41 results on '"Dreyfus DH"'
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2. Correction to: Molecular mimicry, genetic homology, and gene sharing proteomic "molecular fingerprints" using an EBV (Epstein-Barr virus)-derived microarray as a potential diagnostic method in autoimmune disease.
- Author
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Dreyfus DH, Farina A, and Farina GA
- Abstract
The below funding information was missing in the published article.
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- 2019
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3. Immediate Neutrophil-Variable-T Cell Receptor Host Response in Bacterial Meningitis.
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Fuchs T, Puellmann K, Dreyfus DH, Piehler AP, Reuter B, Schwarzbach C, Willmann O, Yepes D, Costina V, Findeisen P, Mahrt J, Wang C, Han J, Beham AW, Neumaier M, and Kaminski WE
- Abstract
Bacterial meningitis is a life-threatening disease that evokes an intense neutrophil-dominated host response to microbes invading the subarachnoid space. Recent evidence indicates the existence of combinatorial V(D)J immune receptors in neutrophils that are based on the T cell receptor (TCR). Here, we investigated expression of the novel neutrophil TCRαβ-based V(D)J receptors in cerebrospinal fluid (CSF) from human patients with acute-phase bacterial meningitis using immunocytochemical, genetic immunoprofiling, cell biological, and mass spectrometric techniques. We find that the human neutrophil combinatorial V(D)J receptors are rapidly induced in CSF neutrophils during the first hours of bacterial meningitis. Immune receptor repertoire diversity is consistently increased in CSF neutrophils relative to circulating neutrophils and phagocytosis of baits directed to the variable immunoreceptor is enhanced in CSF neutrophils during acute-phase meningitis. Our results reveal that a flexible immune response involving neutrophil V(D)J receptors which enhance phagocytosis is immediately initiated at the site of acute bacterial infection.
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- 2019
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4. Molecular mimicry, genetic homology, and gene sharing proteomic "molecular fingerprints" using an EBV (Epstein-Barr virus)-derived microarray as a potential diagnostic method in autoimmune disease.
- Author
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Dreyfus DH, Farina A, and Farina GA
- Subjects
- Animals, Antibody Formation genetics, Autoantibodies genetics, Humans, Proteomics methods, Autoimmune Diseases diagnosis, Autoimmune Diseases genetics, Herpesvirus 4, Human genetics, Molecular Mimicry genetics
- Abstract
EBV (Epstein-Barr Virus) and other human DNA viruses are associated with autoimmune syndromes in epidemiologic studies. In this work, immunoglobulin G response to EBV-encoded proteins which share regions with human immune response proteins from the human host including ZEBRA (BZLF-1 encoded protein), BALF-2 recombinase expressed primarily during the viral lytic replication cycle, and EBNA-1 (Epstein-Barr Virus Nuclear Antigen) expressed during the viral latency cycle respectively were characterized using a laser-printed micro-array ( PEPperprint.com ). IgG response to conserved "A/T hooks" in EBV-encoded proteins such as EBNA-1 and the BALF-2 recombinase related to host DNA-binding proteins including RAG-1 recombinase and histones, and EBV-encoded virokines such as the IL-10 homologue BCRF-1 suggest further directions for clinical research. The author suggests that proteomic "molecular fingerprints" of the immune response to viral proteins shared with human immune response genes are potentially useful in early diagnosis and monitoring of autoantibody production and response to therapy in EBV-related autoimmune syndromes.
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- 2018
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5. Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes.
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Farina A, Peruzzi G, Lacconi V, Lenna S, Quarta S, Rosato E, Vestri AR, York M, Dreyfus DH, Faggioni A, Morrone S, Trojanowska M, and Farina GA
- Subjects
- Adult, Aged, Blotting, Western, Cell Line, Tumor, Cells, Cultured, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections virology, Female, Gene Expression drug effects, Gene Expression immunology, Gene Expression Profiling methods, Herpesvirus 4, Human genetics, Herpesvirus 4, Human physiology, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Immunity, Innate genetics, Male, Middle Aged, Monocytes metabolism, Monocytes virology, Quinolines pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Scleroderma, Systemic genetics, Scleroderma, Systemic metabolism, Thiazoles pharmacology, Toll-Like Receptor 8 genetics, Toll-Like Receptor 8 metabolism, Virus Replication genetics, Virus Replication immunology, Virus Replication physiology, Young Adult, Epstein-Barr Virus Infections immunology, Herpesvirus 4, Human immunology, Immunity, Innate immunology, Monocytes immunology, Scleroderma, Systemic immunology, Toll-Like Receptor 8 immunology
- Abstract
Background: Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc., Methods: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells., Results: Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes., Conclusion: This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.
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- 2017
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6. Differential Diagnosis of Chronic Urticaria and Angioedema Based on Molecular Biology, Pharmacology, and Proteomics.
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Dreyfus DH
- Subjects
- Adaptive Immunity, Autoantibodies blood, Chronic Disease, Complement System Proteins metabolism, Diagnosis, Differential, Humans, Microbiota, Pathology, Molecular, Proteomics, Receptors, Pattern Recognition metabolism, Angioedema diagnosis, Urticaria diagnosis
- Abstract
Differential diagnosis of urticaria and angioedema has been based on the phenotype as either acute or chronic depending on the duration of more than 6 to 8 weeks, respectively. Additional subdivisions include poorly defined terms such as idiopathic, spontaneous, or autoimmune. In this article, the author suggests that an increased understanding of the acquired and innate immune system and data from novel proteomic technology have blurred the lines between these categories of diagnosis. Specific molecular pathways and response to specific medications should be incorporated in classification and diagnosis schemes., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2017
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7. Gene sharing between Epstein-Barr virus and human immune response genes.
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Dreyfus DH
- Subjects
- Animals, Genes, Viral, Humans, Autoimmune Diseases genetics, Herpesvirus 4, Human genetics, Molecular Mimicry, Viral Proteins genetics
- Abstract
Epstein-Barr virus (also termed HHV-4, EBV), a component of the human virome or metagenome, is associated as a co-factor in many common human autoimmune diseases through epidemiologic evidence. Numerous EBV genes are functional as well as structural homologues of important immune response genes. For example, EBV-encoded BCRF1 is a functional homologue of IL-10, a critical cytokine regulator of immune tolerance. BZLF-1, an EBV-encoded transcription factor, contains regions with functional homology to both AP-1 and NF-κB DNA binding immune response regulatory factors. The author proposes a paradigm of "gene sharing" between viral- and host-encoded proteins as extension of molecular mimicry that has been largely overlooked in animal models that consider only host genomic factors rather than viral pathogens and the metagenome. Gene sharing may trigger chaotic behavior in human autoimmune disease through unstable feedback loops and perturbations of immune tolerance.
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- 2017
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8. Genetics and Molecular Biology of Epstein-Barr Virus-Encoded BART MicroRNA: A Paradigm for Viral Modulation of Host Immune Response Genes and Genome Stability.
- Author
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Dreyfus DH
- Subjects
- Animals, Epstein-Barr Virus Infections genetics, Genomic Instability, Host-Pathogen Interactions, Humans, Immunity, NF-kappa B genetics, NF-kappa B metabolism, Trans-Activators metabolism, Epstein-Barr Virus Infections immunology, Herpesvirus 4, Human genetics, Immunomodulation, MicroRNAs genetics, RNA, Viral genetics
- Abstract
Epstein-Barr virus, a ubiquitous human herpesvirus, is associated through epidemiologic evidence with common autoimmune syndromes and cancers. However, specific genetic mechanisms of pathogenesis have been difficult to identify. In this review, the author summarizes evidence that recently discovered noncoding RNAs termed microRNA encoded by Epstein-Barr virus BARF (BamHI A right frame) termed BART (BamHI A right transcripts) are modulators of human immune response genes and genome stability in infected and bystander cells. BART expression is apparently regulated by complex feedback loops with the host immune response regulatory NF- κ B transcription factors. EBV-encoded BZLF-1 (ZEBRA) protein could also regulate BART since ZEBRA contains a terminal region similar to ankyrin proteins such as I κ B α that regulate host NF- κ B. BALF-2 (BamHI A left frame transcript), a viral homologue of the immunoglobulin and T cell receptor gene recombinase RAG-1 (recombination-activating gene-1), may also be coregulated with BART since BALF-2 regulatory sequences are located near the BART locus. Viral-encoded microRNA and viral mRNA transferred to bystander cells through vesicles, defective viral particles, or other mechanisms suggest a new paradigm in which bystander or hit-and-run mechanisms enable the virus to transiently or chronically alter human immune response genes as well as the stability of the human genome.
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- 2017
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9. Serological evidence that activation of ubiquitous human herpesvirus-6 (HHV-6) plays a role in chronic idiopathic/spontaneous urticaria (CIU).
- Author
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Dreyfus DH
- Subjects
- Adult, Antibodies, Viral blood, Autoimmune Diseases immunology, Autoimmune Diseases virology, Drug Hypersensitivity Syndrome immunology, Drug Hypersensitivity Syndrome virology, Female, Herpesvirus 4, Human genetics, Herpesvirus 4, Human immunology, Herpesvirus 6, Human genetics, Humans, Male, Middle Aged, Omalizumab therapeutic use, Urticaria drug therapy, Urticaria physiopathology, Virus Latency, Herpesviridae Infections immunology, Herpesviridae Infections virology, Herpesvirus 6, Human immunology, Herpesvirus 6, Human physiology, Urticaria immunology, Urticaria virology, Virus Activation
- Abstract
Acute infection with viral pathogens in the herpesviridae family can trigger acute urticaria, and reactivation of herpesviridae is associated with cutaneous urticarial-like syndromes such as drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS). Reactivation of latent herpesviridae has not been studied systematically in chronic idiopathic/spontaneous urticaria (CIU). This review proposes that CIU is an inflammatory disorder with autoimmune features (termed 'CVU' for chronic viral urticaria), based on serology consistent with the hypothesis that reactivation of a latent herpesvirus or -viruses may play a role in CIU. Serology obtained from a cohort of omalizumab (Xolair)-dependent patients with severe CIU was consistent with previous HHV-6 infection, persistent viral gene expression and replication. CIU patients also exhibited serological evidence of increased immune response to HHV-4 (Epstein-Barr virus, or EBV) but not all CIU patients were infected with EBV. These observations, combined with case reports of CIU response to anti-viral therapy, suggest that HHV-6, possibly interacting with HHV-4 in cutaneous tissues, is a candidate for further prospective study as a co-factor in CIU., (© 2015 British Society for Immunology.)
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- 2016
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10. Gene silencing and related oligonucleotide therapies for TH2-promoting cytokines.
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Dreyfus DH
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- Animals, Humans, Hypersensitivity immunology, Hypersensitivity metabolism, Receptors, Cytokine metabolism, Th2 Cells immunology, Th2 Cells metabolism
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- 2014
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11. HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses.
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Yan Z, Bryant KF, Gregory SM, Angelova M, Dreyfus DH, Zhao XZ, Coen DM, Burke TR Jr, and Knipe DM
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- Cell Line, Cytomegalovirus drug effects, Herpesvirus 1, Human drug effects, Herpesvirus 2, Human drug effects, Herpesvirus 8, Human drug effects, Humans, Virus Replication drug effects, Antiviral Agents pharmacology, HIV Integrase Inhibitors pharmacology, Simplexvirus drug effects
- Abstract
The catalytic site of the HIV integrase is contained within an RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two proteins with potential RNase H-like folds, the infected cell protein 8 (ICP8) DNA-binding protein, which is necessary for viral DNA replication and exhibits recombinase activity in vitro, and the viral terminase, which is essential for viral DNA cleavage and packaging. Therefore, we hypothesized that HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the terminase. To test this, we evaluated the effect of 118-D-24, a potent HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 µM, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 µM. XZ45 blocked HSV viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8 recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of Kaposi's sarcoma herpesvirus from latent infection. Our results argue that inhibitors of enzymes with RNase H-like folds may represent a general antiviral strategy, which is useful not only against HIV but also against herpesviruses. Importance: The herpesviruses cause considerable morbidity and mortality. Nucleoside analogs have served as effective antiviral agents against the herpesviruses, but resistance can arise through viral mutation. Second-line anti-herpes drugs have limitations in terms of pharmacokinetic properties and/or toxicity, so there is a great need for additional drugs for treatment of herpesviral infections. This study showed that the HIV integrase inhibitors also block herpesviral infection, raising the important potential of a new class of anti-herpes drugs and the prospect of drugs that combat both HIV and the herpesviruses., (Copyright © 2014 Yan et al.)
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- 2014
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12. Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers.
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Dreyfus DH, Na CR, Randolph CC, Kearney D, Price C, and Podell D
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- Adult, Autoantibodies blood, Female, Humans, Lymphocyte Depletion methods, Monitoring, Immunologic, Remission Induction, Rituximab, Treatment Outcome, Angioedema drug therapy, Angioedema etiology, Angioedema immunology, Angioedema physiopathology, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antiphospholipid Syndrome complications, Complement C1 Inhibitor Protein immunology, Immunologic Factors administration & dosage, Myasthenia Gravis complications
- Published
- 2014
13. Herpesviruses and the microbiome.
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Dreyfus DH
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- Animals, Child, Gene-Environment Interaction, Herpesviridae Infections complications, Humans, Hypersensitivity complications, Immunomodulation, Skin pathology, Skin virology, Herpesviridae immunology, Herpesviridae Infections immunology, Hypersensitivity immunology, Microbiota immunology, Skin immunology
- Abstract
The focus of this article will be to examine the role of common herpesviruses as a component of the microbiome of atopic patients and to review clinical observations suggesting that atopic patients might be predisposed to more severe and atypical herpes-related illness because their immune response is biased toward a TH2 cytokine profile. Human populations are infected with 8 herpesviruses, including herpes simplex virus HSV1 and HSV2 (also termed HHV1 and HHV2), varicella zoster virus (VZV or HHV3), EBV (HHV4), cytomegalovirus (HHV5), HHV6, HHV7, and Kaposi sarcoma-associated herpesvirus (termed KSV or HHV8). Herpesviruses are highly adapted to lifelong infection of their human hosts and thus can be considered a component of the human "microbiome" in addition to their role in illness triggered by primary infection. HSV1 and HSV2 infection and reactivation can present with more severe cutaneous symptoms termed eczema herpeticum in the atopic population, similar to the more severe eczema vaccinatum, and drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) is associated with reactivation of HSV6 and possibly other herpesviruses in both atopic and nonatopic patients. In this review evidence is reviewed that primary infection with herpesviruses may have an atypical presentation in the atopic patient and conversely that childhood infection might alter the atopic phenotype. Reactivation of latent herpesviruses can directly alter host cytokine profiles through viral expression of cytokine-like proteins, such as IL-10 (EBV) or IL-6 (cytomegalovirus and HHV8), viral encoded and secreted siRNA and microRNAs, and modulation of expression of host transcription pathways, such as nuclear factor κB. Physicians caring for allergic and atopic populations should be aware of common and uncommon presentations of herpes-related disease in atopic patients to provide accurate diagnosis and avoid unnecessary laboratory testing or incorrect diagnosis of other conditions, such as drug allergy or autoimmune disease. Antiviral therapy and vaccines should be administered promptly when indicated clinically., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2013
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14. Urticaria & angioedema: a rational approach to diagnosis and therapy.
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Dreyfus DH
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- Angioedema etiology, Diagnosis, Differential, Humans, Severity of Illness Index, Time Factors, Urticaria etiology, Angioedema diagnosis, Angioedema drug therapy, Histamine Antagonists therapeutic use, Urticaria diagnosis, Urticaria drug therapy
- Abstract
Urticaria and angioedema are common allergic manifestations and some forms of this disorder may be increasing in both prevalence and severity due to changes in medications, environment and other unknown factors. This review focuses on a rational approach to differential diagnosis and therapy of the most common forms of urticaria and angioedema.
- Published
- 2013
15. Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication.
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Bryant KF, Yan Z, Dreyfus DH, and Knipe DM
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- Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Cell Line, Chlorocebus aethiops, Conserved Sequence, DNA-Binding Proteins genetics, Herpesvirus 1, Human chemistry, Herpesvirus 1, Human genetics, Humans, Molecular Sequence Data, Mutation, Missense, Sequence Alignment, Vero Cells, Viral Proteins genetics, Cations, Divalent metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Herpes Simplex virology, Herpesvirus 1, Human physiology, Viral Proteins chemistry, Viral Proteins metabolism, Virus Replication
- Abstract
Herpes simplex virus 1 (HSV-1) ICP8 is a single-stranded DNA-binding protein that is necessary for viral DNA replication and exhibits recombinase activity in vitro. Alignment of the HSV-1 ICP8 amino acid sequence with ICP8 homologs from other herpesviruses revealed conserved aspartic acid (D) and glutamic acid (E) residues. Amino acid residue D1087 was conserved in every ICP8 homolog analyzed, indicating that it is likely critical for ICP8 function. We took a genetic approach to investigate the functions of the conserved ICP8 D and E residues in HSV-1 replication. The E1086A D1087A mutant form of ICP8 failed to support the replication of an ICP8 mutant virus in a complementation assay. E1086A D1087A mutant ICP8 bound DNA, albeit with reduced affinity, demonstrating that the protein is not globally misfolded. This mutant form of ICP8 was also recognized by a conformation-specific antibody, further indicating that its overall structure was intact. A recombinant virus expressing E1086A D1087A mutant ICP8 was defective in viral replication, viral DNA synthesis, and late gene expression in Vero cells. A class of enzymes called DDE recombinases utilize conserved D and E residues to coordinate divalent metal cations in their active sites. We investigated whether the conserved D and E residues in ICP8 were also required for binding metal cations and found that the E1086A D1087A mutant form of ICP8 exhibited altered divalent metal binding in an in vitro iron-induced cleavage assay. These results identify a novel divalent metal cation-binding site in ICP8 that is required for ICP8 functions during viral replication.
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- 2012
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16. Monitoring of thyroid function in patients who exhibit IgE against thyroperoxidase while taking omalizumab?
- Author
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Dreyfus DH
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- Female, Humans, Male, Anti-Allergic Agents therapeutic use, Antibodies, Anti-Idiotypic therapeutic use, Antibodies, Monoclonal therapeutic use, Autoantibodies blood, Autoantigens immunology, Urticaria drug therapy
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- 2012
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17. Autoimmune disease: A role for new anti-viral therapies?
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Dreyfus DH
- Subjects
- Antibodies, Monoclonal, Murine-Derived administration & dosage, Antibodies, Monoclonal, Murine-Derived therapeutic use, Autoimmunity genetics, B-Lymphocytes immunology, B-Lymphocytes virology, Chronic Disease, Endogenous Retroviruses drug effects, Endogenous Retroviruses immunology, Endogenous Retroviruses metabolism, Epstein-Barr Virus Infections drug therapy, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human drug effects, Herpesvirus 4, Human genetics, Herpesvirus 4, Human immunology, Humans, Immunologic Memory drug effects, Integrase Inhibitors, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic virology, Lymphoproliferative Disorders, Multiple Sclerosis drug therapy, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Multiple Sclerosis virology, Pyrrolidinones, RNA, Small Interfering genetics, RNA, Small Interfering pharmacology, Raltegravir Potassium, Rituximab, Urticaria genetics, Urticaria immunology, Urticaria virology, Viral Vaccines administration & dosage, Viral Vaccines therapeutic use, Antiviral Agents therapeutic use, Autoimmunity immunology, B-Lymphocytes drug effects, Epstein-Barr Virus Infections prevention & control, Lupus Erythematosus, Systemic prevention & control, Multiple Sclerosis prevention & control, Urticaria drug therapy, Vaccination
- Abstract
Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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18. Analysis of an ankyrin-like region in Epstein Barr Virus encoded (EBV) BZLF-1 (ZEBRA) protein: implications for interactions with NF-κB and p53.
- Author
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Dreyfus DH, Liu Y, Ghoda LY, and Chang JT
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- Amino Acid Sequence, Ankyrins genetics, Ankyrins metabolism, Binding Sites genetics, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections epidemiology, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human immunology, Humans, Models, Molecular, Molecular Sequence Data, NF-kappa B genetics, Phylogeny, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary genetics, Sequence Alignment, Trans-Activators genetics, Trans-Activators metabolism, Transcription, Genetic, Tumor Suppressor Protein p53 genetics, Ankyrins chemistry, Epstein-Barr Virus Infections diagnosis, Herpesvirus 4, Human genetics, NF-kappa B metabolism, Trans-Activators chemistry, Tumor Suppressor Protein p53 metabolism
- Abstract
Background: The carboxyl terminal of Epstein-Barr virus (EBV) ZEBRA protein (also termed BZLF-1 encoded replication protein Zta or ZEBRA) binds to both NF-κB and p53. The authors have previously suggested that this interaction results from an ankyrin-like region of the ZEBRA protein since ankyrin proteins such as IκB interact with NF-κB and p53 proteins. These interactions may play a role in immunopathology and viral carcinogenesis in B lymphocytes as well as other cell types transiently infected by EBV such as T lymphocytes, macrophages and epithelial cells., Methods: Randomization of the ZEBRA terminal amino acid sequence followed by statistical analysis suggest that the ZEBRA carboxyl terminus is most closely related to ankyrins of the invertebrate cactus IκB-like protein. This observation is consistent with an ancient origin of ZEBRA resulting from a recombination event between an ankyrin regulatory protein and a fos/jun DNA binding factor. In silico modeling of the partially solved ZEBRA carboxyl terminus structure using PyMOL software demonstrate that the carboxyl terminus region of ZEBRA can form a polymorphic structure termed ZANK (ZEBRA ANKyrin-like region) similar to two adjacent IκB ankyrin domains., Conclusions: Viral capture of an ankyrin-like domain provides a mechanism for ZEBRA binding to proteins in the NF-κB and p53 transcription factor families, and also provides support for a process termed "Ping-Pong Evolution" in which DNA viruses such as EBV are formed by exchange of information with the host genome. An amino acid polymorphism in the ZANK region is identified in ZEBRA from tumor cell lines including Akata that could alter binding of Akata ZEBRA to the p53 tumor suppressor and other ankyrin binding protein, and a novel model of antagonistic binding interactions between ZANK and the DNA binding regions of ZEBRA is suggested that may be explored in further biochemical and molecular biological models of viral replication.
- Published
- 2011
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19. Immune system: success owed to a virus?
- Author
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Dreyfus DH
- Subjects
- Antibody Formation, Genes, RAG-1, Herpesviridae physiology, DNA Viruses physiology, Immune System physiology
- Published
- 2009
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20. Paleo-immunology: evidence consistent with insertion of a primordial herpes virus-like element in the origins of acquired immunity.
- Author
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Dreyfus DH
- Subjects
- Amino Acid Sequence, B-Lymphocytes metabolism, Base Sequence, Cell Line, DNA Transposable Elements, DNA-Binding Proteins metabolism, Herpesviridae genetics, Herpesvirus 4, Human genetics, Homeodomain Proteins metabolism, Humans, Molecular Sequence Data, Nuclear Proteins metabolism, Paleontology methods, Ribonuclease H metabolism, Sequence Homology, Nucleic Acid, Simplexvirus genetics, T-Lymphocytes metabolism, VDJ Recombinases metabolism, Herpesviridae metabolism, Immunity
- Abstract
Background: The RAG encoded proteins, RAG-1 and RAG-2 regulate site-specific recombination events in somatic immune B- and T-lymphocytes to generate the acquired immune repertoire. Catalytic activities of the RAG proteins are related to the recombinase functions of a pre-existing mobile DNA element in the DDE recombinase/RNAse H family, sometimes termed the "RAG transposon"., Methodology/principal Findings: Novel to this work is the suggestion that the DDE recombinase responsible for the origins of acquired immunity was encoded by a primordial herpes virus, rather than a "RAG transposon." A subsequent "arms race" between immunity to herpes infection and the immune system obscured primary amino acid similarities between herpes and immune system proteins but preserved regulatory, structural and functional similarities between the respective recombinase proteins. In support of this hypothesis, evidence is reviewed from previous published data that a modern herpes virus protein family with properties of a viral recombinase is co-regulated with both RAG-1 and RAG-2 by closely linked cis-acting co-regulatory sequences. Structural and functional similarity is also reviewed between the putative herpes recombinase and both DDE site of the RAG-1 protein and another DDE/RNAse H family nuclease, the Argonaute protein component of RISC (RNA induced silencing complex)., Conclusions/significance: A "co-regulatory" model of the origins of V(D)J recombination and the acquired immune system can account for the observed linked genomic structure of RAG-1 and RAG-2 in non-vertebrate organisms such as the sea urchin that lack an acquired immune system and V(D)J recombination. Initially the regulated expression of a viral recombinase in immune cells may have been positively selected by its ability to stimulate innate immunity to herpes virus infection rather than V(D)J recombination Unlike the "RAG-transposon" hypothesis, the proposed model can be readily tested by comparative functional analysis of herpes virus replication and V(D)J recombination.
- Published
- 2009
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21. Gene silencing in the therapy of influenza and other respiratory diseases: Targeting to RNase P by use of External Guide Sequences (EGS).
- Author
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Dreyfus DH, Tompkins SM, Fuleihan R, and Ghoda LY
- Abstract
Respiratory diseases provide an attractive target for gene silencing using small nucleic acids since the respiratory epithelium can be reached by inhalation therapy. Natural surfactant appears to facilitate the uptake and distribution of these types of molecules making aerosolized nucleic acids a possible new class of therapeutics. This article will review the rationale for the use of External Guide Sequence (EGS) in targeting specific mRNA molecules for RNase P-mediated intracellular destruction. Specific destruction of target mRNA results in gene-specific silencing similar to that instigated by siRNA via the RISC complex. The application of EGS molecules specific for influenza genes are discussed as well as the potential for synergy with siRNA. Furthermore, EGS could be adapted to target other respiratory diseases of viral etiology as well as conditions such as asthma.
- Published
- 2007
22. A review of recent patents concerning therapy of respiratory diseases using gene silencing by RNAi (RISC) and EGS (RNAse P).
- Author
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Dreyfus DH and Ghoda L
- Subjects
- Animals, Base Sequence, Humans, Inflammation genetics, Inflammation therapy, Patents as Topic, RNA, Messenger metabolism, RNA-Induced Silencing Complex metabolism, Respiratory Mucosa pathology, Respiratory Tract Diseases genetics, RNA Interference, Respiratory Tract Diseases therapy, Ribonuclease P metabolism
- Abstract
This article will review recent developments in the field of gene silencing as a therapy for respiratory and related inflammatory and immunologic diseases. The respiratory epithelium offers an attractive target for therapies derived from nucleic acids since the respiratory epithelium contains endogenous lipids that can facilitate uptake of polar nucleic acids and related compounds. Both RNAi (RNA Interference) in which a messenger RNA (mRNA) is targeted by an endogenous enzyme complex termed RISC (RNA Interference Silencing Complex, also previously termed RNA Induced Silencing Complex in earlier references) and also gene silencing using EGS (External Guide Sequences) in which a messenger RNA (mRNA) is targeted by an endogenous RNA enzyme termed RNase P are summarized including selected patents. The strengths and limitations of these technologies such as problems of delivery to specific tissues and potential for non-specific inflammatory response and off-targeting are compared. The possibility of therapy designed exploit synergies between both RISC and RNAse P and therapeutic benefits of inhibiting either or both pathways are also considered.
- Published
- 2007
- Full Text
- View/download PDF
23. The DDE recombinases: diverse roles in acquired and innate immunity.
- Author
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Dreyfus DH
- Subjects
- Animals, Homeodomain Proteins metabolism, Homeodomain Proteins physiology, Humans, Integrases metabolism, Integrases physiology, Models, Molecular, RNA-Induced Silencing Complex metabolism, RNA-Induced Silencing Complex physiology, Recombinases physiology, VDJ Recombinases metabolism, VDJ Recombinases physiology, Immunity physiology, Immunity, Innate physiology, Recombinases metabolism
- Abstract
Background: The RAG proteins required for V(D)J recombination of immunoglobulin and T-cell receptor genes in the acquired immune response contain a magnesium ion-binding site termed a DDE site, composed of D (aspartic acid) and E (glutamic acid) amino acids. A similar DDE-like magnesium binding site also is present in transposases, retroviral integrases, and the innate antiviral response enzymes RNAse H and RNA-induced silencing complex (RISC)., Objective: To help clinicians understand immunodeficiency that results from deficiencies of RAG protein functions, such as severe combined immunodeficiency disorders, Omenn syndrome, and ataxia telangiectasia, and to be familiar with the diverse roles of other DDE enzymes., Methods: Literature published in peer-reviewed journals during the past 2 decades that identified and characterized DDE enzymes, including RAG proteins, RISC and RNA silencing, RNAse H, retroviral integrases, transposases, and a putative DDE recombinase required for herpes virus replication, was selectively reviewed and summarized by the author., Results: DDE enzymes play a critical role in acquired immunity through RAG-mediated immunoglobulin and T-cell receptor V(D)J recombination in innate immunity through RISC and RNAse H. Paradoxically, DDE enzymes are critical components of pathogen-specific enzymes such as retroviral integrase and other pathogen-encoded proteins., Conclusion: Because of their critical role in acquired and innate immunity, the DDE recombinases are attractive targets for novel pharmacologic therapies. Currently, retroviral integrase inhibitors in clinical trial for human immunodeficiency virus infection appear to be safe and effective and could provide a paradigm for inactivating DDE sites in other viral pathogens, as well as RAG and RISC.
- Published
- 2006
- Full Text
- View/download PDF
24. Characterization of an anaphylactoid reaction to omalizumab.
- Author
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Dreyfus DH and Randolph CC
- Subjects
- Adult, Angioedema drug therapy, Angioedema immunology, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Humanized, Asthma drug therapy, Asthma immunology, Female, Humans, Ibuprofen therapeutic use, Omalizumab, Rhinitis, Allergic, Perennial drug therapy, Rhinitis, Allergic, Perennial immunology, Urticaria drug therapy, Urticaria immunology, Anaphylaxis chemically induced, Anti-Allergic Agents adverse effects, Anti-Asthmatic Agents adverse effects, Antibodies, Monoclonal adverse effects, Desensitization, Immunologic, Drug Hypersensitivity, Serum Sickness etiology
- Abstract
Background: The novel humanized murine monoclonal antibody omalizumab prevents binding of human IgE to its high-affinity receptor. A contraindication to therapy with omalizumab is allergy to the medication or previous immediate-type hypersensitivity or anaphylaxis to omalizumab or similar medications., Objective: To determine whether a 32-year-old woman with asthma, allergic rhinitis, and idiopathic chronic urticaria and angioedema with anaphylactoid reactions to omalizumab could tolerate the medication in a desensitization protocol., Methods: Omalizumab was administered after pretreatment with nonsteroidal anti-inflammatory drugs (ibuprofen, 600 mg) while the patient was closely monitored in an intensive care unit., Results: Omalizumab was well tolerated using this protocol, but a serum sickness-like reaction developed that required discontinuation of the medication after the seventh dose., Conclusions: Our experience suggests that some patients with anaphylactoid reactions to omalizumab can tolerate the medication when pretreated with nonsteroidal anti-inflammatory drugs but that a serum sickness-like illness may develop, requiring discontinued use of the medication.
- Published
- 2006
- Full Text
- View/download PDF
25. Role of T cells in EBV-infected systemic lupus erythematosus patients.
- Author
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Dreyfus DH
- Subjects
- DNA-Binding Proteins genetics, DNA-Binding Proteins physiology, Epstein-Barr Virus Infections etiology, Gene Expression Regulation, Humans, Lupus Erythematosus, Systemic etiology, Lupus Erythematosus, Systemic immunology, Receptors, Complement 3d genetics, T-Lymphocytes immunology, Trans-Activators genetics, Trans-Activators physiology, Viral Proteins genetics, Viral Proteins physiology, Epstein-Barr Virus Infections immunology, Lupus Erythematosus, Systemic virology, T-Lymphocytes virology
- Published
- 2005
- Full Text
- View/download PDF
26. Modulation of p53 activity by IkappaBalpha: evidence suggesting a common phylogeny between NF-kappaB and p53 transcription factors.
- Author
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Dreyfus DH, Nagasawa M, Gelfand EW, and Ghoda LY
- Subjects
- Amino Acid Sequence, Animals, Ankyrin Repeat, Binding Sites, Burkitt Lymphoma pathology, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Consensus Sequence, Humans, I-kappa B Proteins genetics, I-kappa B Proteins metabolism, Models, Molecular, Molecular Sequence Data, Multigene Family, Mutagenesis, NF-KappaB Inhibitor alpha, Phylogeny, Protein Conformation, Protein Interaction Mapping, Protein Structure, Tertiary, Recombinant Fusion Proteins metabolism, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Transcription, Genetic, Transfection, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Evolution, Molecular, I-kappa B Proteins chemistry, Transcription Factor RelA chemistry, Tumor Suppressor Protein p53 chemistry
- Abstract
Background: In this work we present evidence that the p53 tumor suppressor protein and NF-kappaB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apoptosis. P53 is a homotetrameric transcription factor known to interact with the ankyrin protein 53BP2 (a fragment of the ASPP2 protein). NF-kappaB is also regulated by ankyrin proteins, the prototype of which is the IkappaB family. The DNA binding sequences of the two transcription factors are similar, sharing 8 out of 10 nucleotides. Interactions between the two proteins, both direct and indirect, have been noted previously and the two proteins play central roles in the control of proliferation and apoptosis., Results: Using previously published structure data, we noted a significant degree of structural alignment between p53 and NF-kappaB p65. We also determined that IkappaBalpha and p53 bind in vitro through a specific interaction in part involving the DNA binding region of p53, or a region proximal to it, and the amino terminus of IkappaBalpha independently or cooperatively with the ankyrin 3 domain of IkappaBalpha In cotransfection experiments, kappaBalpha could significantly inhibit the transcriptional activity of p53. Inhibition of p53-mediated transcription was increased by deletion of the ankyrin 2, 4, or 5 domains of IkappaBalpha Co-precipitation experiments using the stably transfected ankyrin 5 deletion mutant of kappaBalpha and endogenous wild-type p53 further support the hypothesis that p53 and IkappaBalpha can physically interact in vivo., Conclusion: The aggregate results obtained using bacterially produced IkappaBalpha and p53 as well as reticulocyte lysate produced proteins suggest a correlation between in vitro co-precipitation in at least one of the systems and in vivo p53 inhibitory activity. These observations argue for a mechanism involving direct binding of IkappaBalpha to p53 in the inhibition of p53 transcriptional activity, analogous to the inhibition of NF-kappaB by kappaBalpha and p53 by 53BP2/ASPP2. These data furthermore suggest a role for ankyrin proteins in the regulation of p53 activity. Taken together, the NFkappaB and p53 proteins share similarities in structure, DNA binding sites and binding and regulation by ankyrin proteins in support of our hypothesis that the two proteins share common descent from an ancestral transcriptional factor.
- Published
- 2005
- Full Text
- View/download PDF
27. An RNA external guide sequence ribozyme targeting human interleukin-4 receptor alpha mRNA.
- Author
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Dreyfus DH, Matczuk A, and Fuleihan R
- Subjects
- Administration, Inhalation, Animals, Base Sequence, Cell Line, Tumor, Humans, Interleukin-13 genetics, Interleukin-13 metabolism, Mice, Nucleic Acid Conformation, Protein Subunits biosynthesis, Protein Subunits genetics, Receptors, Interleukin-4 metabolism, Ribonuclease P metabolism, DNA, Antisense administration & dosage, RNA, Catalytic genetics, RNA, Messenger genetics, Receptors, Interleukin-4 genetics
- Abstract
RNA oligonucleotides termed External Guide Sequence (EGS) and RNAi have been described that target specific gene expression by site-specific cleavage of mRNA. EGS serve as an RNA catalyst or ribozyme by directing bound mRNA to the ubiquitous cellular enzyme RNAse P. We describe an EGS targeting human interleukin (IL)-4 receptor alpha mRNA, an important cytokine receptor in the pathogenesis of asthma and allergic disease expressed in pulmonary tissues. This EGS was designed to explore pulmonary delivery of catalytic RNA oligonucleotides as a novel therapy in asthma and other atopic diseases. Inhaled DNA oligonucleotides termed Respirable Antisense OligoNucleotide Sequences (RASONS) are selectively internalized in lung tissues in a complex with endogenous lipid surfactants present in normal lung and can alter pulmonary gene expression. Potential applications of inhaled RNA oligonucleotides in therapy of pulmonary and related systemic diseases are discussed.
- Published
- 2004
- Full Text
- View/download PDF
28. Anaphylaxis to latex in patients without identified risk factors for latex allergy.
- Author
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Dreyfus DH, Fraser B, and Randolph CC
- Subjects
- Adult, Anaphylaxis diagnosis, Connecticut epidemiology, Cost-Benefit Analysis, Elective Surgical Procedures, Humans, Intraoperative Complications diagnosis, Latex Hypersensitivity epidemiology, Male, Mass Screening economics, Mass Screening methods, Prevalence, Radioallergosorbent Test, Risk Factors, Skin Tests, Time Factors, Anaphylaxis etiology, Intraoperative Complications etiology, Latex Hypersensitivity diagnosis, Rubber adverse effects
- Abstract
We describe a representative patient diagnosed with anaphylaxis to latex occurring during elective surgery in the absence of any previous risk factors for latex allergy. Latex allergy was identified by skin prick testing and confirmed by serological diagnosis testing. We review our experience screening patients for latex allergy in Connecticut over the period 1995-present. Patients without known risk factors for latex allergy in a highly atopic population had a low rate (approximately 1%) of positive skin tests to latex when screened using an allergenic extract characterized for latex allergen by serological diagnosis at 200-500 AU/ml. Our experience suggests that skin prick test screening with serological diagnosis standardized latex extracts can be used to rapidly screen and identify individuals with latex allergy although the cost-effectiveness, sensitivity and safety of screening remains to be determined. Clinicians should consider the diagnosis of latex allergy in all cases of anaphylaxis without identified causes, even in patients without identified risk factors for latex allergy.
- Published
- 2004
29. The syndrome of thyroid autoimmunity and idiopathic chronic urticaria and angioedema presenting as anaphylaxis.
- Author
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Dreyfus DH, Fraser B, and Randolph CC
- Subjects
- Anaphylaxis diagnosis, Anti-Bacterial Agents adverse effects, Autoimmune Diseases diagnosis, Chronic Disease, Diagnosis, Differential, Drug Hypersensitivity diagnosis, Female, Food Hypersensitivity diagnosis, Humans, Middle Aged, Shellfish adverse effects, Syndrome, Thyroid Diseases diagnosis, Anaphylaxis etiology, Angioedema complications, Autoimmune Diseases complications, Thyroid Diseases complications, Urticaria complications
- Abstract
Previous observations have shown that the syndrome of thyroid autoimmunity and idiopathic urticaria and angioedema (ICUA) can be associated with a marked worsening of reactive airway disease. Possibly, mediators released in this syndrome may contribute to acute bronchospasm and associated respiratory symptoms in some patients. In this study, two patients presenting with overlapping clinical presentations of the syndrome of thyroid immunity and ICUA are described in whom a diagnosis of anaphylaxis to food and antibiotics, respectively, was initially suspected but ruled out by testing and challenges. These cases illustrate clinical overlap between presentations of ICUA and anaphylaxis. We suggest that patients with idiopathic anaphylaxis be evaluated for the presence of antithyroid microsomal (peroxidase) antibodies or antithyroglobulin antibodies, particularly because the diagnosis of thyroid antibody-positive ICUA may suggest additional therapeutic options.
- Published
- 2003
30. Stable expression of Epstein-Barr virus BZLF-1-encoded ZEBRA protein activates p53-dependent transcription in human Jurkat T-lymphoblastoid cells.
- Author
-
Dreyfus DH, Nagasawa M, Kelleher CA, and Gelfand EW
- Subjects
- Apoptosis, Cell Nucleus metabolism, Cytoplasm metabolism, DNA-Binding Proteins analysis, Humans, Trans-Activators analysis, Transfection, Tumor Suppressor Protein p53 physiology, DNA-Binding Proteins genetics, Gene Expression, Genes, p53 genetics, Jurkat Cells metabolism, Trans-Activators genetics, Transcription, Genetic, Viral Proteins
- Abstract
Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection. (Blood. 2000;96:625-634)
- Published
- 2000
31. Inactivation of NF-kappaB by EBV BZLF-1-encoded ZEBRA protein in human T cells.
- Author
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Dreyfus DH, Nagasawa M, Pratt JC, Kelleher CA, and Gelfand EW
- Subjects
- DNA-Binding Proteins genetics, Humans, Jurkat Cells, Protein Binding, Recombinant Proteins metabolism, Trans-Activators genetics, Transfection, Viral Proteins genetics, DNA-Binding Proteins metabolism, Herpesvirus 4, Human genetics, NF-kappa B antagonists & inhibitors, T-Lymphocytes virology, Trans-Activators metabolism, Viral Proteins metabolism
- Abstract
We have previously shown that the EBV ZEBRA protein (also denoted EB1, Z, or Zta) encoded by the BZLF open reading frame is expressed in primary human thymocytes and in human T lymphoblastoid cell lines infected by EBV. Expression of EBV-encoded gene products in T lymphocytes could contribute to viral pathogenesis during acute EBV infection as well as in individuals coinfected with EBV and HIV. HPB-ALL and Jurkat T lymphoblastoid cell lines transiently and stably expressing ZEBRA were characterized in this work. Expression of ZEBRA protein in human T lymphoblastoid cells was associated with decreased expression of an NF-kappaB reporter gene, altered expression of the NF-kappaB p50 protein subunit, and decreased DNA binding by components of NF-kappaB. These observations suggest that inactivation of NF-kappaB transcription by ZEBRA in EBV-infected T cells may be a novel mechanism of viral pathogenesis analogous in part to over-expression of the endogenous cytoplasmic inhibitor of NF-kappaB, IkappaBalpha.
- Published
- 1999
32. Asymmetric DDE (D35E)-like sequences in the RAG proteins: implications for V(D)J recombination and retroviral pathogenesis.
- Author
-
Dreyfus DH, Jones JF, and Gelfand EW
- Subjects
- Amino Acid Sequence, Animals, Conserved Sequence, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Homeodomain Proteins chemistry, Humans, Molecular Sequence Data, Nuclear Proteins, Homeodomain Proteins metabolism, Metals metabolism, Models, Biological, Recombination, Genetic, Retroviridae pathogenicity
- Abstract
Experimental evidence suggests that the mechanism of vertebrate V(D)J recombination catalyzed by the vertebrate RAG proteins is similar to both retroviral integration and the transposition of IS630/Tc1-family transposons. The mechanism of both retroviral integration and IS630/Tc1 element transposition is well characterized and utilizes a functional metal ion binding site termed the DDE (or D35E) motif. We have previously identified a DDE-like region in the RAG-2 protein and a similar region within the RAG-1 protein. In this work, we propose that interference between DDE-like regions in the RAG proteins and the DDE-site of the HIV integrase may be a mechanism of retroviral pathogenesis in cells in which both the RAG proteins and retroviral integrase are co-expressed.
- Published
- 1999
- Full Text
- View/download PDF
33. Comparative analysis of invertebrate Tc6 sequences that resemble the vertebrate V(D)J recombination signal sequences (RSS).
- Author
-
Dreyfus DH and Gelfand EW
- Subjects
- Animals, Base Sequence, Caenorhabditis elegans genetics, Chromosome Inversion, DNA Transposable Elements, Gene Deletion, Genes, RAG-1 genetics, Genes, RAG-1 immunology, Models, Genetic, Molecular Sequence Data, Plasmids, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins immunology, Gene Rearrangement
- Abstract
Invertebrate cells lack the p53 recombination checkpoint but contain mobile DNA sequences that transpose by a mechanism in part shared with excision of the V(D)J recombination signal sequences (RSS). In this work, inversion, deletion, and duplication of sequences associated with an invertebrate C. elegans Tc6 element is described. The structure of this C. elegans sequence and other dispersed Tc6 elements suggests that covalently closed 'hairpin' structures are not unique to excision of the V(D)J RSS by the RAG proteins, but rather can be generated by transposases at transposon termini leading to characteristic inversion and duplication events. Comparative analysis of recombination events at invertebrate sequences resembling the vertebrate V(D)J RSS may be useful in understanding V(D)J recombination-mediated recombination events in malignant vertebrate cells or genetic diseases such as ataxia telangectasia, in which the p53 recombination checkpoint is defective.
- Published
- 1999
- Full Text
- View/download PDF
34. EBV infection of T cells: potential role in malignant transformation.
- Author
-
Kelleher CA, Dreyfus DH, Jones JF, and Gelfand EW
- Subjects
- B-Lymphocytes enzymology, B-Lymphocytes virology, Cell Division, Chromosome Mapping, DNA Nucleotidyltransferases metabolism, DNA Probes, DNA, Viral isolation & purification, Epstein-Barr Virus Nuclear Antigens analysis, Genes, Viral physiology, Humans, Recombinases, T-Lymphocyte Subsets, T-Lymphocytes cytology, T-Lymphocytes enzymology, Thymus Gland virology, Viral Proteins genetics, Virus Replication, Herpesviridae Infections, Herpesvirus 4, Human genetics, Herpesvirus 4, Human isolation & purification, Herpesvirus 4, Human physiology, Integrases, T-Lymphocytes virology, Tumor Virus Infections
- Abstract
The presence of Epstein-Barr virus in different T-cell malignancies is now widely reported. In an effort to ascertain whether T cells are susceptible to EBV infection, we and others have detected the EBV receptor, CD21 on a population of immature thymocytes. We showed that EBV is a cofactor in stimulating proliferation of thymocytes. This proliferation may be a relevant factor in EBV-associated T-cell malignancies as well as EBV causation of acute infectious mononucleosis (AIM). We have further identified a subset of thymocytes that is infectable by EBV in which the genome remains linear in the first weeks after infection. We documented the transcription of the switch protein ZEBRA, an alternatively spliced form, RAZ, and EBNA-1 transcription from the Fp promoter. We hypothesise that EBV may be a cofactor in oncogenesis in T cells through several different pathways.
- Published
- 1996
- Full Text
- View/download PDF
35. Epstein-Barr virus infection of T cells: implications for altered T-lymphocyte activation, repertoire development and autoimmunity.
- Author
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Dreyfus DH, Kelleher CA, Jones JF, and Gelfand EW
- Subjects
- Amino Acid Sequence, Humans, Immunoglobulins immunology, Molecular Sequence Data, Recombination, Genetic, Signal Transduction immunology, Autoimmunity immunology, Herpesvirus 4, Human immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes virology
- Published
- 1996
- Full Text
- View/download PDF
36. Steroid-resistant chronic urticaria associated with anti-thyroid microsomal antibodies in a nine-year-old boy.
- Author
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Dreyfus DH, Schocket AL, and Milgrom H
- Subjects
- Adrenal Cortex Hormones therapeutic use, Child, Chronic Disease, Humans, Male, Treatment Failure, Autoantibodies analysis, Thyroxine therapeutic use, Urticaria drug therapy, Urticaria immunology
- Abstract
The case of a 9-year-old boy with severe chronic urticaria of 6 months' duration is described. The urticaria was associated with intractable bronchospasm and abdominal cramping and was unresponsive to antihistamines and high doses of corticosteroids. Even though the child was euthyroid, he was treated with thyroid hormone after the presence of anti-thyroid microsomal antibodies was documented. Within 1 month the patient demonstrated full remission. He remained free of symptoms for 9 months after discontinuation of treatment. After a relapse he again responded to thyroid hormone therapy. Children with chronic, intractable urticaria and documented evidence of anti-thyroid microsomal antibodies may benefit from treatment with thyroid hormone.
- Published
- 1996
- Full Text
- View/download PDF
37. Cystic fibrosis 3849+10kb C > T mutation associated with severe pulmonary disease and male fertility.
- Author
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Dreyfus DH, Bethel R, and Gelfand EW
- Subjects
- Adult, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Homozygote, Humans, Male, Alleles, Bronchiectasis complications, Cystic Fibrosis genetics, Fertility, Point Mutation
- Abstract
A 40-yr-old Hispanic man presented to NJCIRM with end-stage lung disease. Evaluation of this patient 10 yr earlier noted bronchiectasis, normal sweat electrolytes, pancreatic sufficiency, delayed progression of pulmonary disease, and a sperm biopsy consistent with fertility. At the time of admission bronchiectasis was extensive. DNA testing demonstrated homozygosity for the 3849+10kb C > T cystic fibrosis (CF) allele. This is the first description of homozygous expression of this allele in a male patient. Confirmation of fertility was established by demonstrating that his children were carriers of this allele. This patient emphasizes the importance of DNA testing for atypical CF alleles in patients with bronchiectasis of undetermined cause even in the presence of fertility, normal pancreatic function, and normal sweat electrolytes.
- Published
- 1996
- Full Text
- View/download PDF
38. Epstein-Barr virus replicative gene transcription during de novo infection of human thymocytes: simultaneous early expression of BZLF-1 and its repressor RAZ.
- Author
-
Kelleher CA, Paterson RK, Dreyfus DH, Streib JE, Xu JW, Takase K, Jones JF, and Gelfand EW
- Subjects
- Antigens, Viral biosynthesis, Cells, Cultured, DNA, Viral chemistry, Epstein-Barr Virus Nuclear Antigens, Gene Expression Regulation, Viral genetics, Genes, Viral genetics, Humans, Nucleic Acid Conformation, Promoter Regions, Genetic genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Viral biosynthesis, RNA, Viral genetics, T-Lymphocytes cytology, Transcription Factors biosynthesis, Virus Latency genetics, DNA-Binding Proteins biosynthesis, Herpesvirus 4, Human physiology, Immediate-Early Proteins, Repressor Proteins biosynthesis, T-Lymphocytes virology, Trans-Activators biosynthesis, Transcription, Genetic, Viral Proteins biosynthesis, Virus Replication genetics
- Abstract
Epstein-Barr virus (EBV) is known to infect B cells and epithelial cells. We and others have shown that EBV can also infect a subset of thymocytes. Infection of thymocytes was accompanied by the appearance of linear EBV genome within 8 hr of infection. Circularization of the EBV genome was not detected. This is in contrast to the infection in B cells where the genome can circularize within 24 hr of infection. The appearance of the BamHI ZLF-1 gene product, ZEBRA, by RT-PCR, was observed within 8 hr of infection. The appearance of a novel fusion transcript (RAZ), which comprised regions of the BZLF-1 locus and the adjacent BRLF-1 locus, was detected by RT-PCR. ZEBRA protein was also identified in infected thymocytes by immunoprecipitation. In addition, we demonstrated that the EBNA-1 gene in infected thymocytes was transcribed from the Fp promoter, rather than from the Cp/Wp promoter which is used in latently infected B cells. Transcripts encoding gp350/220, the major coat protein of EBV, were identified, but we did not find any evidence of transcription from the LMP-2A or EBER-1 loci in infected thymocytes. These observations suggest that de novo EBV infection of thymocytes differs from infection of B cells. The main difference is that with thymocytes, no evidence could be found that the virus ever circularizes. Rather, EBV remains in a linear configuration from which replicative genes are transcribed.
- Published
- 1995
- Full Text
- View/download PDF
39. Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.
- Author
-
Santisteban I, Arredondo-Vega FX, Kelly S, Debre M, Fischer A, Pérignon JL, Hilman B, elDahr J, Dreyfus DH, and Gelfand EW
- Subjects
- Adenosine Deaminase metabolism, Base Sequence, Binding Sites, Black People genetics, Conserved Sequence, Humans, Infant, Introns, Male, Models, Chemical, Molecular Sequence Data, Polymerase Chain Reaction, RNA Splicing, White People genetics, Zinc metabolism, Adenosine Deaminase genetics, Alanine metabolism, Histidine metabolism, Mutation, Severe Combined Immunodeficiency genetics
- Abstract
Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in alpha helix 4 and beta strand 4 of the alpha/beta barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.
- Published
- 1995
- Full Text
- View/download PDF
40. Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences.
- Author
-
Dreyfus DH
- Subjects
- Animals, Base Sequence, Biological Evolution, Mice, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, Sequence Homology, Nucleic Acid, DNA Transposable Elements, Genes, Immunoglobulin, Genes, Switch, Recombination, Genetic
- Abstract
Sequence similarity between the termini of invertebrate Tcl-like transposable sequences and the signal sequences of the vertebrate immunoglobulin somatic recombination pathway is described. These similarities suggest that the Tcl transposition pathway may share common sequence-specific binding factors with the immunoglobulin somatic recombination pathway.
- Published
- 1992
- Full Text
- View/download PDF
41. A transposon-related palindromic repetitive sequence from C. elegans.
- Author
-
Dreyfus DH and Emmons SW
- Subjects
- Animals, Base Sequence, Blotting, Southern, DNA, Molecular Sequence Data, Polymorphism, Restriction Fragment Length, Sequence Alignment, Caenorhabditis genetics, DNA Transposable Elements, Repetitive Sequences, Nucleic Acid
- Abstract
A family of transposon-like sequences in the C. elegans genome is described. This family, termed the Tc6 family, consists mostly of conserved, 1.6 kb elements. Four Tc6 elements or partial elements have been cloned and the DNA sequences of three were determined. One appears to be a complete element of 1603 nucleotides, consisting of a palindrome of 765 nucleotides, with a central, non-palindromic region of 73 nucleotides. Another has an identical structure except for an internal deletion. A third is a partial element terminating at a probable internal restriction site used for cloning. A fourth clone contained portions of the Tc6 sequence juxtaposed to non-Tc6 sequences. All C. elegans strains examined contain 20-30 Tc6 elements. The ends of Tc6 elements are conserved and have sequence similarity to the ends of C. elegans transposons Tc1 and Tc3. The ends of Tc6 elements also have sequence similarity to the heptamer portion of the immunoglobulin and T-cell receptor recombination signal sequence, raising the possibility of wide phylogenetic conservation of the recombination mechanism. Tc6 elements also share sequence motifs with plant-pathogenic viroid RNA's, possibly indicative of a Tc6 RNA replicative phase.
- Published
- 1991
- Full Text
- View/download PDF
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