Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B6AF1 mice were sensitized to major histocompatibility complex (MHC) antigens by rejection of B10.D2 skin allografts. The effects of various protocols of treatment with antithymocyte serum (ATS), Bordetella pertussis vaccine, and donor strain lymphocytes were tested in these mice, and the results were assessed by in vitro testing for abrogation of circulating cytotoxic T cell memory and in vivo by determining the survival time of a second donor strain skin graft. It was found that a 6-week course of ATS alone abrogated this presensitized state as judged by both the in vitro and in vivo measurements, and that the hyporesponsive state induced by this treatment persisted for at least 4 months.
 ...
PMID:T cell responses to alloantigens. IV. In vivo and in vitro studies of the abrogation of presensitization to major histocompatibility antigens. 704 59

Sulfatides have been established recently as ligands for L-selectin, and we investigated whether they trigger transmembrane signals through ligation of L-selectin. We found that sulfatides trigger the increase of cytosolic free calcium in neutrophils and that this effect was strictly dependent on sulfation of the galactose ring, as non-sulfated galactocerebrosides were not stimulatory. Chymotrypsin and phorbol 12-myristate 13-acetate treatment of neutrophils caused shedding of L-selectin, but not of class I major histocompatibility complex antigens or beta 2 integrins, and blunted the capability of neutrophils to respond to sulfatides with an increase of cytosolic free calcium. Four different anti-L-selectin antibodies (DREG-200, LAM1/3, LAM1/6, and LAM1/10), but not four control antibodies directed against different surface molecules of neutrophils, also triggered an increase of cytosolic free calcium. The anti-L-selectin antibodies were stimulatory both if used in a soluble form, after cross-linking with anti-mouse F(ab')2 fragments, and immobilized to protein A of Staphylococcus aureus through the Fc fragment. With immobilized antibodies, an increase of cytosolic free calcium was found also by plating neutrophils on antibodies bound to protein A-coated coverslips and monitoring the increase of cytosolic free calcium by fluorescence microscopy. Both sulfatides and anti-L-selectin antibody effects were not inhibited by pertussis toxin, thus indicating that a pertussis toxin-sensitive GTP-binding protein was not involved in signal transduction. Sulfatides also triggered an increase of tumor necrosis factor-alpha and interleukin-8 mRNAs in neutrophils. Also to act as stimuli of cytokine mRNA expression, sulfatides required sulfation of the galactose ring, as non-sulfated galactocerebrosides were not stimulatory, and depended on expression of L-selectin, as shedding of this molecules induced by chymotrypsin blunted their effects. These findings suggest that L-selectin can transduce signals activating selective cell function.
 ...
PMID:Sulfatides trigger increase of cytosolic free calcium and enhanced expression of tumor necrosis factor-alpha and interleukin-8 mRNA in human neutrophils. Evidence for a role of L-selectin as a signaling molecule. 750 38

The aim of the present study was to identify murine T-cell epitopes on pertussis toxin subunit S4. Six mouse strains with five different haplotypes at the H-2 locus were immunized with the pertussis toxin B oligomer. Lymph node lymphocytes were isolated and stimulated in an in vitro proliferation assay with pertussis toxin components and 11 overlapping synthetic peptides synthesized on the basis of the primary sequence of S4. In vitro proliferative responses to the synthetic peptides revealed the presence of four distinct murine T-cell epitopes on subunit S4. The recognition of the peptides was major histocompatibility complex restricted. Immunizing four of the six mouse strains with the synthetic peptides showed that the peptides which were demonstrated to contain T-cell epitopes following immunization with the B oligomer were able to induce proliferative responses to detoxified pertussis toxin and pertussis toxin components containing subunit S4. One of the identified murine T-cell epitopes corresponded to one of the major human T-cell epitopes previously identified on subunit S4. It is hoped that this murine model system will facilitate the development of a synthetic immunogen mimicking the protective properties of pertussis toxin.
 ...
PMID:Identification of murine T-cell epitopes on the S4 subunit of pertussis toxin. 767 2

Experimental autoimmune uveoretinitis (EAU) is an intraocular inflammatory disease model induced by retinal specific antigens such as S-antigen and interphotoreceptor retinoid-binding protein (IRBP). The present study was aimed at testing the uveitogenicity of IRBP and an IRBP-derived peptide in various strains of rats with different RT1 (major histocompatibility complex in rats) haplotypes. Immunization with IRBP induced distinct EAU in LEW (RT1l), WKAH (RT1k) W/M (RT1k), LEJ (RT1j), and BUF (RT1b) rats. IRBP also induced a low grade of EAU in SDJ (RT1u), but no disease was detected in TO rats, another strain of the RT1u haplotype. IRBP-derived peptide R16 (aa 1177-1191) induced severe EAU in LEW rats and moderate disease in the WKAH and W/M strains. Immunization with R16 also induced low levels of inflammation in eyes of 75% and 20% of LEJ and BUF rats, respectively, but this peptide did not cause any disease in SDJ and TO rats. Injection of Bordetella pertussis had minimum or no effect on the induction of EAU by peptide R16 in this study. These data thus indicate that peptide R16 can bind to various RT1 molecules in addition to RT1l. Further, our observations support the notion that certain epitopes of IRBP could be uveitogenic in humans with different HLA haplotypes.
 ...
PMID:Interphotoreceptor retinoid-binding protein derived peptide can induce experimental autoimmune uveoretinitis in various rat strains. 785 Nov 21

S-antigen or interphotoreceptor retinoid-binding protein (IRBP), when injected with Freund's complete adjuvant into mice, does not easily cause experimental autoimmune uveoretinitis (EAU). In this report, we describe the results of injecting IRBP with Freund's complete adjuvant, together with the intraperitoneal administration of Bordetella pertussis, into several types of congenic mice (B10, B10A, B10BR, B10D2). These congenic mice, of C57BL/10 (B10) origin, differ at the H-2 locus on chromosome 17. We were able to produce EAU in 38.5% of B10A mice, and 12.5% of B10BR mice, confirming that EAU can develop in these mice that carry the k genotype at the K, I-A, and I-E regions of the major histocompatibility complex (MHC) H-2 locus. We believe that the k genotype of the K, I-A, and I-E regions is important as a factor in the pathogenesis of EAU in congenic B10 mice.
 ...
PMID:[An investigation of factors in the pathogenesis of experimental autoimmune uveoretinitis (EAU) in congenic mice]. 794 37

Cytotoxic T lymphocytes (CTL) recognize antigens derived from endogenously expressed proteins presented on the cell surface in the context of major histocompatibility complex (MHC) class I molecules. Because CTL are effective in antiviral and antitumor responses, the delivery of antigens to the class I pathway has been the focus of numerous efforts. Generating CTL by immunization with exogenous proteins is often ineffective because these antigens typically enter the MHC class II pathway. This review focuses on the usefulness of bacterial toxins for delivering antigens to the MHC class I pathway. Several toxins naturally translocate into the cytosol, where they mediate their cytopathic effects, and the mechanisms by which this occurs has been elucidated. Molecular characterization of these toxins identified the functional domains and enabled the generation of modified proteins that were no longer toxic but retained the ability to translocate into the cytosol. Thus, these modified toxins could be examined for their ability to carry peptides or whole proteins into the cytosolic processing pathway. Of the toxins studied-diphtheria, pertussis, Pseudomonas, and anthrax-the anthrax toxin appears the most promising in its ability to deliver large protein antigens and its efficiency of translocation.
 ...
PMID:Delivery of antigens to the MHC class I pathway using bacterial toxins. 929 31

A synthetic tridecapeptide, corresponding to the 30-42 fragment of the S1 subunit of pertussis toxin, has been structurally characterised by using NMR spectroscopy. The molecule corresponds to a T-cell epitope of the bacterial toxin which has been extensively analysed with the alanine scanning approach to check the relevance of each residue for the biological activity of the peptide. Five of these Ala-substituted analogs have also been spectroscopically studied. In the experimental conditions used, different extents of helicity were found for the six peptides in a way which cannot be related to their capabilities of of binding to major histocompatibility complex (MHC) class II and inducing T-cell proliferation. Backbone flexibility around helical transient conformations seems to constitute the structural intermediate step between the structure of the corresponding sequence within the parental protein and in the MHC class II complex. A model of the latter complex, which accounts for the different biological activities of the analogs, is proposed.
 ...
PMID:NMR studies on the structure/function correlations of T-cell-epitope analogs from pertussis toxin. 966 Jan 85

A CD8(+) cytolytic T-lymphocyte (CTL) response to antigen-presenting cells generally requires intracellular delivery or synthesis of antigens in order to access the major histocompatibility complex (MHC) class I processing and presentation pathway. To test the ability of pertussis toxin (PT) to deliver peptides to the class I pathway for CTL recognition, we constructed fusions of CTL epitope peptides with a genetically detoxified derivative of PT (PT9K/129G). Two sites on the A (S1) subunit of PT9K/129G tolerated the insertion of peptides, allowing efficient assembly and secretion of the holotoxin fusion by Bordetella pertussis. Target cells incubated with these fusion proteins were specifically lysed by CTLs in vitro, and this activity was shown to be MHC class I restricted. The activity was inhibited by brefeldin A, suggesting a dependence on intracellular trafficking events, but was not inhibited by the proteasome inhibitors lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal (LLnL). Furthermore, the activity was present in mutant antigen-presenting cells lacking the transporter associated with antigen processing, which transports peptides from the cytosol to the endoplasmic reticulum for association with MHC class I molecules. PT may therefore bypass the proteasome-dependent cytosolic pathway for antigen presentation and deliver epitopes to class I molecules via an alternative route.
 ...
PMID:Intracellular delivery of a cytolytic T-lymphocyte epitope peptide by pertussis toxin to major histocompatibility complex class I without involvement of the cytosolic class I antigen processing pathway. 991 65

In order to replicate a recently described murine model of Graves' disease, we immunized AKR/N (H-2k) mice i.p., every 2 weeks, with either a clone of fibroblasts expressing both the human TSH receptor (hTSHR) and murine major histocompatibility complex (MHC) class II molecules or with fibroblasts expressing the MHC class II molecules alone. Mice were bled, and their thyroid hormone levels measured, at 6, 12, and up to 18 weeks after the first immunization. Between 11-12 weeks after immunization, a significant number of mice began to die spontaneously and were found to have developed large goiters. Thirty to 40% of mice immunized with hTSHR transfected fibroblasts showed markedly increased serum T3 and T4 hormone levels by 12 weeks compared with controls, with the highest thyroid hormone levels being T3: 420 ng/dl (normal < 70) and T4: 16.5 microg/dl (normal < 5). The murine serum demonstrated the presence of antibodies to the TSHR, as evidenced by inhibition of labeled TSH binding to the hTSHR, and these sera had in vitro thyroid stimulating activity. Many of the hyperthyroid mouse exhibited weight loss and hyperactivity and, on examination, their thyroids had the histological features of thyroid hyperactivity including thyroid enlargement, thyroid cell hypertrophy, and colloid droplet formation--all consistent with Graves' disease. In contrast, a small number of mice (< 5%) developed hypothyroidism with low serum T4 levels and markedly increased TSH concentrations and evidence of thyroid hypoplasia. Both hyperthyroidism and hypothyroidism were successfully transferred to naive mice using ip cells of immunized mice. Surprisingly, hypothyroidism occurred in many recipient mice even after transfer from hyperthyroid donors. These results confirmed that immunization with naturally expressed hTSHR in mammalian cells was able to induce functional TSHR autoantibodies that either stimulated or blocked the mouse thyroid gland and induced hyperthyroidism or thyroid failure. Furthermore, both blocking and stimulating antibodies coexisted in the same mice as evidenced so clearly by the transfer of hypothyroidism from hyperthyroid mice. The addition of a Th2 adjuvant (pertussis toxin) caused approximately 50% of the animals to become hyperthyroid beginning early at 9 weeks, whereas a Th1 adjuvant (CFA) delayed the disease onset such that only 10% were hyperthyroid by 12 weeks. As with human autoimmune thyroid disease, the T cell control of this murine model may be critical and requires more extensive investigation.
 ...
PMID:Regulation and transfer of a murine model of thyrotropin receptor antibody mediated Graves' disease. 1006 67

Bordetella pertussis adenylate cyclase (AC) toxin-hemolysin (ACT-Hly) can penetrate a variety of eukaryotic cells. Recombinant AC toxoids have therefore been recently used for delivery of CD8(+) T-cell epitopes into antigen-presenting cells in vivo and for induction of protective antiviral, as well as therapeutic antitumor cytotoxic T-cell responses. We have explored the carrier potential of the ACT molecule by insertional mutagenesis scanning for new permissive sites, at which integration of two- to nine-residue-long peptides does not interfere with membrane interaction and translocation of ACT. A model CD8(+) T-cell epitope of ovalbumin was incorporated at 10 of these permissive sites along the toxin molecule, and the capacity of ACT constructs to penetrate into cell cytosol and deliver the epitope into the major histocompatibility complex (MHC) class I antigen processing and presentation pathway was examined. While all six constructs bearing the epitope within the Hly portion of ACT failed to deliver the epitope to the MHC class I molecules, all four toxoids with inserts within different permissive sites in the AC domain efficiently delivered the epitope into this cytosolic pathway, giving rise to stimulation of a specific CD8(+) T-cell hybridoma. The results suggest that, in contrast to the AC domain, the hemolysin moiety of ACT does not reach the cytosolic entry of the MHC class I pathway.
 ...
PMID:Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I antigen presentation pathway by Bordetella pertussis adenylate cyclase: delineation of cell invasive structures and permissive insertion sites. 1060 95


<< Previous 1 2 3 Next >>