Disease relevance of Fcer1g

• To determine the role of these autoantibodies, the Fc receptor gamma gene (FcR gamma) was additionally disrupted in Hexb(-/-) mice, as it plays a key role in immune complex-mediated autoimmune diseases [1].
• Thus, following Jo2 treatment, all FcgammaRIIB(-/-) mice survived while 80% of wild-type and all FcR-gamma(-/-) mice died from acute liver failure [2].
• These results suggest that the collagen-induced activation of platelets through the FcR gamma plays a pivotal role in the extension of myocardial ischemia-reperfusion injury [3].
• Platelet Syk was scarcely activated in the FcR gamma(-/-) mice after myocardial ischemia and reperfusion, but significantly activated in the FcR gamma(+/+) mice [3].
• To examine the functional significance of platelet FcR gamma/GPVI complex in the early phase of myocardial ischemia and reperfusion injury in mice, we performed coronary occlusion and reperfusion experiments using wild type mice and FcRgamma-deficient (FcRgamma(-/-)) mice that lack GPVI [3].

High impact information on Fcer1g

• The FcalphaRI alpha chain lacks canonical signal transduction domains but can associate with the FcR gamma-chain that bears an activation motif (ITAM) in the cytoplasmic domain, allowing activatory functions [4].
• The type-II transmembrane lectin CD23 is expressed in the mouse on B cells and follicular dendritic cells [5].
• Here we disrupt the gene coding for murine CD23 (ref. 9) to clarify the role of CD23 in vivo and find that B- and T-cell development is normal in these CD23-deficient mice [5].
• CD23 has been implicated in cellular adhesion, antigen presentation, as a growth and differentiation factor for human B, T and plasma cells, and as a signal transduction molecule (reviewed in refs 3, 8) [5].
• In addition, FcR-gamma chain-deficient mice were found to express partially functional FcgammaRI [6].

Chemical compound and disease context of Fcer1g

• Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor gamma-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury [3].
• A similar inhibition of aggregation to 4N1-1 was obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR gamma chain or SLP-76 and in patients with type I Glanzmann thrombasthenia [7].
• In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via eosinophil activation [8].
• Three of these ligands (complement C3, gp350/220 of EBV, and CD23) interact with the amino terminal 2 of 16 SCR (SCR 1 and 2) [9].
• The role of CD23 on allergen-induced IgE levels, pulmonary eosinophilia and bronchial hyperresponsiveness in mice [10].

Biological context of Fcer1g

• In the fyn(-/-) platelets, tyrosine phosphorylation of FcR gamma chain, phopholipase C (PLC) activity, aggregation, and secretion are reduced, though the time of onset of response is unchanged [11].
• IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain-deficient mice and increased in Fc gamma RII-deficient mice [12].
• Twenty-four hours after the reperfusion, electron microscopy of the injured tissue showed substantially more platelet aggregation and occlusive platelet microthrombi in the capillaries of the damaged areas of the wild type mice than in those of the FcR gamma(-/-) mice [3].
• It is currently suggested that IgE-binding molecules, which are related to CD 23, modulate IgE synthesis according to their degree of glycosylation [13].
• We used primarily noninvasive techniques (changes in body temperature, dye extravasation) to assess systemic anaphylactic responses in nonanesthetized wild-type, Fc epsilonRI alpha chain -/- and FcR gamma chain -/- mice [14].

Anatomical context of Fcer1g

• IL-10 did not upregulate the expression of Fc epsilon receptors (CD23) or class I MHC antigens on small dense B cells or induce their replication as monitored by [3H]thymidine incorporation [15].
• Unexpectedly, the TCR levels of mature T cells in FcR gamma TG zeta KO mice were lower than those of controls [16].
• Therefore, the nonreactivity of the FcR gamma + lymphocytes in the gut or in tumor-bearing mice must be caused by some other phenomenon [16].
• The results demonstrate that expression of GPVI is up-regulated along with the FcR gamma-chain during differentiation of megakaryocytes [17].
• In a previous study we found that if a chronic T-cell-mediated antigen-induced arthritis (AIA) was elicited in knee joints of FcR gamma-chain-deficient mice that lack functional Fc gamma RI and Fc gamma RIII, joint inflammation was comparable but severe cartilage destruction was absent [18].

Associations of Fcer1g with chemical compounds

• Role of Fc receptor gamma-chain in platelet glycoprotein Ib-mediated signaling [19].
• In Brij 35 lysates, FcR gamma-chain was found to constitutively associate with GPIb [19].
• These stable transfectants released serotonin in response to cross-linkage of Fc epsilon RI, demonstrating that the molecular defect of p161+/Fc epsilon RI- mast cells is indeed the loss of Fc epsilon RI gamma expression [20].
• Thus, the mitogenic effect of rDiAg was not due to LPS contamination. rDiAg also enhanced levels of CD23 expression on splenic B cells [21].
• These results have led to the hypothesis that collagen responses mediated by GPVI-Fc Rgamma may require the collagen-binding integrin alpha2beta1 as a co-receptor, but this model has not been supported by a recent study of mouse platelets lacking alpha2beta1 [22].
• FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation [23].

Physical interactions of Fcer1g

• The induction of major histocompatibility complex class II molecules or CD23 by IL-4 was virtually unaffected by TUGm2 antibody [24].
• The platelet collagen receptor glycoprotein VI (GPVI) couples to the immune receptor adaptor Fc receptor gamma-chain (FcRgamma) and signals using many of the same intracellular signaling molecules as immune receptors [25].
• Most strikingly, intraepithelial lymphocytes (IELs) isolated from the small intestine or the colon expressed normal levels of TCR/CD3 complexes on their surface which contained Fc epsilon RI gamma homodimers [26].
• Furthermore, the FcRgamma residues interacting with FcalphaRI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising FcalphaRI residues Leu-217, Leu-220, and Leu-224 [27].

Regulatory relationships of Fcer1g

• GPVI is a 62-kDa membrane glycoprotein expressed in noncovalent association with the Fc receptor gamma chain on human and murine platelets and serves as the major activating receptor for collagen [28].
• Moreover, IL-4 production induced by means of passive IgE sensitization and abrogated in FcR gamma-chain-deficient mice supports the conclusion that this IL-4 production is dependent on IgE/gamma-chain interaction [29].
• First, spleen cells from older lpr mice had an increase in the number and percentage of IgM+ B cells expressing low levels of CD23 [30].
• We fine that day 14.5 CD4-CD8- double-negative (DN) fetal thymocytes of Fc epsilon RI gamma-/- mice express mRNA of both Fc gamma RIIb1 and Fc gamma RIII [31].
• Conversely, experimental graft-versus-host disease induced in Fc receptor gamma-chain-deficient mice showed LPG-like lesions in glomeruli without apoE mutations [32].

Other interactions of Fcer1g

• Development and function of T cells in T cell antigen receptor/CD3 zeta knockout mice reconstituted with Fc epsilon RI gamma [16].
• Mice lacking two ITAM-bearing adapters, DAP12 and the Fc receptor gamma-chain (FcRgamma), are severely osteopetrotic [33].
• Transfected FcR gamma formed a homodimer and associated firmly with the TCR alpha beta dimer but only weakly with the CD3 gamma delta epsilon [34].
• In vitro kinase assay suggested that the CD3 zeta dimer but not the FcR gamma dimer associates with the Fyn kinase [34].
• Compared with the aggregation response of wild-type platelets, that of FcR gamma-chain-deficient platelets in response to vWF plus botrocetin was impaired, implying that FcR gamma-chain is required for the full activation of platelets mediated by GPIb [19].

Analytical, diagnostic and therapeutic context of Fcer1g

• The number of GPIb expressed on FcR gamma-chain-deficient platelets was comparable to that of the wild-type, as assessed by flow cytometry [19].
• The infarct size was significantly smaller in FcRgamma(-/-) mice subjected to occlusion and reperfusion of the coronary artery than in control FcR gamma(+/+) mice [3].
• Finally, bone marrow-derived macrophages from FcR gamma chain-deficient mice, which fail to flux calcium after receptor ligation, failed to inhibit IL-12(p40) mRNA induction [35].
• However, adoptive transfer studies indicated that suppression was seen when normal lymphocytes were used to reconstitute Tg mice, whereas reconstitution of controls with Tg lymphocytes resulted in normal IgE responses, suggesting that critical CD23-bearing cells are irradiation-resistant, nonlymphoid cells [36].
• Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice [37].

References