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71.
Human and Murine Immune Responses to a Novel Leishmania major Recombinant Protein Encoded by Members of a Multicopy Gene Family 总被引:1,自引:0,他引:1 下载免费PDF全文
John R. Webb Antonio Campos-Neto Pamela J. Ovendale Tricia I. Martin Erika J. Stromberg Roberto Badaro Steven G. Reed 《Infection and immunity》1998,66(7):3279-3289
Vaccination of BALB/c mice with Leishmania major promastigote culture filtrate proteins plus Corynebacterium parvum confers resistance to infection with L. major. To define immunogenic components of this protein mixture, we used sera from vaccinated mice to screen an L. major amastigote cDNA expression library. One of the immunoreactive clones thus obtained encoded a novel protein of L. major with a molecular mass of 22.1 kDa. The predicted amino acid sequence of this clone exhibited significant homology to eukaryotic thiol-specific-antioxidant (TSA) proteins. Therefore, we have designated this protein L. major TSA protein. Southern blot hybridization analyses indicate that there are multiple copies of the TSA gene in all species of Leishmania analyzed. Northern blot analyses demonstrated that the TSA gene is constitutively expressed in L. major promastigotes and amastigotes. Recombinant TSA protein containing an amino-terminal six-histidine tag was expressed in Escherichia coli with the pET17b system and was purified to homogeneity by affinity chromatography. Immunization of BALB/c mice with recombinant TSA protein resulted in the development of strong cellular immune responses and conferred protective immune responses against infection with L. major when the protein was combined with interleukin 12. In addition, recombinant TSA protein elicited in vitro proliferative responses from peripheral blood mononuclear cells of human leishmaniasis patients and significant TSA protein-specific antibody titers were detected in sera of both cutaneous-leishmaniasis and visceral-leishmaniasis patients. Together, these data suggest that the TSA protein may be useful as a component of a subunit vaccine against leishmaniasis. 相似文献
72.
Braverman N Chen L Lin P Obie C Steel G Douglas P Chakraborty PK Clarke JT Boneh A Moser A Moser H Valle D 《Human mutation》2002,20(4):284-297
PEX7 encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP), a distinct peroxisome biogenesis disorder. In previous work we described three novel PEX7 mutant alleles, including one, L292X, with a high frequency due to a founder effect. We have now extended our analysis to 60 RCDP probands and identified a total of 24 PEX7 alleles, accounting for 95% of the mutant PEX7 genes in our sample. Of these, 50% are L292X, 13% are IVS9+1G>C, and the remainder are mostly private. IVS9+1G>C occurs on at least three different haplotypes and thus appears to result from recurrent mutation. The phenotypic spectrum of RCDP is broader than commonly recognized and includes minimally affected individuals at the mild end of the spectrum. To relate PEX7 genotype and phenotype, we evaluated the consequence of the disease mutation on PEX7 RNA by Northern analysis and RT/PCR. We evaluated the function of the encoded Pex7 protein (Pex7p) by expressing selected alleles in fibroblasts from RCDP patients and assaying their ability to restore import of a PTS2 marker protein. We find that residual activity of mutant Pex7p and reduced amounts of normal Pex7p are associated with milder and variant phenotypes. 相似文献
73.
Characterization of translational frame exception patients in Duchenne/Becker muscular dystrophy 总被引:8,自引:3,他引:8
Winnard Alissa V.; Klein Christopher J.; Coovert Daniel D.; Prior Thomas; Papp Audrey; Snyder Pamela; Bulman Dennis E.; Ray Peter N.; McAndrew Patricia; King Wendy; Moxley Richard T.; Mendell Jerry R.; Burghes Arthur H.M. 《Human molecular genetics》1993,2(6):737-744
The clinical progression of Duchenne muscular dystrophy (DMD)patients with deletions can be predicted in 93% of cases bywhether the deletion maintains or disrupts the translationalreading frame (frameshift hypothesis). We have identified andstudied a number of patients who have deletions that do notconform to the translational frame hypothesis. The most commonexception to the frameshift hypothesis is the deletion of exons3 to 7 which disrupts the translational reading frame. We identifieda Becker muscular dystrophy (BMD) patient, an intermediate,and a DMD patient with this deletion. In all three cases, dystrophinwas detected and localized to the membrane. One DMD patientwith an inframe deletion of exons 418 produced no dystrophin.One patient with a mild intermediate phenotype and a deletionof exon 45, which shifts the reading frame, produced no dystrophin.Two patients with large inframe deletions had discordant phenotypes(exons 341, DMD; exons 1348, BMD), but both produceddystrophin that localized to the sarcolemma. The DMD patient,113, indicates that dystrophin with an intact carboxy terminuscan be produced in Duchenne patients at levels equivalent tosome Beckers. The dystrophin analysis from these patients, togetherwith patients reported in the literature, indicate that morethan one domain can localize dystrophin to the sarcolemma. Lastely,the data shows that although most patients show correlationof clinical severity to molecular data, there are rare patientswhich do not conform. 相似文献
74.
75.
Two variants of a continuous recognition training procedure were designed in order to query 2 forms of spatial memory. A continuous reinforcement condition (reflecting perceptual memory) and a differential reinforcement condition (reflecting episodic-like memory) were used to test rats on a 12-arm radial maze. After total hippocampal lesions, rats demonstrated intact performance on the continuous reinforcement condition, but impaired performance on the differential reinforcement condition. After parietal lesions, rats demonstrated the reverse pattern of performance: impaired performance on the continuous reinforcement condition and intact performance on the differential reinforcement condition. Thus, a double dissociation appears to exist between parietal cortex and hippocampus for the continuous reinforcement condition (reflecting perceptual memory) versus the differential reinforcement condition (reflecting episodic memory) for spatial location information. 相似文献
76.
Andrea M. Gross Megan Frone Karen W. Gripp Bruce D. Gelb Lisa Schoyer Lisa Schill Beth Stronach Leslie G. Biesecker Dominic Esposito Edjay Ralph Hernandez Eric Legius Mignon L. Loh Staci Martin Deborah K. Morrison Katherine A. Rauen Pamela L. Wolters Dina Zand Frank McCormick Sharon A. Savage Douglas R. Stewart Brigitte C. Widemann Marielle E. Yohe 《American journal of medical genetics. Part A》2020,182(4):866-876
RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates. 相似文献
77.
Vincent-Schneider H Stumptner-Cuvelette P Lankar D Pain S Raposo G Benaroch P Bonnerot C 《International immunology》2002,14(7):713-722
Exosomes are small vesicles (60-100 nm) secreted by various cell types upon the fusion of endosomal compartments with the plasma membrane. Exosomes from antigen-presenting cells (APC), such as B lymphocytes and dendritic cells (DC), bear MHC class II molecules. In addition, the injection of DC-derived exosomes was reported to elicit potent T cell responses in vivo. Here, we analyzed the activation of specific T cells by MHC class II-bearing exosomes in vitro. The rat mast cell line, RBL-2H3, was engineered to express human class II molecules uniformly loaded with an antigenic peptide [HLA-DR1-hemagglutinin (HA)]. These cells secreted exosomes bearing DR1 class II molecules upon stimulation by a calcium ionophore or IgE receptor cross-linking. Exosomes bearing DR1-HA(306-318) complexes activated HA/DR1-specific T cells only weakly, whereas the cross-linking of such exosomes to latex beads increased stimulation of specific T cells. By contrast, the incubation of free exosomes with DC resulted in the highly efficient stimulation of specific T cells. Thus, exosomes bearing MHC class II complexes must be taken up by professional APC for efficient T cell activation. 相似文献
78.
79.
Salmena L Lemmers B Hakem A Matysiak-Zablocki E Murakami K Au PY Berry DM Tamblyn L Shehabeldin A Migon E Wakeham A Bouchard D Yeh WC McGlade JC Ohashi PS Hakem R 《Genes & development》2003,17(7):883-895
Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans. The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption of caspase 8 is lethal in utero. We generated mice with a targeted caspase 8 mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli. caspase 8 ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria. caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency. 相似文献
80.
Monica Fonseca-Aten Pamela J Okada Karen L Bowlware Susana Chavez-Bueno Asuncion Mejias Ana Maria Rios Kathy Katz Kurt Olsen Simon Ng Hasan S Jafri George H McCracken Octavio Ramilo R Doug Hardy 《Annals of allergy, asthma & immunology》2006,97(4):457-463
BACKGROUND: Clarithromycin is postulated to possess immunomodulatory properties in addition to its antimicrobial activity. OBJECTIVE: To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing. METHODS: Children with a history of recurrent wheezing or asthma and who presented with an acute exacerbation of wheezing were enrolled in a double-blind, randomized trial of clarithromycin vs placebo. Concentrations of tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, RANTES, eotaxin, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 were measured in serum and/or nasopharyngeal aspirates before, during, and after therapy. Mycoplasma pneumoniae and Chlamydophila pneumoniae infection were evaluated for by polymerase chain reaction and serologic testing. RESULTS: Nasopharyngeal concentrations of TNF-alpha, IL-1beta, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M. pneumoniae or C. pneumoniae infection. No significant differences were detected in serum cytokines for children treated with clarithromycin compared with placebo. CONCLUSION: Clarithromycin therapy reduces mucosal TNF-alpha, IL-1beta, and IL-10 concentrations in children with an acute exacerbation of recurrent wheezing. 相似文献