Biomedical subjects

J E Salmon

Publications and source records attributed to J E Salmon.

At least 19 recordsLinked to original sources

PubMed1995

Receptors for immunoglobulin G. Molecular diversity and implications for disease.

Our knowledge about human Fc gamma receptors has increased dramatically within the last several years. Their structural diversity presents a rich framework within which to understand how immunoglobulins and immunoglobulin complexes activate such a broad range of cell programs relevant to autoimmune diseases. Alleles of Fc gamma receptors provide a new perspective within which to define the interplay between the qualitative and quantitative humoral immune response and host genotype and to identify heritable risk factors for disease susceptibility. With recent insights into the role of Fc gamma receptors in the pathophysiology of inflammatory lesions, we can also anticipate important advances in therapeutic intervention.

Animals↗

PubMed1995

Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner.

Two classes of receptors for IgG, Fc gamma RIIa and Fc gamma RIIIb, both of which exist in two allelic forms, are expressed on human neutrophils. Neutrophils from normal donors, homozygous for the different allelic phenotypes of Fc gamma RIIIb, have significantly different levels of Fc gamma receptor-mediated phagocytosis of IgG-opsonized erythrocytes (EA). However, the observation that Fc gamma RIIIb mediates phagocytosis of specific mAb-targeted erythrocytes poorly suggests that this receptor may influence EA internalization by Fc gamma RIIa in an allele-sensitive fashion. Donors homozygous for the NA1 allele of Fc gamma RIIIb showed greater activation of Fc gamma RIIa after Fc gamma RIIIb cross-linking than donors homozygous for the NA2 allele of Fc gamma RIIIb. This increase in receptor-specific internalization reflects both an increase in ligand binding by Fc gamma RIIa and an increase in internalization efficiency of targets bound. Activation of Fc gamma RIIa by Fc gamma RIIIb is transferable by supernatants from activated cells and is blocked by inhibitors of reactive oxygen species and the H2O2-myeloperoxidase-chloride system and by serine protease inhibitors. Thus, cross-linking of Fc gamma RIIIb, which leads to neutrophil degranulation and the generation of reactive oxygen intermediates, in turn alters Fc gamma RIIa avidity and efficiency. These oxidant-mediated changes in Fc gamma RIIa function provide a novel mechanism for receptors to collaborate in both an autocrine and paracrine fashion. The allele sensitivity of these effects suggests that Fc gamma receptor polymorphisms may be inherited disease susceptibility factors in host defense against infection and in the development of autoimmunity.

Adult↗

PubMed1995

Activation of cultured vascular endothelial cells by antiphospholipid antibodies.

Circulating antiphospholipid antibodies (aPL) are associated with a syndrome of thrombosis, recurrent fetal loss, and thrombocytopenia. We have demonstrated the activation of cultured human umbilical vein endothelial cells (HUVEC) by IgG from patients with anticardiolipin antibodies (aCL). Incubation of HUVEC for 4 h with purified IgG (100 micrograms/ml) from patients with high-titer aCL induced a 2.3-fold increase in monocyte adhesion over that seen in HUVEC incubated with IgG's from normal subjects. The effect of aCL was not attributable to LPS contamination, Fc receptors, or immune complexes. Monocyte adhesion was not induced when the aCL were added in serum-free media but was restored by the addition of purified beta 2GP1, previously described as a necessary cofactor for aCL reactivity. Purified rabbit polyclonal IgG raised against beta 2GP1 also induced monocyte adhesion when incubated with HUVEC. Preadsorption of patient serum with cardiolipin reduced monocyte adhesion by 60%. Immunofluorescent microscopy demonstrated that endothelial cells incubated with patient IgG expressed cell adhesion molecules, including E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1. These data support the hypothesis that aPL activate vascular endothelial cells, thereby leading to a pro-thrombotic state.

Antibodies, Antiphospholipid↗

PubMed1992

Functional capacity of Fc gamma receptor III (CD16) on human neutrophils.

Receptors for the Fc region of immunoglobulin G (IgG) are a structurally diverse group of molecules. Within the three Fc gamma R families (Fc gamma RI, Fc gamma RII and Fc gamma RIII), the presence of distinct genes and alternative splicing variants leads to a variety of receptor isoforms that are most strikingly different in the transmembrane and intracellular regions. An obvious example of structural variation in the transmembrane and cytoplasmic domains is observed in the Fc gamma RIII family. Fc gamma RIIIB, which is nearly identical to Fc gamma RIIIA in the extracellular domains, lacks both transmembrane and cytoplasmic protein domains and is anchored to the cell through a glycosyl phosphatidylinositol anchor. Analysis of Fc gamma RIII function presents a considerable challenge in understanding the role of different Fc gamma R receptors in polymorphonuclear neutrophil (PMN) function. While one hypothesis for the role of Fc gamma RIII in Fc gamma R-dependent PMN effector functions is that Fc gamma RIII serves as a binding molecule which focuses the IgG ligand for more efficient recognition and intracellular signaling by Fc gamma RII, recent observations from a number of laboratories suggest that Fc gamma RIII on PMN can transduce signals across the membrane independent of ligand-dependent engagement of Fc gamma RII. We will review these data and present recent data which suggest that the role of Fc gamma RIII extends beyond direct initiation of functions to a more complex role of synergistic receptor interactions. These findings will be reviewed in the context of the experimental approaches that have been used to examine the roles of Fc gamma RII and Fc gamma RIII on PMN function.

Antibodies, Monoclonal↗

PubMed1992

Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function.

Two different allelic polymorphisms among the isoforms of human Fc gamma receptors have been defined: the low-responder (LR)-high-responder (HR) polymorphism of huFc gamma RIIA expressed on both PMN and monocytes and the NA1-NA2 polymorphism of the neutrophil Fc gamma RIII (huFc gamma RIIIB). To address the issues of whether the LR-HR polymorphism has a significant impact on Fc gamma R-mediated functions in human blood cells and whether any differences in LR-HR might be related to higher Fc gamma R-mediated phagocytosis in NA1 donors, we examined Fc gamma R-specific binding and internalization by donors homozygous for the two huFc gamma RIIA alleles. PMN from LR homozygotes showed consistently higher levels of internalization of erythrocytes opsonized with pooled human IgG (E-hIgG). The absence of an LR-HR phagocytic difference with erythrocytes opsonized with either anti-Fc gamma RIIA MAb IV.3 or rabbit IgG, as opposed to E-hIgG, suggested that the Fc piece of the opsonin might be important for this LR-HR difference. Accordingly, we studied HR and LR homozygotes with human IgG subclass-specific probes. Both PMN (independent of huFc gamma RIIIB phenotype) and monocytes from LR donors bound and internalized erythrocytes coated with human IgG2 (E-hIgG2) efficiently, whereas phagocytes from HR donors did so poorly. E-hIgG2 internalization was completely abrogated by blockade of the ligand binding site of huFc gamma RIIA with IV.3 Fab, indicating that huFc gamma RIIA is essential for the handling of hIgG2 and that the mechanism of the LR-HR phagocytic difference is at the level of ligand binding to huFc gamma RIIA. In contrast, the difference in internalization of E-hIgG between NA1 and NA2 homozygous donors was independent of the huFc gamma RIIA phenotype and did not manifest differences in ligand binding. Thus, the two known allelic polymorphisms of human Fc gamma R have distinct and independent mechanisms for altering receptor function, which may influence host defense and immune complex handling.

Adult↗

PubMed1992

Novel Fc gamma receptor I family gene products in human mononuclear cells.

Unlike the human Fc gamma RII and Fc gamma RIII families, which exhibit considerable diversity at both the nucleic acid and protein levels, the human Fc gamma RI family has only a single recognized product expressed as a 70-kD cell surface receptor with high affinity for monomeric IgG (hFc gamma RIa1). Using both polymerase chain reaction-based amplification and Northern hybridization, we document multiple interferon-gamma-inducible hFc gamma RI RNA transcripts in human mononuclear cells and neutrophils. The sequences of two of these Fc gamma RI related transcripts indicate that they are alternatively spliced products of a second Fc gamma RI family gene, termed Fc gamma RIB. The cDNA derived from the larger of these transcripts, termed hFc gamma RIb1, encodes a surface molecule that is not recognized by Fc gamma RI specific monoclonal antibodies when transfected into COS-7 cells. Unlike the interferon-gamma-inducible hFc gamma RIA gene product, hFc gamma RIb1 does not bind monomeric IgG with high affinity. However, both hFc gamma RIa1 and hFc gamma RIb1 do bind aggregated human IgG. Previously unrecognized diversity within the hFc gamma RI family includes an interferon-gamma-inducible, putative low affinity Fc gamma receptor that may play an important role in the mechanism by which Fc gamma receptors participate in the humoral immune response.

Amino Acid Sequence↗

PubMed1991

Fc gamma receptor III induces actin polymerization in human neutrophils and primes phagocytosis mediated by Fc gamma receptor II.

Human polymorphonuclear leukocytes (PMN) express two classes of Fc gamma R: Fc gamma RII the 42-kDa receptor with a traditional membrane spanning domain and cytoplasmic tail and Fc gamma RIIIPMN the 50- to 80-kDa receptor with a glycosyl-phatidylinositol membrane anchor expressed on PMN. To explore the capacity of Fc gamma RIIIPMN to generate intracellular signals, we have analyzed the ability of Fab and F(ab')2 anti-Fc gamma R mAb to induce actin filament assembly, a prerequisite for motile behaviors. Multivalent ligation of Fc gamma RIIIPMN, independent of Fc gamma RII, results in an increase in F-actin content that is [Ca2+]i dependent. Multivalent ligation of Fc gamma RII also initiates actin polymerization but uses a [Ca2+]i-independent initial pathway. In addition to providing a mechanism for Fc gamma RIIIPMN triggered effector functions, the increase in F-actin and [Ca2+]i generated by Fc gamma RIIIPMN ligation also serves as a "priming" signal to modify PMN responses to other stimuli. Experiments using erythrocytes specifically coated with anti-Fc gamma RII Fab demonstrate that cross-linking of Fc gamma RIIIPMN with anti-Fc gamma RIII F(ab')2 enhances phagocytosis mediated by Fc gamma RII. Thus, Fc gamma RIIIPMN, a glycosyl-phosphatidylinositol anchored protein, may contribute directly to an intracellular program of actin assembly that may trigger and prime neutrophil effector functions.

Actins↗

PubMed1991

Preferential expression of human Fc gamma RIIIPMN (CD16) in paroxysmal nocturnal hemoglobinuria. Discordant expression of glycosyl phosphatidylinositol-linked proteins.

The isoform of Fc gamma RIII (CD16) expressed on PMN has a GPI membrane anchor, and in paroxysmal nocturnal hemoglobinuria (PNH) there is a deficiency in Fc gamma RIII expression on PMN. Contrary to expectation, however, CD16 expression is preserved (albeit at reduced levels) in all affected PNH PMN that completely lack the GPI-anchored proteins DAF (CD55) and CD59. Fc gamma RIII negative PMN are not observed in any of the six PNH patients examined in this study. Analysis of the molecular weight of both glycosylated and deglycosylated Fc gamma RIII from PMN with reduced Fc gamma RIII expression indicates no variations in size relative to normal donor Fc gamma RIIIPMN. Indeed, the Fc gamma RIII expressed at intermediate levels is phosphatidylinositol-specific phospholipase C (PI-PLC)-sensitive. Thus, there is no evidence suggestive of expression of a transmembrane isoform and all data indicate that Fc gamma RIIIPMN on affected cells in PNH is a GPI-linked isoform. With Fc gamma RIIIPMN expression preserved at reduced levels on affected cells in PNH, PMN from PNH patients retain the capacity to internalize the Fc gamma RIIIPMN-specific probe E-ConA (at reduced levels) as well as IgG-opsonized erythrocytes. Reduced expression of GPI-anchored molecules on PNH PMN is not restricted to Fc gamma RIIIPMN since intermediate levels of CD59 were observed in the PNH PMN that were decay-accelerating factor (DAF)-negative and Fc gamma RIIIPMN intermediate. In addition, discordant expression of GPI-linked molecules in individual cells is not restricted to PMN since DAF+/CD14- monocytes were observed in one PNH patient. These data suggest that, when analyzed on an individual cell level, the GPI anchor defect in PNH is not absolute and must involve either a hierarchy of access of different protein molecules to available GPI anchors, distinct anchor biochemistries for the different proteins, or differential regulation of protein-anchor assembly.

Antigens, CD↗

PubMed1990

Fc gamma receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy. A1 receptors are stimulatory and A2 receptors are inhibitory.

Adenosine, an endogenously released purine, modulates the functions of many cells through surface A1 and A2 receptors. We examined the hypothesis that adenosine receptor ligation regulates Fc gamma R-triggered inflammatory response by polymorphonuclear leukocytes (PMN), a response which is critical to the pathogenesis of immune complex diseases. The effects of adenosine analogs on Fc gamma R-mediated phagocytosis and superoxide anion (O2-) generation in human neutrophils were investigated. 5'(N-ethyl)carboxamidoadenosine (NECA), the most potent A2 receptor agonist, inhibited Fc gamma R-mediated phagocytosis and O2- generation, whereas N6-cyclopentyladenosine (CPA), a highly selective A1 receptor agonist, enhanced these functions. The effects of the adenosine analogs were markedly accentuated in neutrophils adherent to biologic surfaces. Both the inhibition by NECA and the enhancement by CPA of PMN Fc gamma R functions were blocked by the adenosine receptor antagonist 8-p-sulfophenyltheophylline, which suggests that occupancy of surface adenosine receptors mediated the actions of these analogs. Because A1 receptors on PMN are linked to pertussis toxin-sensitive G proteins, our evidence that pertussis toxin blocked the effects on Fc gamma R function brought about by CPA but not by NECA further supports the hypothesis that CPA acts via an A1 receptor. Our data indicate that adenosine A1 and A2 receptors modulate neutrophil Fc gamma R function in opposing ways, allowing for a concentration-dependent, adenosine-regulated feed-back loop. At low concentrations there is enhancement of neutrophil Fc gamma R function via PMN A1 receptors, whereas at higher concentrations (those which may occur at sites of damaged tissues), there is inhibition via A2 receptors. Our observation that adenosine analogs had more potent effects on adherent neutrophils emphasizes the potential importance of adenosine as a modulator of Fc gamma R-triggered inflammation in vivo.

Adenosine↗

PubMed1990

Fc gamma RIII expressed on cultured monocytes is a N-glycosylated transmembrane protein distinct from Fc gamma RIII expressed on natural killer cells.

Fc gamma RIII is a family of protein isoforms encoded by at least two distinct, yet highly homologous, genes. Fc gamma RIII on neutrophils is a glycosylphosphatidylinositol-linked protein with an allelic polymorphism (NA1/NA2) while Fc gamma RIII on NK cells (Fc gamma RIIINK) is an exclusively transmembrane protein without the NA polymorphism. The relationship of the isoform of Fc gamma RIII expressed on cultured monocytes (Fc gamma RIIIM phi) to these two forms, however, is unclear because some evidence suggests lowered expression of Fc gamma RIIIM phi in paroxysmal nocturnal hemoglobinuria (unlike Fc gamma RIIINK) and a unique deglycosylated m.w. for Fc gamma RIIIM phi. In this study we demonstrate that, as with Fc gamma RIIINK, Fc gamma RIIIM phi is resistant to the action of phosphatidylinositol-specific phospholipase C and is expressed at normal levels on affected (glycosylphosphatidylinositol-anchor negative) cultured monocytes from patients with paroxysmal nocturnal hemoglobinuria. Fc gamma RIIIM phi is also shed from the cell surface upon incubation at 37 degrees C. However, Fc gamma RIIIM phi and Fc gamma RIIINK have different m.w. as glycosylated proteins despite the same deglycosylated m.w. Thus, each cell type appears to express distinct glycoforms. These differences in glycosylation may influence the functional properties of the receptor.

Antigens, Differentiation↗

PubMed1990

Phorbol ester-mediated induction of HIV-1 from a chronically infected promonocyte clone: blockade by protein kinase inhibitors and relationship to tat-directed trans-activation.

Potent inhibitors of protein kinases C and A, including 1-(5 isoquinolinyl sulfonyl) 2-methyl piperazine (H7), staurosporine, and 2-aminopurine, depressed phorbol ester-induced HIV-1 virion production and HIV-specific transcripts by greater than 90% in chronically infected promonocytic cells. Suppression was dose-dependent and occurred at concentration that had little effect on cell growth. These effects appeared to be specific to activation of the PKC-diacylglycerol system. They did not alter IUdr-mediated induction of HIV. In addition, PMA enhancement of an HIV-LTR driven reporter gene was not blocked by H7 in the presence or absence of exogenous tat, at concentrations capable of inhibiting upregulation of virus at the cellular level. Insight into the biochemical mechanisms of these processes is critical to understanding interactions of HIV with the immune system, and may eventually uncover new therapeutic strategies.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1990

Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities.

As a model system to explore the functional consequences of structural variants of human Fc gamma receptors (Fc gamma R), we have investigated Fc gamma R-mediated phagocytosis in relation to the NA1-NA2 polymorphism of Fc gamma RIII (CD16) on neutrophils (Fc gamma RIIIPMN). The neutrophil-specific NA antigen system is a biallelic polymorphism with codominant expression demonstrating a gene dose effect with the anti-NA1 MAb CLB-gran 11 in a large donor population. To explore the impact of this allelic variation of Fc gamma RIIIPMN on phagocytosis, we used two Fc gamma RIII-dependent probes, IgG-sensitized erythrocytes (EA) and concanavalin. A-treated erythrocytes (E-ConA). Comparison of Fc gamma R-mediated phagocytosis by PMN from NA1 subjects and from NA2 subjects showed lower levels of phagocytosis of both probes by the NA2 individuals. The difference was most pronounced with lightly opsonized EA: at the lowest level of sensitization the phagocytic index was 72% lower for NA2 donors, whereas at the highest level of sensitization it was 21% lower (P less than 0.003). Blockade of Fc gamma RII with MAb IV.3 Fab amplified by threefold the difference between NA1 and NA2 donors. NA1 and NA2 individuals had identical phagocytic capacities for the non-Fc gamma RIII probes, serum-treated and heat-treated zymosan. These individuals did not show differential quantitative cell surface expression of Fc gamma RIIIPMN measured by a panel of anti-CD16 MAb (3G8, CLB FcR-gran 1, VEP13, BW209/2) and by Scatchard analysis of 125I-IgG dimer binding. The difference in Fc gamma R-mediated phagocytosis was not explicable on the basis of differential collaboration of Fc gamma RIIIPMN alleles with Fc gamma RII, since (a) the difference in phagocytic capacity between NA1 and NA2 individuals was readily apparent with the E-ConA probe (which is independent of Fc gamma RII) and (b) the difference in phagocytosis of EA was magnified by Fc gamma RII blockade. The demonstration that allelic polymorphisms in Fc gamma R can have significant consequences for physiological functions implies that within the structural complexity of human Fc gamma Rs, including both allelic forms and cell type-specific isoforms, there will be differences in quantitative, and perhaps qualitative, function with potential importance for disease processes.

Adult↗

PubMed1990

Human immunodeficiency virus infection of monocytes: relationship to Fc-gamma receptors and antibody-dependent viral enhancement.

Antibodies that augment human immunodeficiency virus (HIV) infectivity of monocytes through Fc receptor (FcR) type III for IgG have been found in the blood of sero-positive patients and immunized chimpanzees. This study investigated the effect of acute and chronic HIV infection, as well as protein kinase C activators capable of up-regulating latent HIV, on the expression of these receptors. In addition, the frequency of this antibody-dependent enhancement (ADE) phenomenon was estimated using purified IgG from HIV-1 seropositive individuals at various clinical stages of infection. The existence of an FcR-dependent pathway for ADE of HIV-1 infection in peripheral blood monocytes and promonocytic U937 cells was confirmed in sera from a small subset of patients, and the phenomenon extended to FcR types I and II. The level of ADE activity was minimal, however, and no relationship between the presence or magnitude of the ADE phenomenon and clinical stage was uncovered. Finally, perturbations which activate a latent HIV infection were shown to concomitantly up-regulate FcR on infected and uninfected cells. This suggests a positive feedback loop linking up-regulation of latent infection, enhanced expression of low affinity HIV receptors such as FcR, and viral spread.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Human Fc gamma RIII (CD16). Isoforms with distinct allelic expression, extracellular domains, and membrane linkages on polymorphonuclear and natural killer cells.

Human Fc gamma RIII (CD16), a low-affinity receptor expressed on several different cell types, has a polymorphism on polymorphonuclear cells (Fc gamma RIIIPMN) identified by the NA1 and NA2 markers. Inasmuch as this polymorphism has functional consequences, an understanding of the structural biology of Fc gamma RIII may provide important insight into receptor function. We analyzed Fc gamma RIIIPMN by SDS-PAGE and found that receptor from individuals allotyped for either NA1 or NA2 contained only one protein after removal of N-linked glycosylations (19 and 21 kDa respectively) whereas receptor from NA1/2 individuals contained both bands. Because some reports indicate that digestion of Fc gamma RIII on NK cells (Fc gamma RIIINK) with N-glycanase also results in two bands on SDS-PAGE, we investigated Fc gamma RIIINK to explore the possibility of a corresponding allelic polymorphism in this receptor. Contrary to expectation, Fc gamma RIIINK from all donors irrespective of their NA allotype contained two bands (20 and 24 kDa) on SDS-PAGE after deglycosylation. In addition, those distinct epitopes on the extracellular domain of Fc gamma RIIIPMN found with mAb B73.1 and CLB gran 11 in association with the NA allotypic differences are expressed (or not expressed) on Fc gamma RIIINK independent of donor NA allotype. Fc gamma RIIIPMN and Fc gamma RIIINK differ at the protein level as they have different m.w. (glycosylated and deglycosylated), different epitopes in the extracellular domain (not attributable to tissue-specific glycosylation), and differential expression of the NA allelic protein polymorphism. Although the membrane anchor of Fc gamma RIIIPMN is a phosphatidylinositol-specific phospholipase C sensitive glycosyl-phosphatidylinositol linkage, Fc gamma RIIINK is insensitive to phosphatidylinositol-specific phospholipase C. However, a form of Fc gamma RIIINK is released from NK cells upon incubation at 37 degrees C. Thus, the basis for the two bands in Fc gamma RIIINK after N-linked deglycosylation is neither coexpression of two molecular isoforms with different membrane anchors nor an identifiable allelic polymorphism in m.w. restricted to Fc gamma RIIINK (p less than 10(-6)). The differences between the two receptors indicate that, independent of cell anchor type, PMN and mononuclear cells must have different molecular isoforms. The allelic variants, different isoforms, alternative anchor mechanisms and release processes provide for an extensive genetic and regulatory diversity in Fc gamma RIII function.

Alleles↗

PubMed1989

High-dose, pulse intravenous methylprednisolone enhances Fc gamma receptor-mediated mononuclear phagocyte function in systemic lupus erythematosus.

The benefit of high-dose, pulse intravenous methylprednisolone (IVMP) for some patients with active lupus nephritis would appear paradoxical, since active nephritis is associated with profound abnormalities in Fc gamma receptor function, and several studies have demonstrated that glucocorticoids decrease monocyte Fc gamma receptor expression and phagocytic function. To resolve this paradox, we investigated the possibility that pulse IVMP might enhance monocyte Fc gamma receptor function in patients with systemic lupus erythematosus (SLE). Circulating immune complex (CIC) levels, Fc gamma receptor-mediated clearance, and Fc gamma receptor-dependent monocyte function were analyzed in 23 SLE patients before and after pulse IVMP (1 gm daily for 3 days). A biphasic response in CIC levels, determined by a staphylococcal protein A binding assay, was observed. Initially, CIC levels increased within 2-4 hours after the first dose of pulse IVMP and then decreased by 50% within 24-48 hours after the completion of therapy. Fc gamma receptor-mediated binding and phagocytosis of IgG-sensitized erythrocytes (EA) by monocytes in vitro were significantly enhanced 24 hours after the final dose of pulse IVMP (pre-IVMP versus post-IVMP 43 +/- 14% versus 53 +/- 12% EA rosettes, P less than 0.01; 3.00 +/- 1.04 versus 3.99 +/- 1.30 EA ingested/monocyte, P less than 0.01). In contrast, there was no change in the phagocytosis of an Fc gamma receptor-independent probe, neuraminidase-treated erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Opsonin-independent ligation of Fc gamma receptors. The 3G8-bearing receptors on neutrophils mediate the phagocytosis of concanavalin A-treated erythrocytes and nonopsonized Escherichia coli.

We report that phagocytosis by human neutrophils of Con A-treated erythrocytes (E-Con A) and nonopsonized Escherichia coli with mannose-binding adhesions is mediated by the Fc gamma receptor bearing the 3G8 epitope. Modulation of Fc receptors by pretreating with aggregated-IgG or with 3G8 anti-Fc gamma receptor mAb markedly inhibited internalization of E-Con A and E. coli without altering their cell surface attachment. Phagocytosis of these probes was specifically blocked by alpha-methylmannoside and D-mannose and not by other monosaccharides. Thus, recognition of E-Con A and E. coli by the Fc receptor is dependent upon the mannose-specific interaction with lectin or lectin-like adhesions. These data demonstrate that ligands other than the classical IgG opsonins can bind to classical immune receptors for IgG through lectin-carbohydrate interactions.

Concanavalin A↗

PubMed1987

Gammaglobulin for intravenous use induces an Fc gamma receptor-specific decrement in phagocytosis by blood monocytes.

Intravenous gammaglobulin (IVIG) increases the circulating platelet count in patients with idiopathic thrombocytopenic purpura in association with mononuclear phagocyte system blockade and decreased blood monocyte phagocytosis. To investigate whether IVIG treatment induces an Fc receptor-specific defect or a generalized phagocytic dysfunction which might impair host defenses, we studied the influence of IVIG on Fc receptor-dependent and Fc receptor-independent internalization by monocytes. In purified monocytes incubated in suspension with IVIG (10 mg IgG/ml) for 48 hr, our data demonstrate that Fc receptor-mediated phagocytosis of IgG-sensitized erythrocytes (EA) is significantly decreased. By contrast, there was no significant change in the phagocytosis of neuraminidase-treated erythrocytes which are internalized via the B-glucan receptor. A similar decrease in EA ingestion was observed in adherent monocytes incubated with IVIG. By contrast, the capacity of IVIG-treated adherent monocytes to internalize tannic acid-treated erythrocytes, an Fc receptor-independent probe, was the same as that of control cells. These findings demonstrate that IVIG does not induce a generalized phagocytic blockade, but rather a selective deficit in Fc gamma receptor-mediated internalization. Thus, Fc receptor-independent mechanisms may provide adequate mononuclear phagocyte system function for host defense in patients receiving IVIG.

Cell Adhesion↗

PubMed1986

Phagocytosis of concanavalin A-treated erythrocytes is mediated by the Fc gamma receptor.

Impaired Fc gamma receptor-mediated phagocytosis has been reported in monocytes from HLA-DR2- and -DR3-positive disease-free individuals compared to normals without these B cell alloantigens. We have noted, however, a decrease in the ingestion of concanavalin A (Con A)-treated rabbit erythrocytes (E-Con A) in the same immunogenetically defined groups (DR2 vs Other: 2.94 +/- 0.84 erythrocytes/monocyte vs 4.16 +/- 1.37, p less than 0.003; DR3 vs Other: 3.35 +/- 1.51 vs 4.16 +/- 1.37, p less than 0.04). These data raised the possibility that carbohydrate-lectin interactions might trigger ingestion mediated by the Fc gamma receptor. To test this hypothesis, we performed receptor modulation and monosaccharide blocking experiments. Modulation of the Fc gamma receptor off the apical cell surface of monocytes by adherence to solid-phase IgG aggregates specifically reduced internalization of E-Con A and IgG-sensitized erythrocytes (EA) to 9.1% and 10.6% of control, respectively (p less than 0.001). Internalization of wheat germ agglutinin-treated erythrocytes, tannic acid-treated erythrocytes, and zymosan was not inhibited. In reciprocal modulation experiments using solid-phase Con A, no effects on phagocytosis of any particle was observed. alpha-Methyl mannoside, 0.1 M in PBS, did not inhibit the internalization of EA but blocked ingestion of E-Con A by 97% (p less than 0.001). Other monosaccharides had little or no effect on the ingestion of any of the phagocytic probes. These data demonstrate that a mechanism integrally involving the Fc gamma receptor mediates the ingestion of E-Con A by human monocytes. This Fc receptor has an oligosaccharide(s) with an exposed mannose which may be functionally significant. Whereas the mannose moiety does not play a crucial role in the interaction of the Fc gamma receptor with the Fc portion of IgG, engagement of the receptor via mannose can initiate internalization. Our findings raise the possibility that nonimmune functions may utilize classical immune system receptors through carbohydrate interactions. Furthermore, the ability of the Fc gamma receptor to trigger internalization is defective in HLA-DR2 and -DR3 normals, whether the receptor is ligated at its classical ligand-binding site or by way of its carbohydrate moieties.

Adult↗