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Streptococcus pneumoniae is a gram-positive bacterial pathogen that causes invasive life-threatening disease worldwide. This organism also commonly colonizes the upper respiratory epithelium in an asymptomatic fashion. To invade, this pathogen must traverse the respiratory epithelial barrier, allowing it to cause disease locally or disseminate hematogenously throughout the body. Previous work has demonstrated that S. pneumoniae choline-binding protein A, a pneumococcal surface protein, interacts specifically with the human polymeric immunoglobulin receptor, which is expressed by cells in the respiratory epithelium. Choline-binding protein A is required for efficient colonization of the nasopharynx in vivo. Additionally, a recent study showed that the R6x laboratory strain of S. pneumoniae invades a human pharyngeal cell line in a human polymeric immunoglobulin receptor-dependent manner. These findings raised the possibility that the interaction between choline-binding protein A and human polymeric immunoglobulin receptor may be a key determinant of S. pneumoniae pathogenesis. However, the strain used in prior invasion studies, R6x, is an unencapsulated, nonpathogenic strain. In the present study we determined the relative ability of strain R6x or pathogenic strains to invade a variety of human polymeric immunoglobulin receptor-expressing epithelial cell lines. The results of this work suggest that human polymeric immunoglobulin receptor-dependent enhanced invasion of epithelial cells by S. pneumoniae is a limited phenomenon that occurs in a strain-specific and cell type-specific manner.
Proteins of the fibroblast growth factor (FGF) family play diverse roles in embryonic development, angiogenesis, and wound healing. The most well studied targets of FGF activity typically are cells of mesodermal and neuroectodermal origin; in addition, expression of FGF-1 (acidic FGF) is increased at several sites of chronic immunologic injury, and recent studies show that FGF-1 also may interact with cells of the immune system. In some human T cells, FGF-1 can induce signals necessary for production of interleukin-2, a key cytokine required for T cell proliferation. To better characterize the interaction of FGF-1 with FGF receptors on T cells, a fusion protein was constructed containing a portion of the constant region of human IgG1 (Fc) at the amino terminus of FGF-1. The Fc-FGF-1 fusion protein retained FGF function as determined by stimulation of tyrosine phosphorylation and DNA synthesis in NIH 3T3 cells. Binding of the intact fusion protein to FGF receptor 1 (FGFR1) on T cells was demonstrated by immunoprecipitation of the receptor bound to Fc-FGF-1 and by flow cytometry showing binding of fusion protein to T cells expressing FGFR1. This functional Fc-FGF-1 protein should prove useful in identifying FGFR-expressing cells.
Anti-alpha 3(IV) collagen autoantibodies have been implicated in the pathogenesis of Goodpasture syndrome, an autoimmune disorder causing glomerulonephritis and pulmonary hemorrhage. Currently treatment involves removal of the entire IgG fraction of plasma by plasmapheresis or adsorption to protein A. The present study shows that the anti-alpha 3(IV)NC1 autoantibodies can be removed from plasma specifically and quantitatively by affinity chromatography utilizing either alpha 3 NC1 domain of bovine type IV collagen or recombinant alpha 3 NC1 domain of human type IV collagen immobilized to agarose beads. This study shows the feasibility of using affinity chromatography, as an alternative to plasmapheresis, to exclusively remove the pathogenic autoantibodies from the plasma of patients with Goodpasture syndrome.
Serological and immunochemical studies showed that monoclonal antibody Q2/70 (MoAb Q2/70), produced by the hybridoma technique, is specific for human Ia-like antigens. This antibody recognizes an antigenic determinant which is different from those defining the serologic polymorphism of Ia-like antigens, and is expressed on subsets of human Ia-like molecules and on lymphoid cells from other species. MoAb Q2/70 inhibits unidirectional MLRs* between allogenic human lymphocytes, but not between murine and human lymphocytes. In ADCC* assays. MoAb Q2/70 mediates lysis of cultured human B lymphoid cells RPMI 4098, effected by murine splenocytes. The antibody is suitable to isolate immunologically functional B lymphocytes from human peripheral blood.
We report on the results of a clinical trial in which 14 transplant candidates were treated with an extracorporeal immunoadsorption system using Protein A that selectively removes immunoglobulin from plasma; we also assessed the dynamics of anti-HLA antibody as a model of IgG removal and re-equilibration, as well as the clinical safety of the procedure. At the end of a treatment course, plasma IgG levels were reduced by 90% +/- 8% of control values (P less than 0.01). In contrast, albumin levels were reduced by only 15% (P less than 0.05). Specific cytotoxic anti-HLA antibody titers were reduced by approximately 18-fold. Panel reactivity was measured as the proportion of a 40-member cell donor panel killed by patients' serum in the presence of complement; in nine of the 14 patients, there was a significant reduction in this parameter (range, 23% to 87%). During the 4-week follow-up period, anti-HLA antibody titers returned to baseline levels. There were no remarkable changes observed in blood chemistries, nor were there any unanticipated adverse reactions seen in the patients treated. We conclude that selective extracorporeal immunoadsorption is a safe and effective way of removing IgG-type antibodies, with potential application to reduction of HLA antibodies in transplant candidates.
Bloodstream infections with staphylococci are accompanied by thromboembolic complications. We have studied the mechanism of the interaction of staphylococci with human blood platelets. Staphylococci that possess protein A, a bacterial receptor for the Fc fragment of immunoglobulin G (IgG), caused aggregation of human platelets in whole plasma accompanied by release of [(3)H]serotonin. These reactions were time and concentration dependent, requiring two or more staphylococci per platelet to give maximal response within 5 min. The interaction between staphylococci and platelets required the presence of cell wall-bound protein A and of IgG with an intact Fc fragment. It did not require an intact complement system. Cell wall-bound protein A (solid phase) was capable of aggregating human platelets in whole plasma. In contrast, free, solubilized protein A (fluid phase) did not cause measurable aggregation, and release of [(3)H]serotonin was reduced. An excess of free, solubilized protein A blocked aggregation of human platelets induced by staphylococci in whole plasma. The role of the Fc fragment of IgG in the staphylococci-human platelet interaction was demonstrated by an experiment in which free, isolated Fc fragment blocked aggregation of platelets in whole plasma induced by staphylococci. Furthermore, binding of (125)I-protein A to human platelets was demonstrated in the presence of complete IgG with intact Fc fragment but not in the presence of the F(ab)(2) fragment. Binding of the protein A-IgG complex to the human platelet Fc receptor was paralleled by the release of [(3)H]serotonin. These results represent a novel example of the interaction of two phylogenetically different Fc receptors, one on prokaryotic staphylococci and the other on human platelets. Their common ligand, IgG, is amplified by one Fc receptor (protein A) to react with another Fc receptor present on human platelets, which results in membrane-mediated aggregation and release reaction occurring in whole plasma. This mechanism can be of significance in the pathomechanism of thromboembolic complications at the site(s) of intravascular staphylococcal infection.
A radioimmunometric antibody-binding assay was developed with the use of 125I-labeled protein A of Staphylococcus aureus (SpA) for the evaluation of xenoantisera to human melanoma-associated antigens. Antisera were produced in New Zealand male albino rabbits by the injection of cultured human melanoma cells or soluble, partially purified melanoma-associated antigens isolated from these cells. Xenoantisera were rendered operationally specific for melanoma-associated antigens by absorption with human red cells and cultured lymphoblasts. The methodologic parameters and the quantitative relationships among xenoantisera, cultured melanoma target cells, and 125I-labeled SpA and their effect on the measurement of xenoantibody binding were critically evaluated. Data indicated the usefulness of the radioimmunometric assay in monitoring the efficacy of absorption and in characterizing the specificity of xenoantisera to melanoma-associated antigens. The radioimmunometric binding assay when modified and used as a binding inhibition assay was effective in the assessment of the serologic activity of soluble melanoma-associated antigens and thus may be used to monitor the progress of antigen purification.