Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0033036 (APC)
10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recognition of viral Ag and of the envelope glycoprotein of HIV (gp120) in particular by human Th cells is critical in the immune response to the viral Ag which includes antibody production and generation of cytotoxic cells. Procedures to increase antigenicity of gp120 are highly desirable in a vaccine perspective. Therefore, to induce activation of gp120-specific T cells by a liminal dose of Ag we enhanced uptake of gp120 by exploiting the galactose receptors on APC. Terminal sialic acid residues were removed by neuraminidase treatment from the carbohydrate side chains of the heavily glycosylated gp120. Galactose residues were exposed and hence recognized by galactose receptors on APC. The experiments demonstrated that 1) human monocytes and dendritic cells, but not cells of the B lineage, bear galactose receptor; 2) galactose receptors are indeed involved because enhanced presentation is inhibited by galactose and acetylgalactosamine and competed for by other asialoglycoproteins; 3) galactose receptors mediate internalization of Ag in intracellular compartments that intersect the processing and presenting pathways, resulting in activation of specific T cells; 4) antigenicity of gp120 for specific T cells can be enhanced by the exposure of galactose residues.
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PMID:Galactose receptors and presentation of HIV envelope glycoprotein to specific human T cells. 131 6

Human T cells spontaneously bind sheep E and this reflects physiologic interactions between specific adhesion molecules, principally T cell CD2, and the sheep equivalent of LFA-3. This interaction is important in T cell adhesion and in transmission of accessory activational signals. In this respect, E rosettes provide a partial analogue for T cell:accessory cell interaction and rosetting induces functional alterations in T cells. In studies of Ag-dependent T cell activation, we have obtained evidence that the formation of covalent Schiff bases between ligands on APC and T cell is an essential element. In our study, the specific chemical criteria defining Schiff base formation were applied to T cell E rosettes formed at room temperature, as follows: 1) Prior formation of Schiff bases on T cell epsilon-amino groups by glutaraldehyde inhibited E rosette formation. 2) Rosette formation was inhibited in the presence of exogenous lysine. 3) Reduction of constitutive T cell aldehydes by NaBH4 inhibited subsequent E rosette formation. In response to these chemical modifications of cellular ligands, T cell E rosette formation and T cell inductive interaction with APC were affected in the same way. 4) Oxidation of NaBH4-treated T cells by NaIO4 or galactose oxidase to regenerate cell-surface aldehydes on N-acetylneuraminic acid or galactose residues respectively, consistently restored E rosette formation. 5) Conversion of reversible Schiff bases to irreversible secondary amines by NaCNBH3 stabilized E rosettes against mechanical disruption. Together, these data demonstrate that E rosettes provide an analogue for the Schiff base-forming reactions that are essential in specific T cell activation.
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PMID:Erythrocyte rosettes provide an analogue for Schiff base formation in specific T cell activation. 236 92

The experiments described here were designed to investigate the role of intracellular acidic organelles in the processing of foreign antigens. Simultaneous addition of antigen and the inactive precursor of an acid protease, cathepsin L, greatly diminished the stimulation of a T-cell hybridoma specific for pigeon cytochrome c. The effect occurred during antigen processing as the presentation of a peptide fragment was unaffected by precursor-cathepsin L. The effect required uptake of the enzyme via mannose-6-PO4 receptors and was specific for antigenic determinants cleavable by the enzyme. The results confirm, without any pharmacologic manipulation, that foreign antigen moves into an acidic environment during some phase of its processing. We also explored the role in antigen processing of one acidic compartment, the early endosome, by examining CHO cells expressing a temperature-sensitive defect in endosomal acidification. These cells were transfected with MHC class II genes to convert them into APC for CD4+T cells. When these cells were incubated at the nonpermissive temperature, their ability to process antigen was impaired. There was no negative effect on presentation of antigenic peptides nor on the uptake and degradation of the antigen. Wildtype CHO cells similarly transfected and tested did not show any aberrancy in antigen processing. The inhibition of processing by the mutant cells was only partial, even under stringent conditions, and the residual processing was eliminated by chloroquine. Our findings provide the first evidence for a contribution by acidified early endosomes to the pathway of antigen processing and suggest that other acidified compartments are also involved.
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PMID:The role of intracellular acidification in antigen processing. 307 87

Aldosterone secretion in man is stimulated by potassium, ACTH, and angiotensin II and is inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA. Dopaminergic control of aldosterone secretion is modified by dietary sodium depletion. To determine the physiological significance of dopaminergic inhibition of aldosterone secretion, we studied the effect of DA on the aldosterone response to upright posture. Twelve normal men were studied while eating an ad libitum sodium diet, and the effect of DA was determined in the supine and upright positions. Plasma aldosterone (PAC), plasma cortisol (F), plasma aldosterone-stimulating factor (ASF), PRA, and blood pressure were measured while the men were supine and after 4 h of upright posture during an infusion of 5% dextrose vehicle and during a DA infusion of 4.0 micrograms/kg X min. The men also were studied as a time control in the supine position while receiving vehicle or DA. PAC increased from a mean basal value of 20.4 +/- 3.2 ng/dl (+/- SE) by 25.9 +/- 5.1 ng/dl to a peak of 44.4 +/- 2.4 ng/dl in response to upright posture during vehicle infusion. The PAC response to upright posture was reduced to 7.4 +/- 1.8 ng/dl (P less than 0.05) when DA was infused. The increase in PRA with upright posture was 3.7 +/- 1.3 ng/ml X h during the vehicle infusion and 4.1 +/- 1.1 ng/ml X h (P = NS) during the DA infusion. ASF, F, and blood pressure were not altered by upright posture and DA. PAC did not change in the six men infused with DA while supine. Therefore, DA inhibits upright aldosterone responses without affecting PRA, ASF, or F.
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PMID:Dopamine inhibits the aldosterone response to upright posture. 351 47

Liquid chromatography under elevated pressure (h.p.l.c.) has been applied to the separation of the phenyl, benzyl, and O-nitrophenyl glycosides of 2-acetamido-2-deoxy-D-galactopyranose and of various mucin-type, di-, tri-, and tetra-saccharides. The separations were carried out with a Whatman Partisil PXS 5/25 PAC column and various proportions of acetonitrile and water in the mobile phase. These methods were subsequently used to separate the substrates and products of the following N-acetylglucosaminyltransferase reactions: UDP-GlcNAc + beta-Gal-(1 leads to 3)-GalNAc-R leads to beta-Gal-(1 leads to 3)-[beta-GlcNAc-(1 leads to 6)]-GalNAc-R + UDP (1); UDP-GlcNAc + beta-Gal-(1 leads to 3)-[beta-GlcNAc-(1 leads to 6)]-GalNAc-R leads to beta-GlcNAc-(1 leads to 3)-beta-Gal-(1 leads to 3)-[beta-GlcNAc-(1 leads to 6)]-GalNAc-R + UDP (2); UDP-GlcNAc + GalNAc-R' leads to beta-GlcNAc-(1 leads to 3)-GalNAc-R' + UDP (3); and UDP-GlcNAc + beta-GlcNAc-(1 leads to 3)-GalNAc-R' leads to beta-GlcNAc-(1 leads to 6)-[beta-GlcNAc-(1 leads to 3)]-GalNAc-R' + UDP (4), where R is = benzyl or o-nitrophenyl, and R' = benzyl or phenyl alpha-D-glycoside. Reaction 1 is catalyzed by a transferase in canine submaxillary glands and porcine gastric mucosa, and reaction 2 by an enzyme in porcine gastric mucosa. Enzyme activities catalyzing reactions 3 and 4 have recently been demonstrated in rat colonic mucosa. Liquid chromatography can be used at the preparative level for the purification and identification of the transferase products, and at the analytical level in the assay of glycosyltransferases.
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PMID:The separation by liquid chromatography (under elevated pressure) of phenyl, benzyl, and O-nitrophenyl glycosides of oligosaccharides. Analysis of substrates and products for four N-acetyl-D-glucosaminyl-transferases involved in mucin synthesis. 622 56

Well-characterized rough mutants are important for the understanding of structures, functions, and biosynthesis of lipopolysaccharide (LPS) in gram-negative organisms. In this study, three series of Pseudomonas aeruginosa LPS-deficient mutants, namely PAC strains derived from serotype O3, AK strains derived from strain PAO1 (serotype O5), and serotype O6-derived mutants were subjected to biochemical analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining as well as immunochemical characterization using LPS-specific monoclonal antibodies. The O-side-chain deficiency among the O6-derived mutants was also examined, and three mutants, A28, R5, and H4, were subsequently chosen for the elucidation of component sugars of the core structure of serotype O6 LPS. LPS of strain A28 has L-rhamnose and proportionally higher amounts of D-glucose, a feature shared by the O5-derived mutant, strain AK1401 (previously demonstrated as a mutant with a core-plus-one O repeat). In contrast strains R5 and H4 were shown to be devoid of L-rhamnose and have low and undetectable amounts of D-glucose, respectively, which indicated their core deficiency. The LPS-deficient or -sufficient characteristics of the P. aeruginosa strains examined correlated will with serum sensitivity data. This report represents a comprehensive analysis of rough mutants derived from O3 and O5 strains that have been used by others in many studies and a first look at the core oligosaccharide region of serotype O6 LPS obtained with the O6-derived mutants generated in this study.
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PMID:Characterization of lipopolysaccharide-deficient mutants of Pseudomonas aeruginosa derived from serotypes O3, O5, and O6. 811 51

We compared the processing and presentation of the model Ag, hen-egg white lysozyme (HEL) expressed in C3.F6 APC as a fusion protein to three different acid hydrolases: cathepsin D, to an unglycosylated form of cathepsin D, and to pepsinogen. As expected from the biology of mannose 6-phosphate (Man-6-P)-containing enzyme, cathepsin D-HEL was delivered to the endosomal/lysosomal system. In contrast, the unglycosylated cathepsin D-HEL was retained in ER/Golgi and some was found in lysosomes. Most of pepsinogen-HEL was rapidly secreted from the APC. All transfectants presented HEL epitopes to T cell hybridomas. Regardless of the main route of traffic of the proteins, the strong I-Ak binding epitope HEL 48-62 was well presented by all. The biochemical forms of this epitope were identical for all. Three other epitopes of HEL that bind I-Ak with less affinity were processed equally well by unglycosylated cathepsin D-HEL and HEL-Ld. The glycosylated cathepsin D-HEL was less efficient in generating the 114-129 epitope. Pepsinogen-HEL was the less efficient of all transfectants in presenting these subdominant epitopes. Soluble cathepsin D-HEL recovered from culture supernatant was strongly immunogenic when added to C3.F6. The uptake was inhibited by free Man-6-P, indicating that the surface Man-6-P receptor can effectively deliver proteins to the class II MHC system.
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PMID:Presentation on class II MHC molecules of endogenous lysozyme targeted to the endocytic pathway. 905

Human peripheral blood monocytes activated by GM-CSF plus IL-4 have recently been found to exhibit characteristics of putative dendritic cells (DC). These cytokine-activated monocytes (CAM) may express novel activation Ag that contribute significantly to their antigen presentation potency. To examine that possibility, mAb specific for CAM were derived. Seven mAb that stained CAM but not unactivated monocytes and other peripheral blood mononuclear cell types were identified. Further screening with a panel of cell lines identified two CAM-specific mAb. The first mAb, 2.1D10, was found to be mannose-receptor specific. A second mAb, 6.3B7, immunoprecipitated a 190-kDa Ag. It stained neither activated B cells nor the putative peripheral blood precursor DC population. Furthermore, 6.3B7 did not recognize determinants in asparagine-linked carbohydrate chains or in sialic acid-containing structures. These mAb against CAM membrane proteins may provide new insights into the requirements for optimal antigen presentation by macrophages and other APC types.
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PMID:Monoclonal antibodies against human dendritic cell-like peripheral blood monocytes activated by granulocyte/macrophage-colony-stimulating factor plus interleukin 4. 951 3

Increased levels of agalactosyl IgG (G0 IgG) are found in several autoimmune diseases, including rheumatoid arthritis, in which they are correlated with severity of the disease. To investigate whether structural alteration of IgG may lead to aberrant processing and presentation of IgG peptides as autoantigens, we have studied uptake of G0 IgG by human dendritic cells and macrophages cultured from PBMC. We found that enzymatic removal of terminal galactose residues, which exposes N-acetylglucosamine residues, increases uptake of soluble IgG mediated by mannose receptor on macrophages and dendritic cells. Efficient uptake appears to require recycling of the receptor, can be blocked by saccharides or Abs reactive with mannose receptor, and is dependent upon the state of maturation of the dendritic cells. No differences between IgG isotypes in ability to be internalized by APC were identified, suggesting that uptake would not be limited to a particular subset of Abs. These results suggest a novel pathway by which Abs or Ag-Ab complexes can be taken into dendritic cells and macrophages, and potentially generate epitopes recognized by T cells. These findings may have particular relevance for autoimmune disorders characterized by high levels of G0 IgG.
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PMID:Binding and uptake of agalactosyl IgG by mannose receptor on macrophages and dendritic cells. 1055 68

Cryptococcosis is a leading cause of death among individuals with compromised T cell function. Soluble Cryptococcus neoformans mannoproteins (MP) have emerged as promising vaccine candidates due to their capacity to elicit delayed-type hypersensitivity and Th type 1-like cytokines, both critical to the clearance of this pathogenic yeast. In this study, the mechanisms responsible for the potent immunostimulatory properties of MP were explored. Using Chinese hamster ovary cells expressing human macrophage mannose receptor (MMR), we determined that MP is a MMR ligand. Functionally, competitive blockade of multilectin mannose receptors (MR) on APCs diminished MP-dependent stimulation of primary T cells from immunized mice and the MP-reactive CD4(+) T cell hybridoma, P1D6, by 72 and 99%, respectively. Removal of O-linked saccharides from MP by beta-elimination inhibited MP-dependent stimulation of P1D6 and primary T cells by 89 and 90%, respectively. In addition, MP-dependent stimulation of P1D6 was abrogated after digestion with proteinase K, suggesting the protein core of MP contributed the antigenic moiety presented by APC. Stimulation of P1D6 by MP also was abolished using APC obtained from invariant chain-deficient mice, demonstrating Ag presentation was MHC class II restricted. Our data suggest that MP is a ligand for the MMR and that T cell stimulation is functionally inhibited either by competitive blockade of MR or by removal of carbohydrate residues critical for recognition. The demonstration that efficient T cell responses to MP require recognition of terminal mannose groups by MMR provides both a molecular basis for the immunogenicity of cryptococcal MP and support for vaccination strategies that target MR.
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PMID:Optimal T cell responses to Cryptococcus neoformans mannoprotein are dependent on recognition of conjugated carbohydrates by mannose receptors. 1188 57


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