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PubMed1995

Cytotoxic antibodies trigger inflammation through Fc receptors.

Pathogenic self-reactive antibodies are a significant cause of morbidity and mortality and contribute to both cytotoxic and immune complex-triggered inflammatory disorders, typified by rheumatic diseases, autoimmune hemolytic anemia, and thrombocytopenia. Roles have been proposed for Fc receptors, complement, and complement receptors in the pathogenesis of these disorders, although the contribution of each to autoimmune injury is unclear. gamma chain-deficient mice lacking Fc gamma RI and Fc gamma RIII are resistant to the development of experimental immune hemolytic anemia induced by polyclonal rabbit anti-mouse red blood cell IgG antibodies. This resistance is primarily a consequence of ineffective erythrophagocytosis, resulting from the lack of Fc gamma Rs on mononuclear phagocytes. Similarly, gamma chain-deficient mice are completely resistant to the development of experimental immune thrombocytopenia induced by mouse anti-platelet antibodies. These data suggest that Fc receptors play an integral role in the pathogenesis of type II hypersensitivity and suggest potential therapeutic benefits of Fc receptor blockade.

Anemia, Hemolytic↗
PubMed2005

Characterization of primitive marrow CD34+ cells that persist after a sublethal dose of total body irradiation.

Knowledge of the molecular events that occur during hematopoietic stem/progenitor cell (HSPC) development is vital to our understanding of blood cell production. To study the functional groups of genes characteristic of HSPCs we isolated a subpopulation of CD34+ bone marrow (BM) cells from nonhuman primates that persisted in vivo after a sublethal dose of total body irradiation (TBI). CD34+ cells isolated during the phase of maximal hematopoietic suppression show a transcriptional profile characteristic of metabolically inactive cells, with strong coordinate downregulation of a large number of genes required for protein production and processing. Consistent with this profile, these CD34+ cells were not able to generate hematopoietic colonies. Transcriptional profiling of these CD34+ cells in conjunction with a pathway analysis method reveals several classes of functionally related genes that are upregulated in comparison to the CD34+ cells obtained prior to TBI. These families included genes known to be associated with self-renewal and maintenance of HSPCs (including bone morphogenetic proteins), resistance to apoptosis (Bcl-2) as well as genes characteristic of a variety of nonhematopoietic tissues (gamma-aminobutyric acid/glycine receptor, complement receptor C1qRp). In contrast, during the period of hematopoietic recovery, the CD34+ cells expressed higher level of genes encoding factors regulating maturation and differentiation of HSPCs. Our data indicate that the primitive BM CD34+ cell population that persists after radiation possesses a transcriptional profile suggestive of pluripotency.

Animals↗
PubMed1999

CR3, FcgammaRIIA and FcgammaRIIIB induce activation of the respiratory burst in human neutrophils: the role of intracellular Ca(2+), phospholipase D and tyrosine phosphorylation.

Human neutrophils express two different types of phagocytic receptors, complement receptors (CR) and Fc receptors. In order to characterize the different signaling properties of each receptor we have used non-adherent human neutrophils and investigated CR3, FcgammaRIIA and FcgammaRIIIB for their signaling capacity. Selective activation of each receptor was achieved by coupling specific antibodies to heat-killed Staphylococcus aureus particles, Pansorbins, through their Fc moiety. Despite the fact that these particles are not phagocytosed, we show that addition of Pansorbins with anti-CD18 antibodies recognizing CR3 induced prominent signals leading to a respiratory burst. Stimulation with anti-FcgammaRIIIB Pansorbins induced about half of the response induced by anti-CR3 Pansorbins, whereas anti-FcgammaRIIA Pansorbins induced an even weaker signal. However, FcgammaRIIA induced strong phosphorylation of p72(syk) whereas FcgammaRIIIB induced only a very weak p72(syk) phosphorylation. During CR3 stimulation no tyrosine phosphorylation of p72(syk) was seen. Both phospholipase D and NADPH oxidase activities were dependent on intracellular calcium. This is in contrast to tyrosine phosphorylation of p72(syk) that occurred even in calcium-depleted cells, indicating that oxygen metabolism does not affect p72(syk) phosphorylation. Inhibitors of tyrosine phosphorylation blocked the respiratory burst induced by both FcgammaRIIA and FcgammaRIIIB as well as CR3. This shows that tyrosine phosphorylation of p72(syk) is an early signal in the cascade induced by FcgammaRIIA but not by CR3.

Antibodies, Monoclonal↗
PubMed1985

Characterization of two murine monoclonal antibodies reactive with human B cells. Their use in a high-yield, high-purity method for isolation of B cells and utilization of such cells in an assay for B-cell stimulating factor.

We describe two monoclonal antibodies, HH1 and HH2. Both reacted selectively with surface immunoglobulin (sIg)-positive human B cells. Both antibodies stained on average 7-8% of peripheral blood mononuclear cells. They have not been found to react with cells or cell lines of other haematopoietic cell lineages, except that HH2 was positive on a small percentage of cells of the erythroid cell line K562. The molecular weight of the HH1 antigen was 95 kD, as established by Western blotting. Neither of these two antibodies reacted with Ig determinants, Fc receptors, complement receptors, or known class-I or class-II molecules. A combination of these antibodies was used in a direct panning technique for high-yield enrichment of normal B lymphocytes from peripheral blood. The enriched B cells could be further purified by lysis of T cells (final yield, on average 72 +/- 8% of initial B cells) or by a second panning (yield, 35 +/- 11%). The purified B cells contained less than 1% contaminating T cells and less than 0.5% monocytes and were used in an assay for B-cell-stimulating factor which they showed a normal and very reproducible proliferative response.

Animals↗
PubMed1986

Normal distribution of complement C3b receptor (CR1) numbers on erythrocytes in blood donors: low levels are associated with HLA-B27.

Blood donors were examined for C3b receptor (CR1) levels on erythrocytes by a microtiter plate enzyme-linked immunosorbent assay and for HLA-A, -B, and -C antigens, C3 phenotypes and blood groups. The CR1 levels among 150 donors varied in the range from 24 to 130% (mean +/- 1 SD = 69.9 +/- 22.9) of an erythrocyte standard, and in accordance with a polygenic model of inheritance the distribution of CR1 was well approximated by a normal curve (chi-square goodness-of-fit test nonsignificant, p = 0.66). Low CR1 levels were associated with HLA-B27 (n = 11, p = 0.05), which was confirmed by investigation of further 20 HLA-B27-positive donors (p = 0.05). The CR1 levels were not associated with a certain C3 phenotype. Possibly, the blood group phenotype M-M + S-s+ is associated with high and the S antigen with low CR1 numbers. The relation between low CR1 numbers and HLA-B27 might be important for the understanding of the association between HLA-B27 and certain inflammatory rheumatological diseases.

Blood Donors↗
PubMed2005

Expression of many immunologically important genes in Mycobacterium tuberculosis-infected macrophages is independent of both TLR2 and TLR4 but dependent on IFN-alphabeta receptor and STAT1.

Macrophages respond to several subcellular products of Mycobacterium tuberculosis (Mtb) through TLR2 or TLR4. However, primary mouse macrophages respond to viable, virulent Mtb by pathways largely independent of MyD88, the common adaptor molecule for TLRs. Using microarrays, quantitative PCR, and ELISA with gene-disrupted macrophages and mice, we now show that viable Mtb elicits the expression of inducible NO synthase, RANTES, IFN-inducible protein 10, immune-responsive gene 1, and many other key genes in macrophages substantially independently of TLR2, TLR4, their combination, or the TLR adaptors Toll-IL-1R domain-containing adapter protein and Toll-IL-1R domain-containing adapter inducing IFN-beta. Mice deficient in both TLR2 and TLR4 handle aerosol infection with viable Mtb as well as congenic controls. Viable Mtb also up-regulates inducible NO synthase, RANTES, IFN-inducible protein 10, and IRG1 in macrophages that lack mannose receptor, complement receptors 3 and 4, type A scavenger receptor, or CD40. These MyD88, TLR2/4-independent transcriptional responses require IFN-alphabetaR and STAT1, but not IFN-gamma. Conversely, those genes whose expression is MyD88 dependent do not depend on IFN-alphabetaR or STAT1. Transcriptional induction of TNF is TLR2/4, MyD88, STAT1, and IFN-alphabetaR independent, but TNF protein release requires the TLR2/4-MyD88 pathway. Thus, macrophages respond transcriptionally to viable Mtb through at least three pathways. TLR2 mediates the responses of a numerically minor set of genes that collectively do not appear to affect the course of infection in mice; regulation of TNF requires TLR2/4 for post-transcriptional control, but not for transcriptional induction; and many responding genes are regulated through an unknown, TLR2/4-independent pathway that may involve IFN-alphabetaR and STAT1.

Adaptor Proteins, Signal Transducing↗
PubMed1999

[Macrophage receptors].

Macrophages play a very important role in specific and nonspecific immune response. They are involved in different processes such as phagocytosis and killing of microorganisms, antigen presentation and production of cytokines etc. Their biological activity, ability to cooperate with other cells and to receive signals from extracellular environment are determined by their surface membrane receptors. The paper describes the structure and role of Fc receptors (FcR), adhesion receptors, complement receptors (CR), CD14 (LPS receptors) and receptors for chemotactic agents, present on the surface of macrophages.

Animals↗
PubMed2001

Ligand-receptor-mediated drug delivery: an emerging paradigm in cellular drug targeting.

Receptor-mediated cellular events have received major attention in the field of drug/gene delivery in the past few years. These events, which are mediated through the endogenous ligands/epitopes, could be exploited for designing site-specific and target-oriented delivery systems. The past decade has seen the development of endogenous ligands and their mimics of exogenous origins to selectively deliver the contained or immobilized moieties to the cellular interiors using a wide range of cell surface receptors/epitopes. Ligand-mediated active targeting has emerged as a novel paradigm in targeting either vascular compartment (first-order), cellular (second-order), or intracellular (third-order) levels. Most carrier systems or bioconjugates explored so far can be used as cargo units for the site-specific presentation and delivery of various bioactives using biorelevant ligands, including antibodies, polypeptides, oligosaccharides (carbohydrates), viral proteins, fusogenic residues, and molecules of endogenous origin. In this review, we describe various ligand-receptor systems that have been investigated to date for targeted or cellular drug delivery. These include blood carbohydrate (lectin) receptors, Fc receptors, complement receptors, interleukin receptors, lipoprotein receptors, transferin receptors, scavenger receptors, receptors/epitopes expressed on tumor cells, and cell adhesion receptors. The role of receptors as molecular target has opened new opportunities for cellular or intracellular targeting using carrier systems appended with targeting handles (ligands). Research in the field of ligand-receptor-based targeted system is expected to be an armamentarium and the focal point of research in the next millennium.

Drug Carriers↗
PubMed1990

[Immunophenotypic analysis of human endothelial cells].

Very Little is known about the immunological attributes of human endothelial cells. In this study, we performed immunologic phenotypic analysis of cultured human dermal microvascular endothelial cells in comparison with human umbilical vein endothelial cells and examined the ability of various biologic response modifiers to alter the phenotypes. Using FACS analysis, both types of the cells appear to lack many of the cell surface markers of immunologically proficient cells, E.G. OKT4, OKT8, Leu7, FcIgG receptor, complement receptors, IL-2 receptor and HLA-Dr, but they possess beta 2-microglobulin and DAF. HLA-Dr antigens can be induced on both types of endothelial cells by gamma-IFN in a dose and time dependent manner. Both types of endothelial cells possess several kinds of Cell Adhesion Molecules (CAMs), such as ICAM-1, CD44, LFA-3, but not LFA-1 or CD2. ICAM-1 but not LFA-3 or CD44 can be upregulated by exposure of both types of endothelial cells to gamma-IFN, IL-1 and TNF. These data suggest that endothelial cells of the dermal microvasculature may play central roles in a variety of different cutaneous inflammation.

Antigens, Surface↗
PubMed1986

Erythrocyte complement C3b receptor (CR1) levels and immune complex-induced manifestations in patients with primary Sjögren's syndrome.

To assess the importance of low C3b receptor (CR1) numbers on erythrocytes for the development of clinical features in patients with primary Sjögren's syndrome (SS), two groups of patients were selected for investigation--one without (n = 13), and one with (n = 21) extraglandular, possibly immune complex-induced, clinical manifestations during the disease course. A preponderance (p less than 0.01) of low CR1 levels was found in patients with primary SS (mean 57%) as compared with normal controls (mean 70%), but the CR1 levels did not differ between the two groups of patients. The CR1 values did not correlate with the levels of circulating immune complexes and C3d. Although the preponderance of low CR1 levels is pathogenetically intriguing, it appears to be of little help in the clinical assessment of patients with primary SS.

Antigen-Antibody Complex↗
PubMed1975

C3 receptors on lymphoid cells: isolation of active membrane fragments and solubilization of receptor complexes.

Complement receptor activity for cell bound C3b and C3d was detected on plasma membrane fragments prepared by nitrogen cavitation from cultured human lymphoid cells. The activity of the membrane fragments reflected the activity of the whole cells in that cells which did not form rosettes (P3J and RPMI 4098) resulted in inactive membranes and cells with high rosette formation (NC37 and Raji) yielded highly active membrane fragments. Two test systems were devised to detect these receptor activities, namely a rosette inhibition and a hemagglutination assay. Solubilization of C3 receptors was accomplished by extraction of active plasma membrane fragments with 2 MKBr. Dissociation and reassociation experiments suggest C3b and C3d receptors to be highly complex molecular structures. It appears that these complement receptors on plasma membranes rely on both protein and lipid moieties for the expression of their activity.

Binding Sites↗
PubMed1986

Influence of glycosylation on allelic and cell-specific Mr variation, receptor processing, and ligand binding of the human complement C3b/C4b receptor.

The human complement C3b/C4b receptor (CR1), a single chain membrane glycoprotein of Mr approximately 200,000, has several cell-specific Mr variations as well as an allelic variation involving four phenotypes whose Mr values span a range of 90,000. We investigated the role of glycosylation in these structural variations and in receptor metabolism. In the human HL-60 promyelocytic leukemic cell line differentiated toward granulocytes or monocytes and in Epstein-Barr virus-transformed B lymphoblastoid cell lines of the common phenotype, CR1 is synthesized as a precursor of Mr = 222,000 that is converted into mature CR1s with differing Mr values. Endoglycosidase F treatment of mature CR1 from all these cell types produced the same lower Mr band. Additionally, the previously noted 5,000 higher Mr of CR1 from human peripheral granulocytes versus erythrocytes was abrogated by endoglycosidase F. Hence these cell-specific variations are due to differences in N-glycosylation. Lectin affinity chromatography shows that these N-linked oligosaccharides are mostly tri- and tetraantennary complex-type species with specific differences in fractionation patterns that correlate with their differing Mrs. In lymphoblastoid cell lines, the four allelic variants each have a precursor 6,000 lower in Mr than the respective mature CR1. In the presence of tunicamycin, each of the CR1 allelic products is 25,000 lower in Mr than the glycosylated receptor. The failure to radiolabel CR1 with [3H]glucosamine in the presence of tunicamycin indicates the lack of O-linked oligosaccharide on CR1. These data, taken together, strongly suggest that the CR1 polymorphism resides at the polypeptide level. Nonglycosylated CR1 synthesized in the presence of tunicamycin had twice the turnover rate of glycosylated CR1. The efficiency of surface membrane insertion and of ligand binding to hemolytically inactive C3 were markedly reduced for nonglycosylated CR1, suggesting that glycosylation is important for the proper expression of CR1 function.

Alleles↗
PubMed2003

The use of selective pharmacological inhibitors to delineate signal transduction pathways activated during complement receptor-mediated degranulation in chicken heterophils.

Complement receptors (CRs), along with Fc receptors, play a primary role in the removal of bacterial pathogens in poultry. The binding of serum-opsonized bacteria to CR results in the secretion of both toxic oxygen metabolites and antibacterial granules. We have previously shown that the stimulation of chicken heterophils with serum-opsonized Salmonella enteritidis induced tyrosine kinase-dependent phosphorylation regulated degranulation. In the present studies, we used selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipases C and D (PLC and PLD), phosphatidylinositol 3'-kinase (PI3-K), and the super family of mitogen-activated protein kinases (MAPKs) on CR-mediated heterophil degranulation. Inhibitors of receptor-linked tyrosine kinases (the tryphostins AG1478 and AG1296) had no attenuating effects on CR-mediated degranulation. However, PP2, a selective inhibitor of the src family of protein tyrosine kinases, and piceatannol, an inhibitor of Syk tyrosine kinases, both significantly attenuated the CR-mediated degranulation. Additionally, the specific inhibitors of PLC, U73122, and PI3-K, LY294002, significantly decreased CR-mediated heterophil degranulation. Two inhibitors of PLD-mediated signaling, 2,3-diphosphoglycerate (2,3-DPG) and 1-butanol, hindered degranulation. Addition of purified PLD restored control levels of degranulation in heterophils in which PLD was inhibited. Lastly, SP600125, a selective inhibitor of c-Jun N-terminal kinase (JNK), inhibited degranulation; whereas neither PD98059, the inhibitor of p38 MAPK, nor SB203580, the inhibitor of extracellular signal-regulated kinase, had any effect on CR-mediated heterophil degranulation. These studies demonstrate that CRs on chicken heterophils lack intrinsic tyrosine kinase activity, but that binding of serum-opsonized bacteria activates both proximal tyrosine kinases (src and Syk kinases), but differentially activates downstream tyrosine kinases (JNK, but not p38 nor ERK). Activation of src and Syk kinases plays a significant role in signal transduction of heterophil degranulation probably by stimulating downstream phosphorylation of PLC, PLD, and PI3-K. PI3-K has also been recently shown to be an upstream mediator of JNK activation, suggesting that this enzyme can induce signaling as both a lipid kinase and protein kinase. Engaging CRs on chicken heterophils activates a proximal tyrosine kinase (src and Syk kinases)-->PLC (PLD)-->PI3-K-->JNK signal transduction pathway that induces degranulation.

Animals↗
PubMed1996

1,25(OH)2D3 and cAMP synergistically induce complement 5a receptor messenger RNA.

Complement 5a receptor (C5aR) mediates both acute and chronic participation of monocytes in the immune response. In the human U937 monoblast, C5aR is maximally expressed 4 days after treatment with 1,25(OH)2D3 (or cycloheximide) and prostaglandin E2 combined. The authors asked whether these agents altered expression of C5aR messenger RNA (mRNA). Unstimulated U937 cells expressed neither C5aR mRNA nor C5a binding. Complement 5aR mRNA rose 3 hours after prostaglandin E2 application and fell to basal levels by 12 hours. This early rise in C5aR mRNA did not cause an acute rise in C5a binding, which gradually increased between 1 and 4 days. Neither 1,25(OH)2D3 nor cycloheximide induced expression of C5aR mRNA in the absence of prostaglandin E2 but did enhance prostaglandin E2-stimulated C5aR mRNA expression and C5a binding. The authors observed a late increase in C5aR mRNA at day 3 in treated cells. Inhibition of this late rise in mRNA with 5,6-dichlorobenzimidazole riboside attenuated C5a binding by 65%, indicating its importance in the generation of C5a binding sites. The expression of functional C5aR is, therefore, a complex process involving regulation at transcriptional and posttranscriptional levels.

1-Methyl-3-isobutylxanthine↗
PubMed1990

An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus.

In the course of examining the structure and function of Fc receptors on peripheral blood cells of patients with systemic lupus erythematosus, we identified a patient whose neutrophils did not react with either monoclonal or polyclonal antibodies to Fc receptor III. However, neutrophils from the patient were comparable to neutrophils from healthy controls with respect to their expression of Fc receptor II, complement receptor 1, complement receptor 3, and the phosphatidylinositol-linked, complement regulatory protein, decay-accelerating factor. The abnormality of expression of Fc receptor III was limited to the patient's neutrophils (her natural killer cells reacted normally with anti-Fc receptor III antibodies), and was associated with abnormal recognition and binding of IgG-coated erythrocytes. Analysis of genomic DNA revealed evidence that failure of the patient's neutrophils to express Fc receptor III was most likely due to an abnormality of the gene that encodes this receptor.

Adult↗
PubMed1977

[Receptors for complement and Fc and T-lymphocyte markers on cells of malignant tumours of man (author's transl)].

32 malignant solid tumours of various histological types were tested for the presence of Fc receptors, complement receptors and T-lymphocyte markers in single-cell suspensions of fresh tissue. Indicator cells were normal SRBC (E), SRBC coated with rabbit antisheep lg (EA) and EA coated with complement (EAC'). Fluorescent microscopy on tumour cells was done with rabbit anti-human IgG-fraction labeled with FITC. Almost all tumours possessed Fc receptors and/or complement-receptors. The presence of T-lymphocyte marker was less frequently found. It is proposed to establish a "receptor classification" in addition to the histologic classification of the tumours.

Animals↗
PubMed1998

Complement opsonization is required for presentation of immune complexes by resting peripheral blood B cells.

Complement receptor 2 (CD21, CR2) is a B cell receptor for complement degradation products bound to Ag or immune complexes. The role of CD21 in mediating Ag presentation of soluble immune complexes by resting B cells was studied. Complement-coated immune complexes were formed by the incubation of influenza virus with serum from immune donors. These complexes bound to peripheral blood B cells in a complement-dependent manner. The binding required CD21 or, to a lesser extent, complement receptor 1 (CR1, CD35). B cells pulsed with immune complexes containing complement elicited a response from a panel of influenza-specific T cell clones, while those pulsed with immune complexes formed in the absence of complement did not. The expression of the early activation marker CD69 and the costimulatory molecule CD86 were not induced by CD21 ligation alone, suggesting that CD21-mediated Ag presentation occurs independently of B cell activation. Up-regulation of these markers required exposure to T cell factors elicited by the recognition of Ag derived from complement-containing immune complexes. These findings suggest that binding of Ag to CD21 enables Ag-nonspecific B cells to participate in the activation of Ag-specific T cells in a process that occurs independently of well-characterized B cell activation events.

Antigen Presentation↗
PubMed1998

Morphine enhances complement receptor-mediated phagocytosis of Cryptococcus neoformans by human microglia.

Recent studies have shown that opiates modulate the function of microglia, the resident macrophages of the brain. In this study, the effect of morphine on phagocytosis by human fetal microglial cells of the opportunistic fungus Cryptococcus neoformans was studied. Contrary to earlier findings with swine microglia, opsonization was required for the phagocytosis of C. neoformans by human microglia. Moreover, morphine (10(-8)M) was shown to augment uptake of opsonized C. neoformans by over 50%. This contrasts with the earlier finding of morphine-induced inhibition of phagocytosis of nonopsonized cryptococci by swine microglia. The effect of morphine on cryptococcal phagocytosis by human microglia was reversed by treatment of microglial cells with mu opiate receptor antagonists as well as by addition of anti-complement receptor antibodies to the cell cultures, indicating that both the mu opiate receptor and the complement receptor are involved in morphine-enhanced phagocytosis. These findings support the concept of opiates as neuroimmunomodulatory agents and demonstrate that the effects of opiates on microglial cells may be influenced by the animal species from which the cells are derived.

Analgesics, Opioid↗