huang, P. Chien, ZK Indik, XQ Pan, and AD Schreiber. "Substitutions and deletions in the cytoplasmic domain of the phagocytic receptor Fc gamma RIIA: effect on receptor tyrosine phosphorylation and phagocytosis [published erratum appears in Blood 1994 Nov 1;84(9):3252]." Blood 84, no. 6 (September 15, 1994): 1753–59. http://dx.doi.org/10.1182/blood.v84.6.1753.1753.
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Abstract Fc gamma RIIA in the absence of other Fc receptors or receptor subunits induces the ingestion of IgG-coated cells. The cytoplasmic domain of Fc gamma RIIA contains two Y-x-x-L sequences similar to those in other Ig gene family receptors plus an additional tyrosine residue not in a Y-x- x-L motif. Upon cross-linking, Fc gamma RIIA is phosphorylated on tyrosine and the cytoplasmic tyrosines, Y275 (Y1), Y282 (Y2), and Y298 (Y3), may be important for its phagocytic activity. Because COS-1 cells can serve as a model for examining molecular structures involved in phagocytosis, substitutions and deletions were introduced into the cytoplasmic domain of Fc gamma RIIA and examined in COS-1 cell transfectants for their effects on phagocytosis and tyrosine phosphorylation. Disruption of a single cytoplasmic Y-x-x-L motif by substitution of tyrosine Y2 or Y3 by phenylalanine or by removing the threonine and leucine residues within the motif inhibited phagocytosis 50% to 65%. Tyrosine phosphorylation of Fc gamma RIIA also was inhibited, although to a greater extent by the substitution of Y3 than of Y2. Replacement of the N-terminal first cytoplasmic domain tyrosine, Y1, which is not within a typical Y-x-x-L, by itself did not inhibit phagocytosis, but replacement of Y1 in mutants lacking Y2 or Y3 virtually eliminated phagocytic activity and receptor tyrosine phosphorylation. Thus, at least two cytoplasmic tyrosines, including at least one typical single Y-x-x-L motif, are required for phagocytosis by Fc gamma RIIA. The data suggest that there is a close but not a simple relationship between phosphorylation of the Fc gamma RIIA cytoplasmic tyrosines and Fc gamma RIIA-mediated phagocytosis. Y3 appears to be particularly important because its removal by truncation or replacement with phenylalanine inhibits both tyrosine phosphorylation and phagocytosis in parallel. Alterations in the 12 residue proline-containing sequence between the two Y-x-x-L motifs also reduced phagocytic activity and tyrosine phosphorylation. Thus, the specific structure of the Fc gamma RIIA cytoplasmic domain accounts for its ability to stimulate phagocytosis in the absence of other subunits.
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Mitchell, MA, MM Huang, P. Chien, ZK Indik, XQ Pan, and AD Schreiber. "Substitutions and deletions in the cytoplasmic domain of the phagocytic receptor Fc gamma RIIA: effect on receptor tyrosine phosphorylation and phagocytosis [published erratum appears in Blood 1994 Nov 1;84(9):3252]." Blood 84, no. 6 (September 15, 1994): 1753–59. http://dx.doi.org/10.1182/blood.v84.6.1753.bloodjournal8461753.
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Fc gamma RIIA in the absence of other Fc receptors or receptor subunits induces the ingestion of IgG-coated cells. The cytoplasmic domain of Fc gamma RIIA contains two Y-x-x-L sequences similar to those in other Ig gene family receptors plus an additional tyrosine residue not in a Y-x- x-L motif. Upon cross-linking, Fc gamma RIIA is phosphorylated on tyrosine and the cytoplasmic tyrosines, Y275 (Y1), Y282 (Y2), and Y298 (Y3), may be important for its phagocytic activity. Because COS-1 cells can serve as a model for examining molecular structures involved in phagocytosis, substitutions and deletions were introduced into the cytoplasmic domain of Fc gamma RIIA and examined in COS-1 cell transfectants for their effects on phagocytosis and tyrosine phosphorylation. Disruption of a single cytoplasmic Y-x-x-L motif by substitution of tyrosine Y2 or Y3 by phenylalanine or by removing the threonine and leucine residues within the motif inhibited phagocytosis 50% to 65%. Tyrosine phosphorylation of Fc gamma RIIA also was inhibited, although to a greater extent by the substitution of Y3 than of Y2. Replacement of the N-terminal first cytoplasmic domain tyrosine, Y1, which is not within a typical Y-x-x-L, by itself did not inhibit phagocytosis, but replacement of Y1 in mutants lacking Y2 or Y3 virtually eliminated phagocytic activity and receptor tyrosine phosphorylation. Thus, at least two cytoplasmic tyrosines, including at least one typical single Y-x-x-L motif, are required for phagocytosis by Fc gamma RIIA. The data suggest that there is a close but not a simple relationship between phosphorylation of the Fc gamma RIIA cytoplasmic tyrosines and Fc gamma RIIA-mediated phagocytosis. Y3 appears to be particularly important because its removal by truncation or replacement with phenylalanine inhibits both tyrosine phosphorylation and phagocytosis in parallel. Alterations in the 12 residue proline-containing sequence between the two Y-x-x-L motifs also reduced phagocytic activity and tyrosine phosphorylation. Thus, the specific structure of the Fc gamma RIIA cytoplasmic domain accounts for its ability to stimulate phagocytosis in the absence of other subunits.
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Boettcher, Sebastian, Christiane Pott, Matthias Ritgen, Wolfgang Hiddemann, Michael Unterhalt, and Michael Kneba. "Evidence for Fcγ Receptor IIIA-Independent Rituximab Effector Mechanisms in Patients with Follicular Lymphoma Treated with Combined Immuno-Chemotherapy." Blood 104, no. 11 (November 16, 2004): 590. http://dx.doi.org/10.1182/blood.v104.11.590.590.
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Abstract The response to the anti-CD20 antibody Rituximab used as a single agent in follicular lymphoma (FL) patients can be predicted by the valine/phenylalanine (V/F) dimorphism of amino acid 158 of Fcγ Receptor IIIA (Fcγ RIIIA) (Cartron et al., Blood99: 754, 2002; Weng and Levy, JCO21: 3940, 2003). This suggested important contributions for Fcγ RIIIA mediated mechanisms like antibody dependent cellular cytotoxicity to the efficacy of the antibody. Recently, the German Low Grade Lymphoma Study Group (GLSG) demonstrated a significant shorter time to treatment failure (TTF) in patients who received standard CHOP (cyclophosphamide d1, doxorubicin d1, vincristin d1, prednisone d1-5) chemotherapy only compared to patients who received Rituximab (d1) plus CHOP (R-CHOP). Estimated median TTF was 2.6 years in FL patients treated with CHOP and was not reached after 3 years observation time in R-CHOP treated FL patients (p<0.0007) (Blood 102, Abstract # 352, 2003). We examined the Fcγ RIIIA dimorphism in 75 FL patients from this GLSG trial who were treated with 6 to 8 cycles R-CHOP followed by interferon maintenance or high dose chemo-radiotherapy and autologous stem cell transplantation. Using a TaqMan assay with allele specific fluorochrome labelled probes we detected a V/V genotype in 8 patients (10.7%), a V/F genotype in 38 patients (50.6%), and an F/F genotype in 29 patients (38.7%). Patients with different Fcγ RIIIA status responded similarly to R-CHOP (CR rate: V/V 37.5%, V/F 36.8%, F/F 24.1%; overall response rate: V/V 100.0 %, V/F 97.4%, F/F 96.6%; ns). Moreover, TTF was not significantly different between the groups with V/V, V/F, and F/F Fcγ RIIIA(log rank p = 0.48) after a median observation time of 24 months. A correlation between the Fcγ RIIIA status and the efficacy of R-CHOP could not be demonstrated in this large patient cohort. On the other hand it is evident that R-CHOP treated patients significantly benefited from the addition of Rituximab to CHOP chemotherapy in comparison to the standard arm of this randomized trial. This observation supports the hypothesis that the anti-lymphoma effects of Rituximab when used in combination with chemotherapy might be mediated by Fcγ RIIIA-independent mechanisms such as complement dependent cytotoxicity or direct apoptosis induction.
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Van den Herik-Oudijk, IE, PJ Capel, T. van der Bruggen, and JG Van de Winkel. "Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms." Blood 85, no. 8 (April 15, 1995): 2202–11. http://dx.doi.org/10.1182/blood.v85.8.2202.bloodjournal8582202.
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To assess the functional capacity of the heterogeneous Fc gamma RII (CD32) family and to identify critical regions for functioning, we generated a panel of B-cell transfectants. The Fc gamma R-negative B-cell line IIA1.6 was transfected with wild-type or mutant human Fc gamma RIIa and IIb molecules. Solely Fc gamma RIIa-expressing IIA1.6 cells were capable of phagocytosing opsonized Staphylococcus aureus bacteria, and cross-linking of Fc gamma RIIa triggered a rapid induction of tyrosine phosphorylation after 20 seconds. Analysis of Fc gamma RIIa mutants identified the immunoreceptor tyrosine-based activation motif (ITAM; previously described as ARH-1 motif) within the IIa cytoplasmic tail to be critical for B-cell activation. In contrast, Fc gamma RIIb isoforms triggered tyrosine phosphorylation on cross-linking with much slower kinetics (> 3 minutes) than Fc gamma RIIa. Furthermore, solely Fc gamma RIIb molecules proved capable of downregulating [Ca2+]i and interleukin-2 production on co-cross-linking with sIgG in IIA1.6. The Fc gamma RIIb-mediated functions were absent in Fc gamma RIIb mutants in which the tyrosine or leucine within the YSLL motif in a conserved 13-aa region (now known as immunoreceptor tyrosine-based inhibitor motif [ITIM]) were changed into phenylalanines. In conclusion, these data show the presence of functionally critical motifs within Fc gamma RII cytoplasmic tails. Fc gamma RIIa contains an ITAM involved in B-cell activatory functions, whereas the downregulatory activity of Fc gamma RIIb isoforms is linked to an ITIM.
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Graziano, Francesco, Annamaria Ruzzo, Fotios Loupakis, Emanuele Canestrari, Daniele Santini, Vincenzo Catalano, Renato Bisonni, et al. "Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer." Journal of Clinical Oncology 26, no. 9 (March 20, 2008): 1427–34. http://dx.doi.org/10.1200/jco.2007.12.4602.
Full textAbstract:
PurposeRegulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.Patients and MethodsPatients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)ndinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.ResultsIn 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ2test = 12.7; P = .001) and treatment response (χ2test = 9.45; P = .008) than EGFR intron-1 L/L carriers.ConclusionAlthough additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
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Kurosaki, T., I. Gander, U. Wirthmueller, and J. V. Ravetch. "The beta subunit of the Fc epsilon RI is associated with the Fc gamma RIII on mast cells." Journal of Experimental Medicine 175, no. 2 (February 1, 1992): 447–51. http://dx.doi.org/10.1084/jem.175.2.447.
Full textAbstract:
Fc epsilon RI is a tetrameric receptor, composed of a ligand recognition subunit, alpha, a beta chain, and dimeric gamma chains. Previous studies have indicated that the dimeric gamma chain is associated with Fc gamma RIIIA (CD16) on natural killer cells and macrophages as well as the clonotypic T cell receptor. Here we show that in mast cells, in addition to the dimeric gamma chains, the beta subunit is associated not only with Fc epsilon RI, but also with Fc gamma RIIIA. Functional reconstitution studies with a mastocytoma cell line indicate that Fc gamma RIIIA composed of alpha, beta, and gamma subunits has the capacity for signal transduction. These studies suggest that through the association of alternative ligand recognition subunits (alpha epsilon, alpha gamma), a common signal transduction complex (beta gamma 2) mediates similar biochemical and effector functions in response to immunoglobulin G (IgG) and IgE.
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Wirthmueller, U., T. Kurosaki, M. S. Murakami, and J. V. Ravetch. "Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain." Journal of Experimental Medicine 175, no. 5 (May 1, 1992): 1381–90. http://dx.doi.org/10.1084/jem.175.5.1381.
Full textAbstract:
To determine the functional role of the two isoforms of Fc gamma RIII (CD16) (IIIA, IIIB), the signal transduction capabilities of wild-type and mutant forms of these receptors were analyzed in transfected lymphoid, myeloid, and fibroblastic cell lines. Functional reconstitution of receptor signalling was observed in hematopoietic T and mast cells, and was absent in nonhematopoietic (CHO) cells. Fc gamma RIIIA, a hetero-oligomeric receptor composed of a ligand-binding subunit alpha and dimeric gamma chains, generated both proximal and distal responses in Jurkat and P815 cells, typical of what is seen in natural killer cells and macrophages upon receptor activation. In contrast, Fc gamma RIIIB, which is normally attached to the cell surface via a glycosyl-phosphatidylinositol anchor, was incapable of transducing signals. After crosslinking, Fc gamma RIIIA signalling was dependent only upon the gamma chain. Fc gamma RIIIA chimeras in which the alpha subunit transmembrane and cytoplasmic domains were substituted with the corresponding gamma chain sequences functioned as well as wild-type hetero-oligomeric receptors. These data indicate that the ability of the Fc gamma RIIIA complex to activate the appropriate pathways for cell activation is cell-type restricted and independent of the transmembrane and cytoplasmic domains of the alpha subunit. The presence of the gamma chain is responsible for the assembly of, as well as the signal transduction by, the functional cell surface complex.
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Indik, ZK, XQ Pan, MM Huang, SE McKenzie, AI Levinson, and AD Schreiber. "Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function." Blood 83, no. 8 (April 15, 1994): 2072–80. http://dx.doi.org/10.1182/blood.v83.8.2072.2072.
Full textAbstract:
Abstract Receptors for the Fc domain of IgG on cells of hematopoietic lineage perform important functions, including stimulation of the ingestion of IgG-coated cells. In examining the function of Fc gamma receptor isoforms by transfection into COS-1 cells, we have observed that Fc gamma RIIA induces the binding and phagocytosis of IgG-sensitized RBCs (EA) and that transfected COS-1 cells can serve as a model for examining the molecular structures involved in mediating a phagocytic signal. We now report that COS-1 cell transfectants expressing the isoforms Fc gamma RIIB1 and Fc gamma RIIB2 and a Fc gamma RIIA mutant without a cytoplasmic tail efficiently bind EA but do not mediate their phagocytosis. Furthermore, wild-type Fc gamma RIIA, but not Fc gamma RIIB1 or Fc gamma RBII2, was phosphorylated on tyrosine upon receptor activation. Tyrphostin 23, which alters tyrosine kinase activity, inhibited the phagocytosis of EA and reduced the phosphorylation of Fc gamma RIIA on tyrosine. Fc gamma RIIB1 and Fc gamma RIIB2 contain one copy of the cytoplasmic sequence YXXL/I implicated in signal transduction, whereas Fc gamma RIIA contains two copies. We therefore inserted YXXL/I sequences at different sites in Fc gamma RIIB2. Low levels of phagocytosis were observed in a Fc gamma RIIB2 mutant bearing the Fc gamma RIIA sequence YMTL and higher levels of phagocytosis were observed in a second Fc gamma RIIB2 mutant that contained both the upstream YMTL and an additional downstream tyrosine-containing motif. Activation of this mutant receptor also induced receptor tyrosine phosphorylation. Thus, these studies indicate that both the number and placement of YXXL sequences in the cytoplasmic domain of the Fc gamma RII receptor family affect both receptor tyrosine phosphorylation and phagocytic competence.
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Indik, ZK, XQ Pan, MM Huang, SE McKenzie, AI Levinson, and AD Schreiber. "Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function." Blood 83, no. 8 (April 15, 1994): 2072–80. http://dx.doi.org/10.1182/blood.v83.8.2072.bloodjournal8382072.
Full textAbstract:
Receptors for the Fc domain of IgG on cells of hematopoietic lineage perform important functions, including stimulation of the ingestion of IgG-coated cells. In examining the function of Fc gamma receptor isoforms by transfection into COS-1 cells, we have observed that Fc gamma RIIA induces the binding and phagocytosis of IgG-sensitized RBCs (EA) and that transfected COS-1 cells can serve as a model for examining the molecular structures involved in mediating a phagocytic signal. We now report that COS-1 cell transfectants expressing the isoforms Fc gamma RIIB1 and Fc gamma RIIB2 and a Fc gamma RIIA mutant without a cytoplasmic tail efficiently bind EA but do not mediate their phagocytosis. Furthermore, wild-type Fc gamma RIIA, but not Fc gamma RIIB1 or Fc gamma RBII2, was phosphorylated on tyrosine upon receptor activation. Tyrphostin 23, which alters tyrosine kinase activity, inhibited the phagocytosis of EA and reduced the phosphorylation of Fc gamma RIIA on tyrosine. Fc gamma RIIB1 and Fc gamma RIIB2 contain one copy of the cytoplasmic sequence YXXL/I implicated in signal transduction, whereas Fc gamma RIIA contains two copies. We therefore inserted YXXL/I sequences at different sites in Fc gamma RIIB2. Low levels of phagocytosis were observed in a Fc gamma RIIB2 mutant bearing the Fc gamma RIIA sequence YMTL and higher levels of phagocytosis were observed in a second Fc gamma RIIB2 mutant that contained both the upstream YMTL and an additional downstream tyrosine-containing motif. Activation of this mutant receptor also induced receptor tyrosine phosphorylation. Thus, these studies indicate that both the number and placement of YXXL sequences in the cytoplasmic domain of the Fc gamma RII receptor family affect both receptor tyrosine phosphorylation and phagocytic competence.
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Porges, A. J., P. B. Redecha, W. T. Kimberly, E. Csernok, W. L. Gross, and R. P. Kimberly. "Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa." Journal of Immunology 153, no. 3 (August 1, 1994): 1271–80. http://dx.doi.org/10.4049/jimmunol.153.3.1271.
Full textAbstract:
Abstract The presence of anti-neutrophil cytoplasmic Abs (ANCA) in many patients with systemic vasculitis suggests that ANCA may play a role in disease pathogenesis. Neutrophils from patients with Wegener's granulomatosis often express ANCA target Ags (myeloperoxidase (MPO) and proteinase 3 (PR3)) on their surface, making these intracellular primary granule enzymes accessible to these autoantibodies. Similarly, normal neutrophils can be induced to translocate MPO and PR3 to the cell surface in vitro, and we demonstrate that murine mAb ANCA IgG, but not IgM, binds to the ANCA target and engages the Fc gamma RIIa ligand-binding site on the surface of human neutrophils. In contrast to ANCA IgM, ANCA IgG also induces an oxidative burst in neutrophils (oxidation of dihydrorhodamine = 91 +/- 15 fluorescence units with anti-PR3 IgG vs 17 +/- 2 with anti-PR3 IgM, p < 0.001). Blockade of the ligand-binding site of Fc gamma RIIa with an antibinding site mAb Fab significantly reduces this ANCA IgG-triggered production of reactive oxygen species (p < 0.01). Similarly, human ANCA bind the ANCA target, engage Fc gamma RIIa, and induce an oxidative burst in neutrophils. The allelic phenotype of Fc gamma RIIa strongly influences the Fc gamma receptor engagement by ligand, and Fc gamma RIIa homozygous donors differ by more than threefold in the quantitative production of reactive oxygen intermediates (ROI) (p < 0.01). Thus, engagement of Fc gamma RIIa by the Fc region of ANCA is one mechanism by which these autoantibodies activate receptor-mediated signal transduction systems in human neutrophils to initiate programs of inflammation and tissue injury. Fc gamma receptor alleles may represent heritable disease risk factors influencing the magnitude of such a process.
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Shen, Z., C. T. Lin, and J. C. Unkeless. "Correlations among tyrosine phosphorylation of Shc, p72syk, PLC-gamma 1, and [Ca2+]i flux in Fc gamma RIIA signaling." Journal of Immunology 152, no. 6 (March 15, 1994): 3017–23. http://dx.doi.org/10.4049/jimmunol.152.6.3017.
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Abstract Tyrosine phosphorylation plays a critical role in Fc gamma RIIA signaling. In a mouse macrophage cell line transfected with human Fc gamma RIIA, cross-linking Fc gamma RIIA led to the transient generation of inositol 1, 4, 5-trisphosphate (IP3), [Ca2+]i flux, and rapid tyrosine phosphorylation of cellular substrates, including Shc, PLC-gamma 1, and a tyrosine kinase p72syk. In addition, tyrosine phosphorylated Fc gamma RIIA was co-precipitated with activated PLC-gamma 1. In contrast, no tyrosine phosphorylation of Shc or PLC-gamma 1 was detected in cells transfected with mutant receptors that failed to trigger [Ca2+]i flux. PMA inhibits both tyrosine phosphorylation of Shc and IP3 production leading to [Ca2+]i flux. However, PMA does not affect tyrosine phosphorylation of PLC-gamma 1 and p72syk. These results suggest that tyrosine phosphorylation of Shc and PLC-gamma 1 is important for the initiation of [Ca2+]i flux, and that activation of protein kinase C may modulate the activity of PLC-gamma 1 through serine/threonine phosphorylation.
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Diamantopoulos, Panagiotis Theodorou, Vassiliki Kalotychou, Athanassios Galanopoulos, Nikolaos Spanakis, Katerina Polonyfi, Georgia Diamantopoulou, Efthymia Bazanis, et al. "Correlation of Fc Gamma RIIA Polymorphisms with EBV-Positivity and LMP1 Expression in Patients with Low Grade B-Cell Lymphomas." Blood 118, no. 21 (November 18, 2011): 1600. http://dx.doi.org/10.1182/blood.v118.21.1600.1600.
Full textAbstract:
Abstract Abstract 1600 Background: It is well known that Fc gamma receptors expressed on monocytes and macrophages enhance the presentation of antibody-bound antigens. Human Fc gamma receptors are coded by genes located on chromosome 1q23. Fc gamma RIIA (CD32) is a transmembrane protein expressed on neutrophils. Efficacy of phagocytosis by polymorphonuclear neutrophils is known to vary between allotypes of Fc gamma RIIa. Polymorphisms of Fc gamma RIIA have been linked to susceptibility to infections by encapsulated bacteria (N. meningitides, H. influenzae) and severe sepsis by several authors. Moreover, susceptibility to perinatal HIV-1 infection has been attributed to polymorphisms of Fc gamma RIIA, and this is the only association of FC gamma RIIA with viral diseases in the literature. FcγRIIA gene has two condominantly expressed alleles the 131-Arg (R131) and the 131-His (H131) allele. R131 binds IgG2 much less avidly than H131. Aim of the study: To propose Fc gamma RIIA polymorphisms as a genetic risk factor for acquisition and latency of EBV infection in patients with lymphoproliferative diseases. Patients and Methods: Forty Greek patients with EBV-unrelated low grade B-cell leukemic lymphomas (chronic lymphocytic leukemia: 23, marginal zone lymphoma: 11, mantle cell lymphoma: 3, hairy cell leukemia: 2, follicular lymphoma: 1), were included in the study. Patients' sera were tested with ELISA for the presence of EBV-VCA IgG antibodies. DNA from peripheral blood was studied by quantitative real time - PCR for the EBV-R gene, while RNA from peripheral blood was studied by RT-PCR for the EBV-LMP1 oncoprotein. Genomic DNA from peripheral blood was tested for Fc gamma RIIA 131Histidin(H)/arginine(R) SNP, by PCR, followed by restriction fragment length polymprphim (RFLP) using the appropriate enzyme (BstUI, Fermentas, Vilnius, Lithuania). We used Pearson Chi-square for the statistical analysis of the results. Results: All but 2 patients were positive for EBV-VCA IgG antibodies. Nineteen patients (47.5%) were EBV-positive. LMP1 was expressed in 13/19 (68.4%) EBV-positive patients. The vast majority (16/19, 84.2%) of EBV positive patients carried the R131 allele (13 were heterozygous and 3 homozygous), while only 3 were homozygous for the H131 allele. Among 21 EBV-negative patients, only 6 (28.5%) carried the R131 allele (4 heterozygous and 2 homozygous) (2-sided p=0001). R131 allele was present in 11/13 (84.6%) LMP1-positive patients in comparison to 6/21 (28.0%) EBV-negative patients (2-sided p=0.002). Discussion: The high prevalence of FC gamma RIIA polymorphisms among EBV-positive patients indicates a possible pathogenetic role of the FC gamma RIIA in acquisition and chronicity of EBV infection. LMP1 is the major oncoprotein of EBV. The correlation of this polymorphism to LMP1 expression is an indication that it may play a major role in the expression of latency phase proteins, a fact that may further be implicated in the pathogenesis of lymphoproliferative diseases in these patients. We continue the study in our centre, increasing the number of patients enrolled. Disclosures: No relevant conflicts of interest to declare.
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Bhowmik, Suman, and Atanu Bora. "Rediscovery of Watson’s Demon Stimula swinhoei swinhoei (Elwes & Edwards, 1897) (Lepidoptera: Hesperiidae: Hesperiinae) in Meghalaya, India after 60 years." Journal of Threatened Taxa 13, no. 8 (July 26, 2021): 19168–70. http://dx.doi.org/10.11609/jott.6425.13.8.19168-19170.
Full textAbstract:
The authors report the rediscovery of the grass skipper Watson’s Demon Stimula swinhoei swinhoei from Riwai village, Meghalaya. The nominotypical subspecies found in India was last recorded 60 years ago by Cantlie from Khasi Hills, Meghalaya in 1956, and since then no records of this species have been found in the literature of the state. The authors recorded one individual of the species on 20 February 2016 while it was feeding on bird droppings adjacent to a hill stream in Riwai village, Khasi Hills, Meghalaya. The species might have been overlooked by past workers due to its similarities with Ancistroides nigrita.
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Editorial Team. "Winner of the 2006/2007 RIWA Award." Evidence Based Library and Information Practice 2, no. 1 (March 14, 2007): 161. http://dx.doi.org/10.18438/b8hp4t.
Full textAbstract:
It is with great pleasure that the Research in the Workplace Award (RIWA)* assessment panel announces the winning proposal in 2006/2007 to be for a multi-site randomised controlled trial to determine the impact of providing a virtual reference service (Access Specialist Knowledge - ASK) to the local Primary Care and Mental Health Trusts within the UK National Health Service.
The project will be led by Rachel Southon, Royal Surrey County Hospitals NHS Trust, in collaboration with Vicki Veness, also of Royal Surrey County Hospitals NHS Trust and John Loy, Avon & Wiltshire Mental Health Partnership NHS Trust.
The project will commence in April 2007 and the assessment panel believes it will yield measurable outcomes and provide an evidence base for developing services to primary care. The project is due for completion by March 2008 and will be followed by a comprehensive programme of dissemination.
A copy of the winning proposal can be accessed via the RIWA* web site at: http://ifmh.org.uk/RIWA.html. The proposal was considered to be well planned and an exemplary model of a proposal in terms of identifying an important question and an appropriate methodology with which to address it.
RIWA* is a biennial award and details of projects which have previously been funded, together with news of future awards, can be found on the RIWA* web site at: http://ifmh.org.uk/RIWA.html.
RIWA 2006/2007 is managed by IFM Healthcare and is sponsored by National Library for Health CPD Forum, IFM Healthcare, the Health Libraries Group, the University Medical School Librarians Group, and the University Health Sciences Libraries and Libraries for Nursing.
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Pradhan, Vandana, Manisha Patwardhan, Anita Nadkarni, and Kanjaksha Ghosh. "Fc RIIA Genotypes and Its Association with Anti-C1q Autoantibodies in Lupus Nephritis (LN) Patients from Western India." Autoimmune Diseases 2010 (2010): 1–6. http://dx.doi.org/10.4061/2010/470695.
Full textAbstract:
To identify Fc RIIA genotypes in Systemic Lupus Erythematosus (SLE) patients and their association with anti-C1q antibodies.Methods. Fc RIIA genotyping was done in eighty Indian SLE patients and eighty healthy controls using allele-specific PCR. Anti-C1q antibodies were measured by ELISA.Results. LN patients showed higher SLEDAI (6–32) as compared to SLE patients without renal manifestations and had SLEDAI between 6–23. Fc RIIA polymorphic frequency in SLE patients was R131/H131 (67.5%), R131/R131 (20%) and H131/ H131 (12.5%) as against that of normal population (62.5%, 10%, and 27.5%), respectively. Sixty two patients (77.5%) showed positivity for anti-C1q antibodies. LN patients showed elevated levels of anti-C1q antibodies () as compared to SLE patients without nephritis ( U/mL). Among anti-C1q positive patients, 71% had R131/H131 genotype, 22.6% had R131/R131 and remaining 6.4%, patients had H131/H131 genotype. All anti-C1q positive patients with R131/R131 genotype had elevated levels of anti-C1q antibodies (>100 U/ml), whereas among anti-C1q negative patients, none had R131/R131 genotype.Conclusion. This first report on Indian SLE patients supports the hypothesis that Fc RIIA R131 variant over expression may constitute a susceptibility factor for development of severe SLE manifestations in LN patients.
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Suter, U., G. Texido, and H. Hofstetter. "Expression of human lymphocyte IgE receptor (Fc epsilon RII/CD23). Identification of the Fc epsilon RIIa promoter and its functional analysis in B lymphocytes." Journal of Immunology 143, no. 9 (November 1, 1989): 3087–92. http://dx.doi.org/10.4049/jimmunol.143.9.3087.
Full textAbstract:
Abstract Two species, Fc epsilon RIIa and Fc epsilon RIIb, of the human low-affinity receptor for IgE (Fc epsilon RII/CD23) have recently been described. They differ by only six amino acids in the cytoplasmic N-terminus and are generated by different cell-specific transcriptional start sites that lead to distinct 5'-leader sequences in the corresponding mRNA. In this study, we present the analysis of the promoter which is regulating the expression of the B cell-specific Fc epsilon RIIa. Our data show that this promoter is flanked by several long repetitive elements that are influencing transcription in the Burkitt lymphoma B cell line Jijoye. Serial deletions of the 5'-flanking region of the promoter revealed two major regulatory segments that have either inhibitory or enhancing effects on transcription. In addition, IL-4 caused a two- to four-fold up-regulation of the Fc epsilon RIIa promoter activity and the DNA element responsible was mapped within the first 250 bp of the 5'-flanking region. These results were confirmed by transferring the DNA segment containing the putative IL-4 responsive element to a heterologous thymidine kinase promoter. It was concluded that IL-4 augments the Fc epsilon RIIa expression by transcriptional regulation.
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Gröger, M., G. Sarmay, E. Fiebiger, K. Wolff, and P. Petzelbauer. "Dermal microvascular endothelial cells express CD32 receptors in vivo and in vitro." Journal of Immunology 156, no. 4 (February 15, 1996): 1549–56. http://dx.doi.org/10.4049/jimmunol.156.4.1549.
Full textAbstract:
Abstract Immune complexes are thought to be the major cause of cutaneous necrotizing vasculitis, but the mechanism of immune complex targeting to specific vessels is largely unknown. In myelomonocytic cells, immune complex binding and receptor-mediated endocytosis are mediated by Fc gamma R. We asked whether dermal microvascular endothelial cells (DMEC) express Fc gamma Rs. In cryostat sections of normal human skin, mAb IV.3 or AT10, both recognizing CD32 (Fc gamma RII), localizes to the luminal surface of DMEC of the superficial but not of the deep vascular plexus. All DMEC do not express CD16 (Fc gamma RIII) or CD64 (Fc gamma RI) molecules. Adult skin-derived DMEC in culture express CD32 (Fc gamma RII) molecules, as measured by FACS, but are negative for CD16 or CD64. HUVEC, tested for comparison, do not express CD16, 32, or 64 proteins. By reverse-transcriptase PCR and subsequent Southern blot analysis, the isoform of the CD32 molecule expressed on DMEC is determined as Fc gamma RIIa. HUVEC do not contain Fc gamma RIIa or Fc gamma RIIb mRNA. In DMEC, Fc gamma RIIa cross-linking results in immediate intracellular free Ca2+ ([Ca2+]i) concentration fluxes and in rapid internalization of the occupied receptors. We conclude that DMEC are equipped with fully functional Fc gamma RIIa molecules.
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Van Den Herik-Oudijk, I. E., N. A. Westerdaal, N. V. Henriquez, P. J. Capel, and J. G. Van De Winkel. "Functional analysis of human Fc gamma RII (CD32) isoforms expressed in B lymphocytes." Journal of Immunology 152, no. 2 (January 15, 1994): 574–85. http://dx.doi.org/10.4049/jimmunol.152.2.574.
Full textAbstract:
Abstract The low affinity IgG receptor Fc gamma RII (CD32) represents the most widely distributed class of human Fc gamma R. To analyze the biologic functions of different Fc gamma RII isoforms, we stably transfected Fc gamma RIIb1, IIb1*, IIb2, IIa, and a IIa tail- mutant to the mouse IIA1.6 B lymphoma cell line. Of these, Fc gamma RIIb1* represents a receptor variant that is identical to IIb1 except for a single amino acid difference in the cytoplasmic tail (amino acid position 11) where a tyrosine (IIb1) is replaced by an aspartic acid (IIb1*). Evaluation of capping ability showed the Fc gamma RIIb1 molecules to cap effectively, which was even more apparent with IIb1*. None of the Fc gamma RIIa, IIa tail-, or IIb2 isoforms capped significantly. Internalization of Fc gamma R-antibody complexes proved very efficient for both the Fc gamma RIIa and IIb2 isoforms, whereas the IIb1 molecules internalized moderately compared with IIb1*, which internalized less efficiently. Notably, human IgG aggregates were internalized effectively by Fc gamma RIIa and moderately by IIb2. Neither Fc gamma RIIb1 nor IIb1* proved capable of internalizing such IgG aggregates. Cross-linking of the different Fc gamma R molecules showed Fc gamma RIIa capable of triggering increases in [Ca2+]i. Fc gamma R expressed on B cells were able to down-regulate [Ca2+]i on co-cross-linking with slgG. Notably, all three Fc gamma RIIb receptors proved active in this respect, in contrast to Fc gamma RIIa. The cell distribution of these Fc gamma RII isoforms was analyzed in a panel of human B cell lines to complement the IIA1.6 B cell model. Fc gamma RIIa was found expressed both at message and protein levels in all tested human B cell lines. In the pre-B cell lines evaluated, no Fc gamma RIIb molecules were detectable, whereas both Fc gamma RIIb1 and IIb2 molecules were found present in more mature B cell lines. These data support both a complex expression pattern of Fc gamma RII isoforms in B cell lines and functional differences between these B cell molecules.
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Letourneur, O., I. C. Kennedy, A. T. Brini, J. R. Ortaldo, J. J. O'Shea, and J. P. Kinet. "Characterization of the family of dimers associated with Fc receptors (Fc epsilon RI and Fc gamma RIII)." Journal of Immunology 147, no. 8 (October 15, 1991): 2652–56. http://dx.doi.org/10.4049/jimmunol.147.8.2652.
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Abstract The receptor for IgE (Fc epsilon RI) is a multimeric complex containing one alpha chain, one beta chain with four transmembrane domains and one homodimer of disulfide-linked gamma-chains. The Fc epsilon RI gamma-chains form additional disulfide-linked dimers with the homologous zeta- and eta-chains, as part of the TCR complex. The low affinity receptor for IgG (Fc gamma RIII)2 on NK cells is also associated with zeta-chains. Here we show that the gamma-chain is expressed in NK cells both as a group of heterogenous gamma gamma homodimers and also as a heterodimer bound to zeta. Fc gamma RIIIA is associated with three types of dimers zeta zeta, gamma zeta, and notably gamma gamma as well. In fact, gamma gamma appears to be the predominant species associating with Fc gamma RIIIA. The surface expressed Fc epsilon RI also associates with the same group of heterogenous gamma gamma homodimers. We also show that there is no C-terminal posttranslational cleavage of gamma occurring before its insertion into the plasma membrane as previously suggested. Thus, like the TCR, Fc gamma RIIIA may form a variety of receptor isoforms, though at present we do not understand the functional implications of these structures.