Publications by authors named "David H Dreyfus"

28 Publications

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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.

Immunol Res 2019 Oct;67(4-5):460

Rheumatology, Boston University School of Medicine, Arthritis Center, 72 E. Concord Street, E-5, Boston, MA, 02118, USA.

The below funding information was missing in the published article.
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http://dx.doi.org/10.1007/s12026-019-09108-5DOI Listing
October 2019

Immediate Neutrophil-Variable-T Cell Receptor Host Response in Bacterial Meningitis.

Front Neurol 2019 2;10:307. Epub 2019 Apr 2.

Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany.

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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http://dx.doi.org/10.3389/fneur.2019.00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454057PMC
April 2019

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.

Immunol Res 2018 12;66(6):686-695

Rheumatology, Boston University School of Medicine, Arthritis Center, 72 E. Concord Street, E-5, Boston, MA, 02118, USA.

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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http://dx.doi.org/10.1007/s12026-018-9045-0DOI Listing
December 2018

Genetics and Molecular Biology of Epstein-Barr Virus-Encoded BART MicroRNA: A Paradigm for Viral Modulation of Host Immune Response Genes and Genome Stability.

Authors:
David H Dreyfus

J Immunol Res 2017 28;2017:4758539. Epub 2017 Apr 28.

Clinical Faculty Yale School of Medicine and Keren LLC, 488 Norton Parkway, New Haven, CT 06511, USA.

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-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 IB that regulate host NF-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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http://dx.doi.org/10.1155/2017/4758539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458376PMC
March 2018

Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes.

Arthritis Res Ther 2017 02 28;19(1):39. Epub 2017 Feb 28.

Rheumatology, Boston University School of Medicine, Arthritis Center, 72 E. Concord Street, E-5, Boston, MA, 02118, USA.

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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http://dx.doi.org/10.1186/s13075-017-1237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331713PMC
February 2017

Differential Diagnosis of Chronic Urticaria and Angioedema Based on Molecular Biology, Pharmacology, and Proteomics.

Authors:
David H Dreyfus

Immunol Allergy Clin North Am 2017 02 28;37(1):201-215. Epub 2016 Oct 28.

Yale School of Medicine, Gesher LLC, Allergy, Asthma and Clinical Immunology, 4 Clifton Avenue, Waterbury CT 06710, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.iac.2016.08.010DOI Listing
February 2017

Gene sharing between Epstein-Barr virus and human immune response genes.

Authors:
David H Dreyfus

Immunol Res 2017 02;65(1):37-45

Yale School of Medicine, New Haven, CT, USA.

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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http://dx.doi.org/10.1007/s12026-016-8814-xDOI Listing
February 2017

Gene silencing and related oligonucleotide therapies for TH2-promoting cytokines.

Authors:
David H Dreyfus

J Allergy Clin Immunol 2014 Sep 18;134(3):762. Epub 2014 Jul 18.

Keren Pharmaceutical, New Haven and Clinical Faculty, Yale SOM, New Haven, Conn. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.06.008DOI Listing
September 2014

HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses.

mBio 2014 Jul 1;5(4):e01318-14. Epub 2014 Jul 1.

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA

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.
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http://dx.doi.org/10.1128/mBio.01318-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161245PMC
July 2014

Herpesviruses and the microbiome.

Authors:
David H Dreyfus

J Allergy Clin Immunol 2013 Dec 20;132(6):1278-86. Epub 2013 Apr 20.

Department of Pediatrics, Clinical Faculty, Yale School of Medicine, New Haven, and the Center for Allergy, Asthma, and Immunology, Waterbury, Conn. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaci.2013.02.039DOI Listing
December 2013

Urticaria & angioedema: a rational approach to diagnosis and therapy.

Authors:
David H Dreyfus

Skin Therapy Lett 2013 Jan;18(1):4-9

Department of Pediatrics, Waterbury Hospital, Waterbury, CT, USA.

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.
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January 2013

Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication.

J Virol 2012 Jun 4;86(12):6825-34. Epub 2012 Apr 4.

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

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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http://dx.doi.org/10.1128/JVI.00374-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393532PMC
June 2012

Monitoring of thyroid function in patients who exhibit IgE against thyroperoxidase while taking omalizumab?

Authors:
David H Dreyfus

J Allergy Clin Immunol 2012 Jan 21;129(1):269-70; author reply 270. Epub 2011 Nov 21.

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http://dx.doi.org/10.1016/j.jaci.2011.10.040DOI Listing
January 2012

Analysis of an ankyrin-like region in Epstein Barr Virus encoded (EBV) BZLF-1 (ZEBRA) protein: implications for interactions with NF-κB and p53.

Virol J 2011 Sep 5;8:422. Epub 2011 Sep 5.

Department of Pediatrics, Yale SOM, 488 Norton Parkway, New Haven, CT 06511, USA.

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.
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http://dx.doi.org/10.1186/1743-422X-8-422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180424PMC
September 2011

Autoimmune disease: A role for new anti-viral therapies?

Authors:
David H Dreyfus

Autoimmun Rev 2011 Dec 18;11(2):88-97. Epub 2011 Aug 18.

Pediatrics, Yale University School of Medicine, New Haven, CT, United States.

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.
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http://dx.doi.org/10.1016/j.autrev.2011.08.005DOI Listing
December 2011

Immune system: success owed to a virus?

Authors:
David H Dreyfus

Science 2009 Jul;325(5939):392-3

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http://dx.doi.org/10.1126/science.325_392cDOI Listing
July 2009

Paleo-immunology: evidence consistent with insertion of a primordial herpes virus-like element in the origins of acquired immunity.

Authors:
David H Dreyfus

PLoS One 2009 Jun 3;4(6):e5778. Epub 2009 Jun 3.

Allergy and Clinical Immunology/Pediatrics, Yale School of Medicine New Haven, New Haven, CT, USA.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005778PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686171PMC
June 2009

Gene silencing in the therapy of influenza and other respiratory diseases: Targeting to RNase P by use of External Guide Sequences (EGS).

Biologics 2007 Dec;1(4):425-32

Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA;

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721295PMC
December 2007

A review of recent patents concerning therapy of respiratory diseases using gene silencing by RNAi (RISC) and EGS (RNAse P).

Recent Pat Inflamm Allergy Drug Discov 2007 Feb;1(1):49-55

Pediatrics, Yale School of Medicine and Medical Director, Founder Keren Pharmaceutical Inc., 488 Norton Parkway, New Haven CT 06511, USA.

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.
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http://dx.doi.org/10.2174/187221307779815147DOI Listing
February 2007

The DDE recombinases: diverse roles in acquired and innate immunity.

Authors:
David H Dreyfus

Ann Allergy Asthma Immunol 2006 Nov;97(5):567-76; quiz 576-8, 602

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut 06511, USA.

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.
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http://dx.doi.org/10.1016/S1081-1206(10)61083-6DOI Listing
November 2006

Characterization of an anaphylactoid reaction to omalizumab.

Ann Allergy Asthma Immunol 2006 Apr;96(4):624-7

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.

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.
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http://dx.doi.org/10.1016/S1081-1206(10)63560-0DOI Listing
April 2006

Role of T cells in EBV-infected systemic lupus erythematosus patients.

Authors:
David H Dreyfus

J Immunol 2005 Sep;175(6):3460; author reply 3461

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http://dx.doi.org/10.4049/jimmunol.175.6.3460DOI Listing
September 2005

Modulation of p53 activity by IkappaBalpha: evidence suggesting a common phylogeny between NF-kappaB and p53 transcription factors.

BMC Immunol 2005 Jun 21;6:12. Epub 2005 Jun 21.

Division of Basic Sciences, Department of Pediatrics, National Jewish Medical Research Center, Denver, CO 80262 USA.

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.
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http://dx.doi.org/10.1186/1471-2172-6-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1184076PMC
June 2005

An RNA external guide sequence ribozyme targeting human interleukin-4 receptor alpha mRNA.

Int Immunopharmacol 2004 Aug;4(8):1015-27

Department of Pediatrics, Yale School of Medicine, 488 Norton Parkway, New Haven, CT 06511, USA.

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.
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http://dx.doi.org/10.1016/j.intimp.2004.03.012DOI Listing
August 2004

Anaphylaxis to latex in patients without identified risk factors for latex allergy.

Conn Med 2004 Apr;68(4):217-22

Waterbury Hospital, Yale School of Medicine, Waterbury, CT, USA.

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.
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April 2004

The syndrome of thyroid autoimmunity and idiopathic chronic urticaria and angioedema presenting as anaphylaxis.

Allergy Asthma Proc 2003 May-Jun;24(3):171-4

Department of Pediatrics, Waterbury Hospital, Yale School of Medicine, Waterbury, Connecticut, USA.

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.
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November 2003