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Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells.

Engagement of killer cell inhibitory receptors (KIRs) with their MHC class I ligands inhibits T and NK lymphocyte activation. In humans, killer cell activatory receptors (KARs) are highly homologous to KIRs, interact with an identical set of MHC class I molecules, and are encoded by individual genes belonging to the Ig-like superfamily. In contrast to KIRs, engagement of KARs leads to T and NK cell activation. We identified a set of disulfide-linked dimers selectively associated with KARs. KAR-associated polypeptides (KARAPs) are phosphorylated on tyrosine and serine residues. Reconstitution of KAR cell surface expression in the absence of KARAPs correlates with the failure of KAR to transduce any detectable activation signals. These results indicate that KARs are included in a multimeric complex with phosphorylated KARAPs and define a novel set of polypeptides that are likely to be involved in the control of lymphocyte activation upon MHC class I recognition.

Cells, Cultured↗

A new 12-kilodalton dimer associated with pre-TCR complex and clonotype-independent CD3 complex on immature thymocytes.

We have characterized the pre-TCR/CD3 complex and the clonotype-independent CD3 (CIC) complex expressed on the cell surface of the immature cell line KKF which we previously identified as the cell line expressing only TCR beta-chain associated with the CD3 complex on the cell surface. We now show that KKF expresses the pT alpha-beta heterodimer-CD3 complex and also the CIC complex on the cell surface by surface biotinylation. In addition, not only the CIC complex but also the pT alpha-beta complex was found to be associated with the molecular chaperon calnexin. Whereas the CD3 zeta-chain was very weakly associated with the pre-TCR/CD3 complex, a 12-kDa molecule (designated pTAC12 as pre-TCR-associated chain) was more stably associated as a dimer with the pre-TCR complex as well as the CIC complex on KKF cells. The significance of pTAC12 dimer in the CD3 complex of immature thymocytes in vivo was demonstrated by coprecipitation of pTAC12 with the CD3 complex in thymocytes from SCID mice. These results show that pTAC12 is a component of the pT alpha-beta complex as well as the CIC complex, and they suggest that pTAC12 may play a role in signaling through and/or in the expression of the pre-TCR/CD3 complex.

Animals↗

HIV-1 gp120 induces an association between CD4 and the chemokine receptor CXCR4.

For efficient entry into target cells, certain T cell-tropic HIV-1 isolates require both CD4 and the coreceptor CXCR4. However, the molecular interactions among CD4, CXCR4, and the HIV-1 envelope glycoproteins are only now being elucidated. Here we show that the binding of soluble gp120 from one macrophage-tropic and four T cell-tropic viruses to a CD4+, but not to a CD4-, T cell line, decreased the binding of an mAb specific for CXCR4 to its epitope, implying an interaction among gp120, CD4, and CXCR4. To confirm such an interaction, we conducted double- and triple-color confocal laser scanning microscopy on CD4+/CXCR4+ cells and determined the extent of CD4 and CXCR4 colocalization by a semiquantitative analysis. In the absence of gp120, a low level of constitutive colocalization between CD4 and CXCR4 was observed. Treatment with T cell-tropic-derived gp120 and, to a lesser extent, macrophage-tropic-derived gp120, increased the colocalization of CD4 with CXCR4, and triple staining indicated that gp120 was associated with the CD4-CXCR4 complexes. Cocapping of the gp120-CD4-CXCR4 complexes at 37 degrees C resulted in the cointernalization of a proportion of the gp120-CXCR4 complexes into intracellular vesicles. These data demonstrate that the binding of gp120 to CD4+ T cells induces the formation of a trimolecular complex consisting of gp120, CD4, and the HIV-1 coreceptor molecule CXCR4.

Animals↗

Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture.

To determine their roles in the assembly of glutamatergic postsynaptic sites, we studied the distributions of NMDA- and AMPA-type glutamate receptors; the NMDA receptor-interacting proteins alpha-actinin-2, PSD-95, and chapsyn; and the PSD-95-associated protein GKAP during the development of hippocampal neurons in culture. NMDA receptors first formed nonsynaptic proximal dendrite shaft clusters within 2-5 d. AMPA receptors were diffuse at this stage and began to cluster on spines at 9-10 d. NMDA receptor clusters remained partially nonsynaptic and mainly distinct from AMPA receptor clusters until after 3 weeks in culture, when the two began to colocalize at spiny synaptic sites. Thus, the localization of NMDA and AMPA receptors must be regulated by different mechanisms. alpha-Actinin-2 colocalized with the NMDA receptor only at spiny synaptic clusters, but not at shaft nonsynaptic or synaptic clusters, suggesting a modulatory role in the anchoring of NMDA receptor at spines. PSD-95, chapsyn, and GKAP were present at some, but not all, nonsynaptic NMDA receptor clusters during the first 2 weeks, indicating that none is essential for NMDA receptor cluster formation. When NMDA receptor clusters became synaptic, PSD-95 and GKAP were always present, consistent with an essential function in synaptic localization of NMDA receptors. Furthermore, PSD-95 and GKAP clustered opposite presynaptic terminals several days before either NMDA or AMPA receptors clustered at these presumptive postsynaptic sites. These results suggest that synapse development proceeds by formation of a postsynaptic scaffold containing PSD-95 and GKAP in concert with presynaptic vesicle clustering, followed by regulated attachment of glutamate receptor subtypes to this scaffold.

Actinin↗

Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation.

Fc gamma RIIB are low-affinity receptors for IgG whose intracytoplasmic domain contains an immunoreceptor tyrosine-based inhibition motif (ITIM). Fc gamma RIIB inhibit cell activation triggered by receptors that signal via immunoreceptor tyrosine-based activation motifs. This inhibition requires ITIM tyrosyl phosphorylation and is correlated with the binding of SH2 domain-containing phosphatases that may mediate the inhibitory signal. In the present work, we investigated the mechanism of Fc gamma RIIB phosphorylation and its consequences in mast cells. We demonstrate that the phosphorylation of Fc gamma RIIB requires coaggregation with Fc epsilon RI and that, once phosphorylated, Fc gamma RIIB selectively recruit the inositol polyphosphate 5 phosphatase SHIP, in vivo. In vitro, however, the phosphorylated Fc gamma RIIB ITIM binds not only SHIP, but also the two protein tyrosine phosphatases, SHP-1 and SHP-2. We show that the coaggregation of Fc gamma RIIB with Fc epsilon RI does not prevent Fc epsilon RI-mediated activation of lyn and syk. Both kinases can phosphorylate Fc gamma RIIB in vitro. However, when coaggregated with Fc epsilon RI, Fc gamma RIIB was in vivo phosphorylated in syk-deficient mast cells, but not in lyn-deficient mast cells. When Fc epsilon RI are coaggregated with Fc gamma RIIB by immune complexes, Fc epsilon RI-associated lyn may thus phosphorylate Fc gamma RIIB. By this mechanism, Fc epsilon RI initiate ITIM-dependent inhibition of intracellular propagation of their own signals.

Animals↗

Interleukin-6 production by human neutrophils after Fc-receptor cross-linking or exposure to granulocyte colony-stimulating factor.

Polymorphonuclear neutrophils (PMNs) are essential effector cells in host defense and tissue inflammatory responses. These responses may be initiated after cross-linking of cell surface Fc receptors that bind the constant portion of IgG (FcgammaR). We evaluated the effect of cross-linking FcgammaRI or FcgammaRII on interleukin-6 (IL-6) production by purified PMNs from normal donors or from patients being treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF). In PMNs from normal donors, IL-6 mRNA was detected by reverse transcriptase-polymerase chain reaction only after FcgammaRI or FcgammaRII cross-linking. We also found that IL-6 mRNA could be detected in PMNs after either in vitro or in vivo rhG-CSF treatment in the absence of FcgammaR cross-linking. IL-6 protein was found to be produced intracellularly and secreted by PMNs after cross-linking FcgammaRI or FcgammaRII or after rhG-CSF stimulation. Cross-linking FcgammaRI or FcgammaRII on PMNs from patients treated with rhG-CSF resulted in a synergistic increase in IL-6 secretion. Upregulation of IL-6 production by PMNs after rhG-CSF treatment may contribute to a clinical engraftment syndrome that occurs during periods of rapid increase in PMN numbers in patients receiving rhG-CSF.

Gene Expression Regulation↗

Mutations in the alphaIIb and beta3 genes that cause Glanzmann thrombasthenia can be distinguished by a simple procedure using transformed B-lymphocytes.

Glanzmann thrombasthenia (GT) is caused by a defect in either glycoprotein (GP)IIb (alphaIIb) or GPIIIa (beta3) genes and therefore screening of both genes is required for mutation identification. The beta subunit of the GPIIb/IIIa complex (beta3) forms a complex with another alpha subunit (alpha(v)) yielding the alpha(v)beta3 vitronectin receptor (VnR). GT patients with mutations in the GPIIIa gene that cause diminished synthesis of GPIIIa are deficient in both GPIIb/IIIa and VnR, whereas patients with mutations in the GPIIb gene are deficient in GPIIb/IIIa, yet express normal or increased VnR in their platelets. The presence or absence of VnR in platelet membranes of GT patients has therefore been used for distinguishing between mutations in the GPIIb gene and mutations in the GPIIIa gene. However, the method of assessing VnR in platelets is cumbersome and use of fresh platelets is indispensible. In the present work we devised a procedure for detection of the VnR in B-lymphocytes transformed by Epstein-Bar virus (EBV). The transformed lymphocytes transcribed GPIIIa mRNA but not GPIIb mRNA and expressed VnR on their surface. Using flow cytometry analysis or immuno-precipitation and western blotting VnR was found in B-lymphocytes of GT patients bearing a well characterized mutation in the GPIIb gene. In contrast, in B-lymphocytes of GT patients bearing 2 different mutations in the GPIIIa gene no VnR was detectable. Thus, for determining which gene is mutated in a GT patient, EBV-transformed B-lymphocytes are useful and can as well be used for analyses of GPIIIa mRNA and genomic DNA. Ten ml of blood are sufficient for the procedure.

B-Lymphocytes↗

A novel AP180-related protein in vesicles that concentrate at acetylcholine receptor clusters.

Monoclonal antibodies were generated to vesicular membranes of clathrin coated vesicles enriched for acetylcholinesterase (AChE). One of these, C172, recognizes vesicles which accumulate in muscle cells around nuclei associated with acetylcholine receptor AChR clusters. Immunoblots of muscle extracts and brain purified clathrin coated vesicles show that C172 recognizes a 100 kd band in muscle, but a 180 kd band in brain. Western blots of purified AP180 protein stained with the two antibodies AP180.1 and C172 displayed the same staining pattern. Tryptic digests probed with peptide antibodies (PS26 and PS27) generated to known sequences of AP180 were used to map the epitope for C172 within the brain AP180 sequence. On immunoblots of digested AP180, all AP180 antibodies and C172 recognized a 100 kd tryptic fragment, however only C172 recognized a smaller 60 kd. Our results suggest that the C172 epitope is located within amino acids 305-598 of the AP180 sequence. Confocal fluorescence microscopy of myoblasts and myotubes stained with the C172 antibody gives a punctate immunofluorescence pattern. Myoblasts stained with C172 revealed a polarized distribution of vesicles distinct from that observed when cells are stained with gamma adaptin antibody which is known to localize to trans Golgi network. Myotubes stained with C172 antibody reveal a linear array of vesicular staining. Quantitative analysis of C172 reactive vesicles revealed a significant increase in number of vesicles present around the nuclei associated with the acetylcholine receptor clusters. These vesicles did not colocalize with the Golgi cisternae. These results indicate that a protein with homology to the neuron-specific coated vesicle protein AP180, is present in muscle cells associated with vesicles showing significant concentration around postsynaptic nuclei present in close proximity to AChR clusters.

Adaptor Proteins, Vesicular Transport↗

Characterization of an associated 16-kDa tyrosine phosphoprotein required for Ly-49D signal transduction.

Ly-49D is an activating receptor on NK cells that does not become tyrosine phosphorylated upon activation. This report demonstrates that immunoprecipitation of Ly-49D, following pervanadate treatment or specific Ab cross-linking, coprecipitates a 16-kDa tyrosine-phosphorylated protein (pp16). Immunoblotting experiments and data from TCR-zeta/Fc epsilonRIgamma double knockout mice confirm that pp16 is not TCR-zeta, TCR-eta, or Fc epsilonRIgamma. Association of pp16 with Ly-49D involves a transmembrane arginine since mutation to leucine (Ly-49D[R54L]) abolishes association with pp16 in transfected P815 cells. In addition, Ly-49D(R54L) transfectants fail to mediate Ca2+ mobilization following Ab cross-linking. Therefore, signaling through Ly49D on NK cells depends on association with a distinct tyrosine phosphoprotein (pp16) in a manner analogous to that of TCR and FcR. Expression of this novel signaling peptide in both the NK and myeloid lineages indicates that pp16 is likely involved in the signal transduction cascade of additional receptor families.

Animals↗

Superclustering of B cell receptor and Fc gamma RIIB1 activates Src homology 2-containing protein tyrosine phosphatase-1.

Fc gamma RIIB1 (CD32) is a receptor that binds the Fc domain of Ag-complexed IgG. Coaggregation of B cell receptor (BCR) and Fc gamma RIIB1 generates a dominant negative signal that inhibits B cell activation. In Ag-specific Id-positive B cells, the co-cross-linking of BCR and Fc gamma RIIB1 by anti-Id Ab resulted in the association of both Src homology 2-containing protein tyrosine phosphatase (SHP-1) and Src homology 2-containing inositol phosphatase (SHIP) with the Fc gamma RIIB1; however, only SHIP activity was detected. "Superclustering" of the BCR and Fc gamma RIIB1 complex induced by stimulation with anti-Id Ab plus polyvalent Ag synergistically activated SHP-1. The degree of co-cross-linking between BCR and Fc gamma RIIB1 may determine the activation status of SHP-1 and SHIP.

Animals↗

Roles of chemokines and receptor polarization in NK-target cell interactions.

We report that the ability of NK cells to produce chemokines is increased in NK-target cell conjugates. The chemokines produced play a critical role in the polarization and recruitment of NK cells as well as in the NK effector-target cell conjugate formation. Chemokines induce the formation of two specialized regions in the NK cell: the advancing front or leading edge, where chemokine receptors CCR2 and CCR5 cluster, which might guide the cells toward the chemotactic source, and the uropod, where adhesion molecules ICAM-1 and -3 are redistributed. NK cell polarity was intrinsically involved in conjugate formation. The redistribution of both adhesion receptors and CCR was preserved during the formation of NK-target cell conjugates. Time-lapse videomicroscopy studies of the formation of effector-target conjugates showed that morphologic poles are also functionally distinct; while the binding to target cells was preferentially mediated through the leading edge, the uropod was found at the rear of migrating NK cells and recruited additional NK cells to the vicinity of K562 target cells. Inhibition of cell polarization and adhesion receptor redistribution blocked the formation of NK-K562 cell conjugates and the cytotoxic activity of NK cells. We discuss the implication of NK-cell polarization in the development of cytotoxic responses.

Antigens, CD↗

Affinity labeling of a human platelet membrane protein with 5'-p-fluorosulfonylbenzoyl adenosine. Concomitant inhibition of ADP-induced platelet aggregation and fibrinogen receptor exposure.

Incubation of washed human blood platelets with 5'-p-fluorosulfonylbenzoyl [3H]adenosine (FSBA) covalently labels a single polypeptide of Mr = 100,000. Protection by ADP has suggested that an ADP receptor on the platelet surface membrane was modified. The modified cells, unlike native platelets, failed to aggregate in response to ADP (100 microM) and fibrinogen (1 mg/ml). The extent of binding of 125I-fibrinogen and aggregation was inhibited to a degree related to the incorporation of 5'-p-sulfonylbenzoyl adenosine (SBA) into platelets, indicating FSBA could inhibit the exposure of fibrinogen receptors by ADP necessary for aggregation. Incubation of SBA platelets with alpha-chymotrypsin cleaved the covalently labeled polypeptide and concomitantly reversed the inhibition of aggregation and fibrinogen binding. Platelets proteolytically digested by chymotrypsin prior to exposure to FSBA did not require ADP for aggregation and fibrinogen binding. Moreover, subsequent exposure to FSBA did not inhibit aggregation or fibrinogen binding. The affinity reagent FSBA can displace fibrinogen bound to platelets in the presence of ADP, as well as promote the rapid disaggregation of the platelets. The apparent initial pseudo-first order rate constant of dissociation of fibrinogen was linearly proportional to FSBA concentrations. These studies suggest that a single polypeptide can be altered either by ADP-induced conformational changes or proteolysis by chymotrypsin to reveal latent fibrinogen receptors and promote aggregation of platelets after fibrinogen binding.

Adenosine↗

Molecular determinants for PICK1 synaptic aggregation and mGluR7a receptor coclustering: role of the PDZ, coiled-coil, and acidic domains.

PSD-95/Disc-large/ZO-1 (PDZ) domain-containing proteins play a central role in synaptic organization by their involvement in neurotransmitter receptor clustering and signaling complex assembly. The protein interacting with protein kinase C (PICK1), a synaptic PDZ domain protein that also contains a coiled-coil and acidic domain, binds to several synaptic components including the metabotropic glutamate receptor mGluR7a. Coexpression of PICK1 and mGluR7a in heterologous cells induces coclustering of these two proteins. To examine the role of the different structural motifs of PICK1 in synaptic aggregation of PICK1 and mGluR7a coclustering, several PICK1 mutants were generated to analyze their distribution in transfected hippocampal cultured neurons and to test their ability to induce coclusters with mGluR7a when coexpressed in fibroblast cells. The PDZ and coiled-coil domains are both required, whereas the acidic region plays an inhibitory role in these processes. Our data suggest that synaptic aggregation and receptor coclustering depend on PICK1 binding to a target membrane receptor, e.g. mGluR7a, by a PDZ-mediated interaction and on PICK1 oligomerization through the coiled-coil domain. This study defined three structural signals within PICK1 regulating its synaptic localization and receptor coclustering activity, which could represent molecular substrates involved in synaptic development and plasticity.

Animals↗

Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75.

Aggregated beta-amyloid (Abeta) binds to the neurotrophin receptor p75 and induces signaling. We examined this signaling process in different cell lines which express p75 either naturally (Schwannoma RN22 cells) or which are stably transfected with wild-type p75 (MDCKwt and PCNA cells) or with a truncated form of p75 comprising only extracellular and transmembrane domains (MDCKtm cells). While Abeta in higher concentrations (10-100 microM) is known to cause apoptosis via p75, our experiments focused on the effects of low concentrations of Abeta (25 nM) which may occur in early stages of Alzheimer disease. Application of Abeta caused tyrosine phosphorylation of wild-type p75 and induced the Ras-ERK pathway as has been reported for nerve growth factor (NGF). Since Ras activation and ERK phosphorylation (via MEK) could not be observed in MDCKtm cells and since they were clearly reduced in cells transfected with a p75 antisense construct, these effects should have been mediated by p75. Abeta also induced Ras and ERK activation in cerebellar neurons of 2-day-old rats which express p75 at that developmental stage but not TrkA; other Trk receptors were inhibited by K252a. In these neurons, Abeta led to quick formation, branching and elongation of processes. But while NGF distinctly promoted neurite branching and elongation, Abeta was less effective in neurite elongation and counts of small processes and of growth cones remained clearly elevated after 24-h stimulation; these peculiarities might be linked to aberrant neuronal connections reported for an animal model of Alzheimer disease. Essentially, the observed effects were mediated by interaction of Abeta and p75.

Alzheimer Disease↗

Transmembrane signaling by the high-affinity IgE receptor on membrane preparations.

Aggregating the receptor with high affinity for IgE (Fc epsilon RI) stimulates a variety of phenomena in mast cells. Previous efforts to reproduce some of these events in broken-cell preparations such as isolated membranes have had limited success, possibly because the phenomena being monitored were too distal from the initial events. One of the earliest responses is now known to be the phosphorylation of tyrosine residues on several proteins, including the beta and gamma subunits of Fc epsilon RI. We show that in cell sonicates or on partially purified membranes derived from tumor mast cells, aggregating Fc epsilon RI stimulates phosphorylation of receptor tyrosine residues. As in the intact cells, receptor-mediated phosphorylation occurs only on receptors that are themselves aggregated. Because even in the unfractionated sonicates the phosphorylation of other cellular components was not detectably enhanced, and because the evidence is against the receptor itself being a kinase, our results suggest that phosphorylation of Fc epsilon RI is one of the earliest events stimulated by the receptor--an event that can now be investigated on simpler biological preparations than previously available.

Animals↗

Components of Torpedo electric organ and muscle that cause aggregation of acetylcholine receptors on cultured muscle cells.

The synaptic portion of a muscle fiber's basal lamina sheath has molecules tightly bound to it that cause aggregation of acetylcholine receptors (AChRs) on regenerating myofibers. Since basal lamina and other extracellular matrix constituents are insoluble in isotonic saline and detergent solutions, insoluble detergent-extracted fractions of tissues receiving cholinergic input may provide an enriched source of the AChR-aggregating molecules for detailed characterization. Here we demonstrate that such an insoluble fraction from Torpedo electric organ, a tissue with a high concentration of cholinergic synapses, causes AChRs on cultured chick muscle cells to aggregate. We have partially characterized the insoluble fraction, examined the response of muscle cells to it, and devised ways of extracting the active components with a view toward purifying them and learning whether they are similar to those in the basal lamina at the neuromuscular junction. The insoluble fraction from the electric organ was rich in extracellular matrix constituents; it contained structures resembling basal lamina sheaths and had a high density of collagen fibrils. It caused a 3- to 20-fold increase in the number of AChR clusters on cultured myotubes without significantly affecting the number or size of the myotubes. The increase was first seen 2-4 h after the fraction was added to cultures and it was maximal by 24 h. The AChR-aggregating effect was dose dependent and was due, at least in part, to lateral migration of AChRs present in the muscle cell plasma membrane at the time the fraction was applied. Activity was destroyed by heat and by trypsin. The active component(s) was extracted from the insoluble fraction with high ionic strength or pH 5.5 buffers. The extracts increased the number of AChR clusters on cultured myotubes without affecting the number or degradation rate of surface AChRs. Antiserum against the solubilized material blocked its effect on AChR distribution and bound to the active component. Insoluble fractions of Torpedo muscle and liver did not cause AChR aggregation on cultured myotubes. However a low level of activity was detected in pH 5.5 extracts from the muscle fraction. The active component(s) in the muscle extract was immunoprecipitated by the antiserum against the material extracted from the electric organ insoluble fraction. This antiserum also bound to extracellular matrix in frog muscles, including the myofiber basal lamina sheath. Thus the insoluble fraction of Torpedo electric organ is rich in AChR-aggregating molecules that are also found in muscle and has components antigenically similar to those in myofiber basal lamina.

Animals↗

A quick simple method of determining platelet aggregability following glycoprotein IIb/IIIa receptor inhibitor administration.

Platelet aggregation assessment after therapeutic administration of a GP IIb/IIIa inhibitor has been difficult in routine practice due to the inherent nature of platelet preparation and aggregometry. Platelet microaggregation was performed via the utilisation of a Coulter counter. Citrate and heparin were evaluated as the anticoagulants, and ADP and adrenaline were evaluated as the stimulants. Aprotinin was also assessed. ReoPro was utilised in all assays as the GP IIb/IIIa inhibitor. Platelet microaggregation using the described methodology provides a quick, simple, reliable, and clinically valid method of assessing the percentage platelet inhibition due to the presence of a GP IIb/IIIa inhibitor.

Abciximab↗

[Cellular interactions of IgE: towards a new function for IgE].

The anaphylactic function of IgE has been intensively investigated. The Fc epsilon receptor on mast cells or basophils combines with the last two constant domains of the epsilon heavy chain. The Fc epsilon receptor is apparently a glycoprotein, monovalent and free in the plasma membrane. The interaction between the antigen (allergen) and the corresponding IgE antibody combined with the Fc epsilon receptor results in the aggregation of the receptors. Receptor dimerization suffices to trigger the cell. Compartments can be described in mast cells or basophils, the activity of which depends upon the number of formed receptor dimers on the corresponding membrane area. Beyond a threshold number of dimerized receptors, the cell compartment is triggered, which in the presence of Ca++ leads to the discharge of mast cell mediators, an increasing function of the dimer number. Excess receptor aggregation or the absence of aggregation (i.e. IgE-Ag2 complexes) deactivates the cell, which occurs more often in the absence of Ca++. Thus, IgE molecules play a passive role only in allowing the aggregation of the receptors which delivers the activating signal. But through the composition of IgE-antigen complexes bound to the receptors, IgE also modulates the cell function according two antagonistic reactions in permanent balance, i.e. activation or deactivation. IgE molecules are also involved in immediate type reactions in inducing the release of lysosomal enzymes from mononuclear phagocytes. But IgE antibody can also, when complexed with the antigen, trigger macrophage cytotoxicity for the corresponding target, which indicates a new function of IgE in the effector mechanisms of immunity of particular importance in immunity to schistosomes. A receptor for aggregated IgE has been characterized on the membrane of macrophages. The binding of IgE to its macrophage receptor triggers the cell, as shown by the resulting increase in cyclic GMP, calcium uptake and accelerated turn-over of lysosomal enzymes. A receptor for IgE has also been described on lymphoid cells, B cells, null cells and recently T cells, and the appearance of the receptor is modulated by IgE molecules themselves, suggesting a homeostatic role of IgE molecules. IgE appears thus to play various functions, the most dramatic being the triggering of anaphylactic reactions. But the role of IgE in activating mononuclear phagocytes or lymphoid cells might also prove to be of importance in immunity.

Animals↗