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1
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 und 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, Nr. 1 (01.01.1994): 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.
2
Yanaga, F., A. Poole, J. Asselin, R. Blake, G. L. Schieven, E. A. Clark, C. L. Law und 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, Nr. 2 (15.10.1995): 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.
3
Warmerdam, P. A., J. G. van de Winkel, A. Vlug, N. A. Westerdaal und 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, Nr. 4 (15.08.1991): 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.
4
Van den Herik-Oudijk, IE, PJ Capel, T. van der Bruggen und JG Van de Winkel. „Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms“. Blood 85, Nr. 8 (15.04.1995): 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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Van den Herik-Oudijk, IE, MW Ter Bekke, MJ Tempelman, PJ Capel und JG Van de Winkel. „Functional differences between two Fc receptor ITAM signaling motifs“. Blood 86, Nr. 9 (01.11.1995): 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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Indik, ZK, XQ Pan, MM Huang, SE McKenzie, AI Levinson und AD Schreiber. „Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function“. Blood 83, Nr. 8 (15.04.1994): 2072–80. http://dx.doi.org/10.1182/blood.v83.8.2072.2072.
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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.
7
Indik, ZK, XQ Pan, MM Huang, SE McKenzie, AI Levinson und AD Schreiber. „Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function“. Blood 83, Nr. 8 (15.04.1994): 2072–80. http://dx.doi.org/10.1182/blood.v83.8.2072.bloodjournal8382072.
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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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Mitchell, MA, MM Huang, P. Chien, ZK Indik, XQ Pan und 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, Nr. 6 (15.09.1994): 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.
9
Mitchell, MA, MM Huang, P. Chien, ZK Indik, XQ Pan und 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, Nr. 6 (15.09.1994): 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.
10
Van Den Herik-Oudijk, I. E., N. A. Westerdaal, N. V. Henriquez, P. J. Capel und J. G. Van De Winkel. „Functional analysis of human Fc gamma RII (CD32) isoforms expressed in B lymphocytes.“ Journal of Immunology 152, Nr. 2 (15.01.1994): 574–85. http://dx.doi.org/10.4049/jimmunol.152.2.574.
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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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Gröger, M., G. Sarmay, E. Fiebiger, K. Wolff und P. Petzelbauer. „Dermal microvascular endothelial cells express CD32 receptors in vivo and in vitro.“ Journal of Immunology 156, Nr. 4 (15.02.1996): 1549–56. http://dx.doi.org/10.4049/jimmunol.156.4.1549.
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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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Porges, A. J., P. B. Redecha, W. T. Kimberly, E. Csernok, W. L. Gross und R. P. Kimberly. „Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.“ Journal of Immunology 153, Nr. 3 (01.08.1994): 1271–80. http://dx.doi.org/10.4049/jimmunol.153.3.1271.
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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.
13
Hoffmeyer, F., K. Witte, U. Gebhardt und R. E. Schmidt. „The low affinity Fc gamma RIIa and Fc gamma RIIIb on polymorphonuclear neutrophils are differentially regulated by CD45 phosphatase.“ Journal of Immunology 155, Nr. 8 (15.10.1995): 4016–23. http://dx.doi.org/10.4049/jimmunol.155.8.4016.
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Abstract Stimulation of human polymorphonuclear neutrophils through ligation and cross-linking of the low affinity Fc gamma RIIa and Fc gamma RIIIb using mAb Fab and F(ab')2 fragments led to transient intracellular calcium mobilization and activation of the respiratory burst. Fc gamma RIIIb engagement resulted in a different pattern of intracellular calcium flux, and induction of the respiratory burst was significantly more effective than in the case of Fc gamma RIIa. These data demonstrate that the capacity of Fc gamma RIIIb to transduce transmembrane signals itself contributes to full cell activation. Treatment with a mAb F(ab')2 fragment recognizing CD45 phosphatase suppressed Fc gamma R-induced calcium mobilization in a dose-dependent manner. An ongoing intracellular calcium mobilization was immediately terminated when activation was followed by co-cross-linking Fc gamma R and CD45. This suggests that the initial steps of Fc gamma R signal transduction pathways are influenced by the state of tyrosine phosphorylation. Combined cross-linking of both receptors, however, was hardly susceptible to CD45. Also, inhibition of respiratory burst by CD45 in the case of Fc gamma RIIIb was minimal compared with that for Fc gamma RIIa. Signal transduction pathways of low affinity Fc gamma RIIa and Fc gamma RIIIb are differentially regulated by CD45, underlining the essential function of Fc gamma R-mediated tyrosine phosphorylation in polymorphonuclear neutrophil activation.
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Haagen, I. A., A. J. Geerars, M. R. Clark und J. G. van de Winkel. „Interaction of human monocyte Fc gamma receptors with rat IgG2b. A new indicator for the Fc gamma RIIa (R-H131) polymorphism.“ Journal of Immunology 154, Nr. 4 (15.02.1995): 1852–60. http://dx.doi.org/10.4049/jimmunol.154.4.1852.
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Abstract Rat mAbs receive considerable interest for immunologic intervention in man. The rat IgG2b isotype has previously been found to be optimally active both in vivo and in vitro. We found that both a rat IgG2b CD3 mAb and a monovalent hybrid rat IgG2b-mouse IgG1 bispecific Ab triggered T cell activation in PBMC. Inhibition analyses with mAb blocking different human IgG Fc receptors (Fc gamma R) showed a dimorphic pattern. In donors expressing an Fc gamma RIIa-R/R131 allotype (previously defined on the basis of interaction with mouse (m) IgG1 as "high responder") anti-Fc gamma RI mAb 197 inhibited rat IgG2b induced T cell mitogenesis almost completely. In Fc gamma RIIa-H/H131 ("low responder" allotype) donors, however, both anti-Fc gamma RI mAb 197 and anti-Fc gamma RII mAb IV.3 were essential for optimal inhibition of mitogenesis. T cell proliferation experiments performed with the use of Fc gamma R-transfected fibroblasts as accessory cells showed the high affinity Fc gamma RIa (CD64) to interact with both rat IgG2b and rat IgG2b-mlgG1 hybrid CD3 mAb. The use of the two types of Fc gamma RIIa (CD32)-transfectants instead showed rat IgG2b CD3 mAb to interact solely with the IIa-H/H131 allotype. Interestingly, rat IgG2b-mlgG1 hybrid mAb did not interact effectively with this low affinity Fc gamma R. This suggests a requirement for only one rat IgG2b H chain for Fc gamma RIa-mediated binding, whereas two identical H chains seem to be necessary for proper interaction with Fc gamma RIIa. Ab-sensitized RBC-rosette experiments performed with the use of a rat IgG2b anti-NIP mAb confirmed the interaction pattern observed with rat CD3 mAb, supporting the phenomena to be isotype-, and not mAb-, dependent. These analyses point to a unique reactivity pattern for rat IgG2b Abs, interacting both with the high affinity Fc gamma RIa in all donors and Fc gamma RIIa of individuals expressing the IIa-H131 allotype.
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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, Nr. 21 (18.11.2011): 1600. http://dx.doi.org/10.1182/blood.v118.21.1600.1600.
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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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Suter, U., G. Texido und 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, Nr. 9 (01.11.1989): 3087–92. http://dx.doi.org/10.4049/jimmunol.143.9.3087.
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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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Shen, Z., C. T. Lin und 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, Nr. 6 (15.03.1994): 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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Pradhan, Vandana, Manisha Patwardhan, Anita Nadkarni und 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.
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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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Kocher, M., M. E. Siegel, J. C. Edberg und R. P. Kimberly. „Cross-linking of Fc gamma receptor IIa and Fc gamma receptor IIIb induces different proadhesive phenotypes on human neutrophils.“ Journal of Immunology 159, Nr. 8 (15.10.1997): 3940–48. http://dx.doi.org/10.4049/jimmunol.159.8.3940.
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Abstract Activation of polymorphonuclear leukocytes (PMN) plays an important role in vascular injury associated with systemic vasculitis and in models of autoantibody- and immune complex-mediated disease. The potential role of intravascular activation of PMN, however, is confounded by the observation that some stimuli injected i.v. (e.g., IL-8 and C5a) lead to L-selectin shedding by PMN, which inhibits attachment to endothelium and may be functionally anti-inflammatory. To explore the impact of Fc gamma receptor (Fc gamma R)-mediated activation on the PMN adhesive phenotype, Fc gamma RIIa (CD32) and Fc gamma RIIIb (Cd16) were targeted with receptor-specific reagents, and the expression of adhesion molecules-mediating rolling (L-selectin) and firm adhesion (CD11b/CD18) was measured. Engagement of either Fc gamma RIIa or Fc gamma RIIIb leads to activation, demonstrated by degranulation (upregulation of CD66b), and to increased expression of total CD11b/CD18 and functional CD11b/CD18 (I-domain). In contrast, L-selectin shedding induced by PMN Fc gamma R was divergent. Despite the 5- to 10-fold greater expression and engagement at saturation, activation via Fc gamma RIIIb led to little or no change in L-selectin expression. Stimulation of PMN with intact murine anti-receptor IgG1 showed a contribution of Fc gamma RIIa receptor polymorphisms, underscoring the direct influences of Fc gamma R allotypes on receptor function. These observations suggest that Fc gamma RIIIb-mediated activation of circulating PMN may lead to a proadhesive phenotype likely to promote systemic vascular damage. This Fc gamma R-mediated adhesive phenotype will vary with the receptors engaged and their allotypes, which, in turn, reflect properties of the immune complex and the genetics of the host.
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Indik, ZK, JG Park, S. Hunter und AD Schreiber. „The molecular dissection of Fc gamma receptor mediated phagocytosis“. Blood 86, Nr. 12 (15.12.1995): 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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Ierino, F. L., M. D. Hulett, I. F. McKenzie und P. M. Hogarth. „Mapping epitopes of human Fc gamma RII (CDw32) with monoclonal antibodies and recombinant receptors.“ Journal of Immunology 150, Nr. 5 (01.03.1993): 1794–803. http://dx.doi.org/10.4049/jimmunol.150.5.1794.
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Abstract Fc gamma RII is a low affinity FcR for IgG with two Ig-like extracellular domains (D1 gamma and D2 gamma), a transmembrane domain, and a cytoplasmic domain. The production, characterization, and epitope analysis of four anti-human Fc gamma RII mAb (8.2, 8.7, 8.26, and 7.30) are detailed, and the mAb are compared with two defined CDw32 mAb, IV.3 and CIKM5. Reactivity of all mAb with Fc gamma RII was demonstrated by (a) specific binding to Fc gamma RII+ L cells (produced after transfection of L cells with human Fc gamma RIIa cDNA, HFc3.0), by using flow cytometry, (b) inhibition of the binding of SRBC sensitized with rabbit antibody (EA) to Fc gamma RII+ L cells, and (c) immunoprecipitation and SDS-PAGE, which detected a 42-kDa protein on K562 and U937 cells and a single 45-kDa protein on Fc gamma RII+ L cells. The mAb were able to detect different forms of Fc gamma RII, by flow cytometry, on Daudi cells (8.7 and 7.30) and U937 cells (8.2, IV.3, and CIKM5); 8.26 stained Daudi cells with intermediate fluorescence and U937 cells with the highest fluorescence, relative to the remaining mAb. Binding to transiently expressed isoforms of Fc gamma RII (a and b1) and four allelic variants of Fc gamma RIIa in COS-7 cells did not distinguish the mAb epitopes. Further mapping of the mAb epitopes was determined by (a) EA inhibition assays, (b) mAb blocking studies, and (c) the binding of the mAb to segments of human Fc gamma RIIa by using genetically engineered chimeric receptors. Chimeric receptors expressing either D1 gamma linked to domain 2 of Fc epsilon RI or domain 1 of Fc epsilon RI linked to D2 gamma were produced by exchanging homologous, but antigenically different, regions of Fc gamma RIIa and the high affinity receptor for IgE. Four clusters of mAb were identified, each mapping to discrete epitopes of Fc gamma RII. Cluster I (mAb 8.2 and CIKM5) defines a combinatorial epitope with determinants in D1 gamma and D2 gamma distant from the IgG Fc binding site, inasmuch as F(ab')2 fragments of 8.2 and CIKM5 do not inhibit the binding of EA to Fc gamma RII. The epitopes of clusters 2 (mAb 8.26), 3 (mAb IV.3), and 4 (mAb 8.7 and 7.30) are located entirely in D2 gamma and all involve the IgG Fc binding region, because F(ab')/F(ab')2 fragments of the mAb inhibit EA binding to Fc gamma RII. Thus, all mAb that inhibit the binding of EA map totally to D2 gamma; it is likely the IgG Fc binding region is also contained in D2 gamma.
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Matsuda, M., J. G. Park, D. C. Wang, S. Hunter, P. Chien und 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, Nr. 7 (Juli 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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Tomiyama, Y., TJ Kunicki, TF Zipf, SB Ford und RH Aster. „Response of human platelets to activating monoclonal antibodies: importance of Fc gamma RII (CD32) phenotype and level of expression“. Blood 80, Nr. 9 (01.11.1992): 2261–68. http://dx.doi.org/10.1182/blood.v80.9.2261.2261.
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Abstract Certain monoclonal antibodies (MoAbs) specific for platelet membrane glycoproteins are known to be capable of activating platelets, and it is generally thought that platelets from normal subjects are equally susceptible to stimulation by such MoAbs. We found that platelets from 20 normal donors varied significantly in their sensitivity to three IgG1 murine MoAbs specific for membrane glycoproteins CD9, GPIV (CD36), and the GPIIb/IIIa complex (CD41), respectively. The response of platelets to these MoAbs was blocked by prior addition of MoAb IV.3 specific for the Fc gamma RII receptor, indicating that activation was Fc receptor mediated. Platelets that responded poorly to these MoAbs failed to bind the MoAb 41H.16, specific for the “responder” form of Fc gamma RII, but platelets that responded well reacted with this MoAb. The average number of Fc gamma RII receptors on platelets from “responders” and “non-responders” was approximately the same. However, the number of Fc gamma RII receptors expressed influenced sensitivity of a subgroup of “responder” platelets to the anti-CD41 MoAb. These platelets were judged on the basis of MoAb binding studies to be heterozygous for the two alleles of Fc gamma RIIA. In contrast to their varying sensitivity to IgG1 MoAbs, members of the platelet panel responded equally well to 50H.19, an IgG2a MoAb specific for CD9, and these responses could not be blocked by MoAb IV.3 in the presence of plasma. This appears to be because of dual actions of 50H.19 on platelets: one FcR-dependent and the other complement-dependent. Our findings confirm previous reports that certain IgG1 MoAbs activate platelets through binding of their Fc domains to Fc gamma RII receptors and demonstrate that this response is influenced both by Fc gamma RII phenotype and (in the case of the anti-CD41 MoAb) by the number of Fc gamma RII receptors expressed. The failure of nonresponding platelets to bind detectable amounts of MoAb 41H.16, which is thought to recognize all Fc gamma RII receptors except for one allele of the Fc gamma RIIA gene, is consistent with the possibility that Fc gamma RIIA gene products, but not Fc gamma RIIB or Fc gamma RIIC gene products, are expressed on platelets.
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Tomiyama, Y., TJ Kunicki, TF Zipf, SB Ford und RH Aster. „Response of human platelets to activating monoclonal antibodies: importance of Fc gamma RII (CD32) phenotype and level of expression“. Blood 80, Nr. 9 (01.11.1992): 2261–68. http://dx.doi.org/10.1182/blood.v80.9.2261.bloodjournal8092261.
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Certain monoclonal antibodies (MoAbs) specific for platelet membrane glycoproteins are known to be capable of activating platelets, and it is generally thought that platelets from normal subjects are equally susceptible to stimulation by such MoAbs. We found that platelets from 20 normal donors varied significantly in their sensitivity to three IgG1 murine MoAbs specific for membrane glycoproteins CD9, GPIV (CD36), and the GPIIb/IIIa complex (CD41), respectively. The response of platelets to these MoAbs was blocked by prior addition of MoAb IV.3 specific for the Fc gamma RII receptor, indicating that activation was Fc receptor mediated. Platelets that responded poorly to these MoAbs failed to bind the MoAb 41H.16, specific for the “responder” form of Fc gamma RII, but platelets that responded well reacted with this MoAb. The average number of Fc gamma RII receptors on platelets from “responders” and “non-responders” was approximately the same. However, the number of Fc gamma RII receptors expressed influenced sensitivity of a subgroup of “responder” platelets to the anti-CD41 MoAb. These platelets were judged on the basis of MoAb binding studies to be heterozygous for the two alleles of Fc gamma RIIA. In contrast to their varying sensitivity to IgG1 MoAbs, members of the platelet panel responded equally well to 50H.19, an IgG2a MoAb specific for CD9, and these responses could not be blocked by MoAb IV.3 in the presence of plasma. This appears to be because of dual actions of 50H.19 on platelets: one FcR-dependent and the other complement-dependent. Our findings confirm previous reports that certain IgG1 MoAbs activate platelets through binding of their Fc domains to Fc gamma RII receptors and demonstrate that this response is influenced both by Fc gamma RII phenotype and (in the case of the anti-CD41 MoAb) by the number of Fc gamma RII receptors expressed. The failure of nonresponding platelets to bind detectable amounts of MoAb 41H.16, which is thought to recognize all Fc gamma RII receptors except for one allele of the Fc gamma RIIA gene, is consistent with the possibility that Fc gamma RIIA gene products, but not Fc gamma RIIB or Fc gamma RIIC gene products, are expressed on platelets.
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de Haas, M., M. Kleijer, R. van Zwieten, D. Roos und AE von dem Borne. „Neutrophil Fc gamma RIIIb deficiency, nature, and clinical consequences: a study of 21 individuals from 14 families“. Blood 86, Nr. 6 (15.09.1995): 2403–13. http://dx.doi.org/10.1182/blood.v86.6.2403.bloodjournal8662403.
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Several individuals have been described whose neutrophils lack the normally abundantly expressed IgG Fc gamma receptor IIIb (Fc gamma RIIIb). We now studied the responsible genomic defect and analyzed the medical history in detail of 21 Fc gamma RIIIb-negative donors identified in 14 unrelated families. We developed a polymerase chain reaction allele-specific-primer annealing assay to genotype for the NA polymorphism of the Fc gamma RIIIB gene. All Fc gamma RIIIb-deficient individuals were negative for both the NA1 and the NA2 allele. In all cases the complete absence of the Fc gamma RIIIB alleles was confirmed using a Southern blot-based restriction fragment length polymorphism assay. Furthermore, an additional deletion of the next more telomeric located Fc gamma RIIC gene was found. Family studies showed that at least one Fc gamma RIIIB allele was absent in both parents in 6 families, whereas in 2 families the father had a normal phenotype. Two individuals suffered from an autoimmune thyroiditis. Four individuals had had multiple episodes of infection, 3 had only incidental infections, and 14 never had any serious infection. Genotyping showed a normal Fc gamma RIIa phenotype distribution among the Fc gamma RIIIb- negative individuals, thus excluding the possibility that the presence of the favorable IgG2-binding low-responder isoform of Fc gamma RIIa (131-H) contributed to the overall absence of recurrent bacterial infections.
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Robinson, A., J. Gibbins, B. Rodriguez-Linares, PM Finan, L. Wilson, S. Kellie, P. Findell und SP Watson. „Characterization of Grb2-binding proteins in human platelets activated by Fc gamma RIIA cross-linking“. Blood 88, Nr. 2 (15.07.1996): 522–30. http://dx.doi.org/10.1182/blood.v88.2.522.bloodjournal882522.
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Glutathione-S-transferase (GST)-Grb2 fusion proteins have been used to identify the potential role of Grb2-binding proteins in platelet activation by the platelet low-affinity IgG receptor, Fc gamma RIIA. Two tyrosine phosphoproteins of 38 and 63 kD bind to the SH2 domain of Grb2 following Fc gamma RIIA stimulation of platelets. Both are located in the particulate fraction following platelet activation and are also able to bind to a GST-construct containing the SH2 and SH3 domains of phospholipase C gamma 1. p38 also forms a complex with the tyrosine kinase csk in stimulated cells and is a substrate for the kinase. The SH3 domains of Grb2 form a stable complex with SOS1 and two proteins of 75 kD and 120 kD, which undergo tyrosine phosphorylation in Fc gamma RIIA stimulated cells. The 75-kD protein is recognized by antibodies to SLP-76, which has recently been isolated from T cells and sequenced. Tyrosine phosphorylation of p38 and p63 is also observed in platelets stimulated by the tyrosine kinase-linked receptor agonist collagen and by the G protein-coupled receptor agonist thrombin, although phosphorylation of SLP-76 is only observed in collagen-stimulated platelets. p38 and p63 may provide a docking site for Grb2, thereby linking Grb2 SH3-binding proteins SOS1, SLP-76, and p120 to downstream signalling events.
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Marois, Louis, Guillaume Paré, Myriam Vaillancourt, Emmanuelle Rollet-Labelle und Paul H. Naccache. „Functional cooperation between Fc gamma RIIa and Fc gamma RIIIb on human neutrophils“. Cytokine 48, Nr. 1-2 (Oktober 2009): 28. http://dx.doi.org/10.1016/j.cyto.2009.07.107.
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Reumaux, D., PJ Vossebeld, D. Roos und AJ Verhoeven. „Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies“. Blood 86, Nr. 8 (15.10.1995): 3189–95. http://dx.doi.org/10.1182/blood.v86.8.3189.3189.
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Abstract Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.
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Reumaux, D., PJ Vossebeld, D. Roos und AJ Verhoeven. „Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies“. Blood 86, Nr. 8 (15.10.1995): 3189–95. http://dx.doi.org/10.1182/blood.v86.8.3189.bloodjournal8683189.
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Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.
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Adamian, Robert, Paul McCleary, Toishi Sharma und David J. Schneider. „PLATELET FC RIIA EXPRESSION IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE“. Journal of the American College of Cardiology 79, Nr. 9 (März 2022): 1014. http://dx.doi.org/10.1016/s0735-1097(22)02005-8.
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Indik, ZK, JG Park, XQ Pan und AD Schreiber. „Induction of phagocytosis by a protein tyrosine kinase“. Blood 85, Nr. 5 (01.03.1995): 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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Yamamoto, K., T. Kobayashi, N. Sugita, H. Tai und H. Yoshie. „The Fc?RIIa polymorphism influences production of interleukin-1 by mononuclear cells“. International Journal of Immunogenetics 34, Nr. 5 (Oktober 2007): 369–72. http://dx.doi.org/10.1111/j.1744-313x.2007.00701.x.
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Sharma, Toishi, Sean Robert McMahon und David J. Schneider. „PLATELET FC¥RIIA EXPRESSION, A POWERFUL MARKER OF CARDIOVASCULAR RISK IN WOMEN“. Journal of the American College of Cardiology 81, Nr. 8 (März 2023): 1287. http://dx.doi.org/10.1016/s0735-1097(23)01731-x.
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Tuijnman, WB, PJ Capel und JG van de Winkel. „Human low-affinity IgG receptor Fc gamma RIIa (CD32) introduced into mouse fibroblasts mediates phagocytosis of sensitized erythrocytes“. Blood 79, Nr. 7 (01.04.1992): 1651–56. http://dx.doi.org/10.1182/blood.v79.7.1651.1651.
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Abstract Multiple isoforms of human (h) Fc gamma RII are currently recognized. We set up experiments to evaluate the significance of different hFc gamma RII (CD32) isoforms in the uptake of IgG-coated particles. Therefore, a panel of stable hFc gamma RII-transfected fibroblasts was constructed to study phagocytosis. It was observed that over 40% of 3T6 fibroblasts transfected with hFc gamma RIIa cDNA phagocytose human erythrocytes (E) coated with mouse (m) IgG1 or mIgG2a (EA). This was in contrast to cells expressing a tail-minus variant of Fc gamma RII (hFc gamma RIItail-). Fibroblasts transfected with hFc gamma RIIb1 cDNA infrequently internalized EA. There was no difference in EA binding by these transfectants; all three clones formed more than 80% EA-rosettes. Uptake of particles was dependent on the degree of E sensitization, and was inhibitable by CD32 monoclonal antibody AT10. Preincubation of cells with cytochalasin D blocked internalization completely, with no effect on binding. This shows that phagocytosis underlies the observed E internalization. Immunofluorescence studies using an anticathepsin D antiserum showed the maturation of phagosomes, containing antibody- coated E, into lysosomes. In conclusion, our studies show, for the first time, that fibroblasts possess the basic machinery for ingestion of erythrocytes, and are capable of phagocytosis only when equipped with an appropriate receptor. hFc gamma RIIa and, to a lesser extent hFc gamma RIIb1, are suited for this task, which seems dictated by the cytoplasmic domain.
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Tuijnman, WB, PJ Capel und JG van de Winkel. „Human low-affinity IgG receptor Fc gamma RIIa (CD32) introduced into mouse fibroblasts mediates phagocytosis of sensitized erythrocytes“. Blood 79, Nr. 7 (01.04.1992): 1651–56. http://dx.doi.org/10.1182/blood.v79.7.1651.bloodjournal7971651.
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Multiple isoforms of human (h) Fc gamma RII are currently recognized. We set up experiments to evaluate the significance of different hFc gamma RII (CD32) isoforms in the uptake of IgG-coated particles. Therefore, a panel of stable hFc gamma RII-transfected fibroblasts was constructed to study phagocytosis. It was observed that over 40% of 3T6 fibroblasts transfected with hFc gamma RIIa cDNA phagocytose human erythrocytes (E) coated with mouse (m) IgG1 or mIgG2a (EA). This was in contrast to cells expressing a tail-minus variant of Fc gamma RII (hFc gamma RIItail-). Fibroblasts transfected with hFc gamma RIIb1 cDNA infrequently internalized EA. There was no difference in EA binding by these transfectants; all three clones formed more than 80% EA-rosettes. Uptake of particles was dependent on the degree of E sensitization, and was inhibitable by CD32 monoclonal antibody AT10. Preincubation of cells with cytochalasin D blocked internalization completely, with no effect on binding. This shows that phagocytosis underlies the observed E internalization. Immunofluorescence studies using an anticathepsin D antiserum showed the maturation of phagosomes, containing antibody- coated E, into lysosomes. In conclusion, our studies show, for the first time, that fibroblasts possess the basic machinery for ingestion of erythrocytes, and are capable of phagocytosis only when equipped with an appropriate receptor. hFc gamma RIIa and, to a lesser extent hFc gamma RIIb1, are suited for this task, which seems dictated by the cytoplasmic domain.
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Richards, M. L., D. H. Katz und F. T. Liu. „Complete genomic sequence of the murine low affinity Fc receptor for IgE. Demonstration of alternative transcripts and conserved sequence elements.“ Journal of Immunology 147, Nr. 3 (01.08.1991): 1067–74. http://dx.doi.org/10.4049/jimmunol.147.3.1067.
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Abstract The complete sequence of the murine low affinity Fc receptor for IgE (Fc epsilon RII), including the 5' and 3' flanking sequences, is reported. The murine Fc epsilon RII gene spans 12.9 kb and includes 12 exons surrounding 11 introns. The composite exon sequence is virtually identical to previously reported murine Fc epsilon RII cDNA sequences. Much of the proximal promoter regions of the mouse and human homologues of Fc epsilon RII show remarkable homology to each other, including three promoter elements previously identified for MHC class II genes. The reported exon/intron structure of the human FC epsilon RII is similar to the murine homologue, except that the latter has an additional exon coding for a fourth amino acid repetitive sequence (vs three in the human gene). RNase protection studies have identified an additional transcript within intron 2 of murine Fc epsilon RIIa, similar to the human Fc epsilon RIIb form but with a different predicted sequence of the first six amino acids. This transcript is present in the mRNA of purified splenic B cells, but not in the mRNA of the Fc epsilon RII+ B lymphoma cell line M12.4.5. The murine Fc epsilon RII gene contains a large intron (4.2 kb) separating the lectin and nonlectin coding regions, and several repetitive sequences are found clustered within this intron. These results emphasize the importance of the demarcation between these domains and allude to their evolutionary and functional significance.
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Bredius, R. G., C. E. de Vries, A. Troelstra, L. van Alphen, R. S. Weening, J. G. van de Winkel und T. A. Out. „Phagocytosis of Staphylococcus aureus and Haemophilus influenzae type B opsonized with polyclonal human IgG1 and IgG2 antibodies. Functional hFc gamma RIIa polymorphism to IgG2.“ Journal of Immunology 151, Nr. 3 (01.08.1993): 1463–72. http://dx.doi.org/10.4049/jimmunol.151.3.1463.
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Abstract To assess the function of IgG subclass antibodies we studied the opsonization of Staphylococcus aureus (STAW) and Haemophilus influenzae type b (Hib) by natural IgG1 and IgG2 antibodies from five healthy individuals. Phagocytosis by polymorphonuclear leukocytes (PMN) was analyzed using FITC-labeled bacteria and flow cytometry. All PMN donors were typed for the High- and Low-Responder phenotype of the human Fc gamma receptor (hFc gamma) type IIa (CD32) and the NA1/NA2 allotype of the hFc gamma RIIIb (CD16). When PMN were used that were heterozygous for hFc gamma RIIa and hFc gamma RIIIb, phagocytosis of STAW opsonized with IgG1 antibodies was similar to that with IgG2, both in the presence and absence of a source of complement (agammaglobulinemic serum). Phagocytosis of Hib opsonized with IgG2 anti-Hib proved significantly lower (p < 0.05) than with IgG1 anti-Hib using preparations from 4 of the 5 individuals tested. IgG2 anti-Hib from one donor, however, proved more effective than IgG1 anti-Hib. The properties of PMN with hFc gamma RIIaLR,LR and hFc gamma RIIaHR,HR were compared, using hFc gamma RIIIb NA1/NA2-matched PMN. hFc gamma RIIaHR,HR PMN were virtually incapable of phagocytosing STAW and Hib opsonized with IgG2 anti-bodies without complement, in contrast to hFc gamma RIIaLR,LR PMN. Phagocytosis of IgG2-oposonized bacteria by hFc gamma RIIaLR,LR PMN was effectively inhibited by mAb against hFc gamma RIIa (IV.3). IgG1-mediated phagocytosis was blocked by mAb against hFc gamma RIIIb (CLB/FcRGran 1) to a greater extent than by anti-hFc gamma RIIa mAb. Inhibition studies with mAb against CR3 (B2.12) and hFc gamma RIIa showed that both receptors cooperated in phagocytosis. We conclude that PMN phagocytosis can be effectively mediated by antibacterial IgG2 anti-STAW and anti-Hib. Thus, IgG2 may have a critical role in the immune defense against these bacteria. However, the role of antibacterial IgG2 in opsonization and phagocytosis may be limited in individuals homozygous for hFc gamma RIIaHR.
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Salmon, J. E., S. Millard, L. A. Schachter, F. C. Arnett, E. M. Ginzler, M. F. Gourley, R. Ramsey-Goldman, M. G. Peterson und R. P. Kimberly. „Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.“ Journal of Clinical Investigation 97, Nr. 5 (01.03.1996): 1348–54. http://dx.doi.org/10.1172/jci118552.
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Welker, A., J. Zlamal, A. Aliotta, L. Veuthey, L. Alberio und T. Bakchoul. „Investigation of antibody-induced Fc-gamma-RIIA-mediated procoagulant platelet formation in real-time“. Hämostaseologie 45, S 01 (Februar 2025): S80. https://doi.org/10.1055/s-0044-1801666.
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Chen, Tiffany F., Stephen L. Sazinsky, Damian Houde, David J. DiLillo, Julie Bird, Kevin K. Li, George T. Cheng et al. „Engineering Aglycosylated IgG Variants with Wild-Type or Improved Binding Affinity to Human Fc Gamma RIIA and Fc Gamma RIIIAs“. Journal of Molecular Biology 429, Nr. 16 (August 2017): 2528–41. http://dx.doi.org/10.1016/j.jmb.2017.07.001.
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Bazilio, A. P., V. S. T. Viana, R. Toledo, V. Woronik, E. Bonfa und R. C. Monteiro. „Fc RIIa polymorphism: a susceptibility factor for immune complex-mediated lupus nephritis in Brazilian patients“. Nephrology Dialysis Transplantation 19, Nr. 6 (05.03.2004): 1427–31. http://dx.doi.org/10.1093/ndt/gfh121.
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Worth, R. G., M. K. Kim, A. L. Kindzelskii, H. R. Petty und A. D. Schreiber. „Signal sequence within Fc RIIA controls calcium wave propagation patterns: Apparent role in phagolysosome fusion“. Proceedings of the National Academy of Sciences 100, Nr. 8 (03.04.2003): 4533–38. http://dx.doi.org/10.1073/pnas.0836650100.
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Lu, Jinghua, Lorraine L. Marnell, Carolyn Mold, Terry W. Du Clos und Peter D. Sun. „Structure of SAP Bound to Fc γ RIIa Suggests the Regulation of Inflammation by Pentraxins“. FASEB Journal 22, S2 (April 2008): 540. http://dx.doi.org/10.1096/fasebj.22.2_supplement.540.
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Ozturk, C., G. Aksu, A. Berdeli und N. Kutukculer. „Fc gamma RIIa, IIIa and IIIb polymorphisms in Turkish children susceptible to recurrent infectious diseases“. Clinical and Experimental Medicine 6, Nr. 1 (März 2006): 27–32. http://dx.doi.org/10.1007/s10238-006-0090-y.
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Johnson, S. A., C. M. Pleiman, L. Pao, J. Schneringer, K. Hippen und J. C. Cambier. „Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases.“ Journal of Immunology 155, Nr. 10 (15.11.1995): 4596–603. http://dx.doi.org/10.4049/jimmunol.155.10.4596.
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Abstract Signal transduction by T and B cell Ag receptors and certain receptors for Ig Fc regions (Fc gamma RI, hFc gamma RIIA, Fc gamma RIII, Fc alpha R, and Fc epsilon RI) involves a conserved sequence motif, termed an immunoreceptor tyrosine-based activation motif (ITAM) and found in multiple receptor chains. Phosphorylation of the two ITAM tyrosines is a critical event in signal transduction. To address the function of this phosphorylation, we assessed the ability of nonphosphorylated and biphosphorylated ((p)2ITAM) ITAM peptides to bind and modify the activity of src and syk family kinases in vivo and in vitro. All (p)2ITAMs, but not their nonphosphorylated counterparts, induced extensive protein tyrosine phosphorylation in permeabilized cells. However, the patterns of proteins phosphorylated differed among (p)2ITAMs. This phosphorylation was found to reflect activation of the src family kinase Lyn, but not Syk. In vitro studies using purified Lyn showed that src family kinase activation resulted from a direct interaction with (p)2ITAM. Binding studies demonstrated clear differences in binding specificity of (p)2ITAMs. Most strikingly, Ig alpha (p)2ITAM and TCR-zeta c and CD3 epsilon (p)2ITAMs exhibit inverse binding preferences for src and syk family kinases. Taken together, these findings demonstrate a novel mechanism by which src family tyrosine kinases are activated, and are consistent with the possibility that different ITAMs may preferentially activate distinct signaling pathways as a consequence of distinct effector Src homology 2 domain (SH2) binding preference.
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Brooks, D. G., W. Q. Qiu, A. D. Luster und J. V. Ravetch. „Structure and expression of human IgG FcRII(CD32). Functional heterogeneity is encoded by the alternatively spliced products of multiple genes.“ Journal of Experimental Medicine 170, Nr. 4 (01.10.1989): 1369–85. http://dx.doi.org/10.1084/jem.170.4.1369.
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The structural heterogeneity of the human low affinity receptor for IgG, FcRII(CD32), has been elucidated through the isolation, characterization, and expression of cDNA clones derived from myeloid and lymphoid RNA. These clones predict amino acid sequences consistent with integral membrane glycoproteins with single membrane spanning domains. The extracellular domains display sequence homology to other Fc gamma Rs and members of the Ig supergene family. A minimum of three genes (Fc gamma RIIa, IIa', and Fc gamma RIIb) encode these transcripts, which demonstrate highly related extracellular and membrane spanning domains. IIa/IIa' differ substantially in the intracytoplasmic domain from IIb. Alternative splicing of the IIb gene generates further heterogeneity in both NH2- and COOH-terminal domains of the predicted proteins. Comparison to the murine homologues of these molecules reveals a high degree of conservation between the products of one of these genes, Fc gamma RIIb, and the murine beta gene in primary sequence, splicing pattern, and tissue distribution. In contrast, the sequence of IIa' indicates its relationship to the beta-like genes, with mutation giving rise to a novel cytoplasmic domain, while IIa is a chimera of both alpha- and beta-like genes. Expression of these cDNA molecules by transfection results in the appearance of IgG binding molecules that bear the epitopes defined by the FcRII(CD32) mAbs previously described.
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Parren, P. W., P. A. Warmerdam, L. C. Boeije, P. J. Capel, J. G. van de Winkel und L. A. Aarden. „Characterization of IgG FcR-mediated proliferation of human T cells induced by mouse and human anti-CD3 monoclonal antibodies. Identification of a functional polymorphism to human IgG2 anti-CD3.“ Journal of Immunology 148, Nr. 3 (01.02.1992): 695–701. http://dx.doi.org/10.4049/jimmunol.148.3.695.
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Abstract T cell activation induced by mouse anti-CD3 mAb has shown to be dependent on the Ig isotype of these antibodies. A study of isotype dependency of human antibodies, however, seems more relevant to human effector systems, especially in view of the availability of humanized antibodies for clinical applications. We constructed a panel of mouse and mouse/human chimeric anti-CD3 mAb, which differ only in their CH region and hence have identical binding sites and affinity. By using these antibodies, we now studied their ability to induce T cell proliferation in human PBMC and analyzed the classes of IgG FcR involved in these responses. The human (h)IgG1, hIgG3, and hIgG4, as well as mouse (m)IgG2a and mIgG3 anti-CD3 mAb induced an Fc gamma RI (CD64)-dependent T cell proliferation in all donors. Activation with hIgG2 and mIgG1 anti-CD3 mAb was observed to be mediated via the low affinity Fc gamma RII (CD32). It was found that leukocytes in a normal donor population display a functional polymorphism with respect to hIgG2 anti-CD3 responsiveness. This polymorphism was found to be inversely related to the previously defined Fc gamma RII-polymorphism to mIgG1 anti-CD3 mAb. Monocytes expressing the Fc gamma RII mIgG1 low responder (LR) allele support hIgG2 anti-CD3 induced T cell proliferation efficiently, whereas cells homozygous for the Fc gamma RII mIgG1 high responder (HR) allele do not. This observation could be confirmed in T cell activation studies using hFc gamma RIIa-transfected mouse fibroblasts, expressing either the mIgG1 anti-CD3 HR or LR Fc gamma RII-encoding cDNA.
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Richards, M. L., und D. H. Katz. „Regulation of the murine Fc epsilon RII (CD23) gene. Functional characterization of an IL-4 enhancer element.“ Journal of Immunology 152, Nr. 7 (01.04.1994): 3453–66. http://dx.doi.org/10.4049/jimmunol.152.7.3453.
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Abstract The murine B cell IgE receptor (Fc epsilon RII, CD23) has been implicated in various functions including IgE regulation, Ag presentation, and B cell differentiation/activation. We have undertaken a series of studies to identify promoter sequences that are important for the constitutive and IL-4-induced expression of the murine Fc epsilon RII in M12.4.5 B lymphoma cells. By use of RNase protection analysis it was established that murine splenic B cells and M12.4.5 cells predominantly express the Fc epsilon RIIa form and that this receptor subtype accounts for the vast majority of IL-4-induced Fc epsilon RII mRNA in B cells. A 101-bp segment of the murine Fc epsilon RII proximal promoter coupled to a heterologous SV40 promoter was found to impart IL-4 inducibility in reporter assays. Removal of either 10 bp from the 5' end or 17 bp from the 3' end of this 101-bp fragment substantially reduced the IL-4 response. Both of these terminal deletions removed sequences that share homology with established IL-4 response elements of MHC class II and Ig (gamma 1 and epsilon) heavy chain genes. In addition, near the center of this 101-bp fragment lies a sequence that is highly homologous with NF-kappa B/LPS response elements previously identified upstream of the A alpha gene. DNA fragments containing this sequence together with one of the putative IL-4 response elements were able to impart a small LPS/IL-4 response in M12.4.5 cells. These results suggest that IL-4 and LPS induction of murine B cell Fc epsilon RII expression is mediated by a complex of transcription factors.
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Raaz-Schrauder, Dorette, Arif B. Ekici, Luis E. Munoz, Lutz Klinghammer, Reinhard E. Voll, Jeanette H. W. Leusen, Jan G. J. van de Winkel et al. „Patients with unstable angina pectoris show an increased frequency of the Fc gamma RIIa R131 allele“. Autoimmunity 45, Nr. 7 (20.06.2012): 556–64. http://dx.doi.org/10.3109/08916934.2012.682665.
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GORCHAKOVA, O. „P1208 Recombinant human C-reactive protein inhibits platelet function independent of Fc? RIIa-R-H131 genotype“. European Heart Journal 24, Nr. 5 (März 2003): 227. http://dx.doi.org/10.1016/s0195-668x(03)94500-3.
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