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Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern 2018 University of Massachusetts Medical School

Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern

Open Access Articles

Presentation of antigenic peptides on MHC-II molecules is essential for tolerance to self and for initiation of immune responses against foreign antigens. DO (HLA-DO in humans, H2-O in mice) is a non-classical MHC-II protein that has been implicated in control of autoimmunity and regulation of neutralizing antibody responses to viruses. These effects likely are related to a role of DO in selecting MHC-II epitopes, but previous studies examining the effect of DO on presentation of selected CD4 T cell epitopes have been contradictory. To understand how DO modulates MHC-II antigen presentation, we characterized the full spectrum of peptides presented by ...


Protective Versus Pathologic Pre-Exposure Cytokine Profiles In Dengue Virus Infection, Heather Friberg, Coreen M. Beaumier, Sangshin Park, Pamela P. Pazoles, Timothy P. Endy, Anuja Mathew, Jeffrey R. Currier, Richard G. Jarman, Kathryn B. Anderson, Steven Hatch, Stephen J. Thomas, Alan L. Rothman 2018 Walter Reed Army Institute of Research

Protective Versus Pathologic Pre-Exposure Cytokine Profiles In Dengue Virus Infection, Heather Friberg, Coreen M. Beaumier, Sangshin Park, Pamela P. Pazoles, Timothy P. Endy, Anuja Mathew, Jeffrey R. Currier, Richard G. Jarman, Kathryn B. Anderson, Steven Hatch, Stephen J. Thomas, Alan L. Rothman

Open Access Articles

BACKGROUND: Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.

METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed ...


Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. McCauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban 2018 University of Massachusetts Medical School

Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. Mccauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban

Open Access Articles

HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, HIV-1 establishes proviruses in long-lived CD4(+) memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Here we show that the HIV-1 provirus activates innate immune signaling in isolated dendritic cells, macrophages, and CD4(+) T cells. Immune activation requires transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. If rev is provided in trans, all HIV-1 coding sequences are dispensable for activation except those cis-acting sequences required ...


Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson 2018 National Institute of Arthritis and Musculoskeletal and Skin Diseases

Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson

University of Massachusetts Medical School Publications

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAD4 in TLR-7-dependent lupus autoimmunity were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, immune ...


Cd11b Regulation Of B Cell Receptor Signaling In Health And Systemic Lupus Erythematosus., Paul Lorenzo Dascani 2018 University of Louisville

Cd11b Regulation Of B Cell Receptor Signaling In Health And Systemic Lupus Erythematosus., Paul Lorenzo Dascani

Electronic Theses and Dissertations

Loss of function mutation in CD11b has been associated with incidence of systemic lupus erythematosus (SLE), a disease driven by B cell production of pathogenic autoimmune antibody. Our previous work has revealed the ability of CD11b to regulate B cell receptor (BCR) signaling and control autoimmune disease in mice. However, how CD11b regulates the immune response under normal conditions remains unknown. Through the use of a CD11b knockout model, we demonstrated that CD11b-deficient mice have an elevated antigen-specific humoral response in a Th2 type immunization. Deletion of CD11b resulted in elevated serum IgM and IgG antibody, increases in antigen-specific germinal ...


The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman 2018 University of Massachusetts Medical School

The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman

Open Access Articles

Macroautophagy and cell death both contribute to innate immunity, but little is known about how these processes integrate. Drosophila larval salivary glands require autophagy for developmentally programmed cell death, and innate immune signaling factors increase in these dying cells. Here, we show that the nuclear factor kappaB (NF-kappaB) factor Relish, a component of the immune deficiency (Imd) pathway, is required for salivary gland degradation. Surprisingly, of the classic Imd pathway components, only Relish and the PGRP receptors were involved in salivary gland degradation. Significantly, Relish controls salivary gland degradation by regulating autophagy but not caspases. In addition, expression of either ...


Hitchhiker's Guide To Migration: Effects Of Experimental Parasitic Infection And Other Immune Challenges On Migratory Traits Of Sparrows, Tosha R. Kelly 2018 The University of Western Ontario

Hitchhiker's Guide To Migration: Effects Of Experimental Parasitic Infection And Other Immune Challenges On Migratory Traits Of Sparrows, Tosha R. Kelly

Electronic Thesis and Dissertation Repository

Seasonal migration exposes animals to a variety of habitats and parasites, and if infected migratory birds migrate successfully there is great potential for birds to transport infectious diseases long distances. Our current understanding of whether birds contribute to the spread of disease relies upon observational field studies that are limited in their ability to discern cause from effect. Using captive and field-based experiments for my doctoral research, I answered three research questions: (1) are nocturnal migratory restlessness (Zugunruhe) and body condition affected by mounting an acute phase immune response during migration; (2) what are the impacts of parasitic infection on ...


Genetic Models Reveal Cis And Trans Immune-Regulatory Activities For Lincrna-Cox2, Roland Elling, Zhaozhao Jiang, Shiuli Agarwal, Mona Motwani, Jennie Chan, Shrutie Sharma, Katherine A. Fitzgerald, Susan Carpenter 2018 University of Massachusetts Medical School

Genetic Models Reveal Cis And Trans Immune-Regulatory Activities For Lincrna-Cox2, Roland Elling, Zhaozhao Jiang, Shiuli Agarwal, Mona Motwani, Jennie Chan, Shrutie Sharma, Katherine A. Fitzgerald, Susan Carpenter

Open Access Articles

An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA-Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA-Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Transcriptomic studies from various tissues revealed that deletion of the lincRNA-Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2 ...


Immunization With Recombinant Myelin Oligodendrocyte Glycoprotein Identifies Autoreactive T Cells As A Limiting Factor In Autoreactive Germinal Center Maintenance, Rajiv William Jain 2018 The University of Western Ontario

Immunization With Recombinant Myelin Oligodendrocyte Glycoprotein Identifies Autoreactive T Cells As A Limiting Factor In Autoreactive Germinal Center Maintenance, Rajiv William Jain

Electronic Thesis and Dissertation Repository

Germinal center (GC) responses are responsible for the protection provided by immunizations but can also drive autoimmunity. B and T cells collaborate in the GC to target the same antigen (Ag) to inform B cell differentiation; however, the properties of Ags differ substantially in autoimmunity and foreign-Ag driven immunity. Currently, it is not well understood how properties of the Ag itself influence the initiation or progression of GC responses, limiting our ability to develop effective vaccinations and predict the progression of autoimmune responses. The purpose of this thesis is to assess how GC responses initiate and progress when immunizing with ...


Protection Induced By A Francisella Tularensis Subunit Vaccine Delivered By Glucan Particles, Adam O. Whelan, Helen C. Flick-Smith, Jane Homan, Zu T. Shen, Zoe Carpenter, Payam Khoshkenar, Ambily Abraham, Nicola J. Walker, Stuart M. Levitz, Gary R. Ostroff, Petra C. F. Oyston 2018 Dstl Porton Down

Protection Induced By A Francisella Tularensis Subunit Vaccine Delivered By Glucan Particles, Adam O. Whelan, Helen C. Flick-Smith, Jane Homan, Zu T. Shen, Zoe Carpenter, Payam Khoshkenar, Ambily Abraham, Nicola J. Walker, Stuart M. Levitz, Gary R. Ostroff, Petra C. F. Oyston

Open Access Articles

Francisella tularensis is an intracellular pathogen causing the disease tularemia, and an organism of concern to biodefence. There is no licensed vaccine available. Subunit approaches have failed to induce protection, which requires both humoral and cellular immune memory responses, and have been hampered by a lack of understanding as to which antigens are immunoprotective. We undertook a preliminary in silico analysis to identify candidate protein antigens. These antigens were then recombinantly expressed and encapsulated into glucan particles (GPs), purified Saccharomyces cerevisiae cell walls composed primarily of beta-1,3-glucans. Immunological profiling in the mouse was used to down-selection to seven lead ...


Interleukin-1 Receptor-Associated Kinase 4 (Irak4) Plays A Dual Role In Myddosome Formation And Toll-Like Receptor Signaling, Dominic De Nardo, Katherine R. Balka, Yamel Cardona Gloria, Vikram R. Rao, Eicke Latz, Seth L. Masters 2018 University of Melbourne

Interleukin-1 Receptor-Associated Kinase 4 (Irak4) Plays A Dual Role In Myddosome Formation And Toll-Like Receptor Signaling, Dominic De Nardo, Katherine R. Balka, Yamel Cardona Gloria, Vikram R. Rao, Eicke Latz, Seth L. Masters

Open Access Articles

Toll-like receptors (TLRs) form part of the host innate immune system, in which they act as sensors of microbial and endogenous danger signals. Upon TLR activation, the intracellular Toll/interleukin-1 receptor domains of TLR dimers initiate oligomerization of a multiprotein signaling platform comprising myeloid differentiation primary response 88 (MyD88) and members of the interleukin-1 receptor-associated kinase (IRAK) family. Formation of this myddosome complex initiates signal transduction pathways, leading to the activation of transcription factors and the production of inflammatory cytokines. To date, little is known about the assembly and disassembly of the myddosome and about the mechanisms by which these ...


Dietary Docosahexaenoic Acid Prevents Silica-Induced Development Of Pulmonary Ectopic Germinal Centers And Glomerulonephritis In The Lupus-Prone Nzbwf1 Mouse, Melissa A. Bates, Peyman Akbari, Kristen N. Gilley, James G. Wagner, Ning Li, Anna K. Kopec, Kathryn A. Wierenga, Daven Jackson-Humbles, Christina Brandenberger, Andrij Holian, Abby D. Benninghoff, Jack R. Harkema, James J. Pestka 2018 Michigan State University

Dietary Docosahexaenoic Acid Prevents Silica-Induced Development Of Pulmonary Ectopic Germinal Centers And Glomerulonephritis In The Lupus-Prone Nzbwf1 Mouse, Melissa A. Bates, Peyman Akbari, Kristen N. Gilley, James G. Wagner, Ning Li, Anna K. Kopec, Kathryn A. Wierenga, Daven Jackson-Humbles, Christina Brandenberger, Andrij Holian, Abby D. Benninghoff, Jack R. Harkema, James J. Pestka

Animal, Dairy, and Veterinary Science Faculty Publications

Ectopic lymphoid structures (ELS) consist of B-cell and T-cell aggregates that are initiated de novo in inflamed tissues outside of secondary lymphoid organs. When organized within follicular dendritic cell (FDC) networks, ELS contain functional germinal centers that can yield autoantibody-secreting plasma cells and promote autoimmune disease. Intranasal instillation of lupus-prone mice with crystalline silica (cSiO2), a respirable particle linked to human lupus, triggers ELS formation in the lung, systemic autoantibodies, and early onset of glomerulonephritis. Here we tested the hypothesis that consumption of docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid with anti-inflammatory properties, influences the temporal profile of ...


Characterization Of Interleukin (Il)-1Β Regulatory Elements And Chromatin Conformation In Macrophage Activation, Woohyun Cho 2018 The University of Western Ontario

Characterization Of Interleukin (Il)-1Β Regulatory Elements And Chromatin Conformation In Macrophage Activation, Woohyun Cho

Electronic Thesis and Dissertation Repository

IL-1β is a potent inflammatory cytokine promptly expressed in activated myeloid cells. PU.1 is a lineage-determining transcription factor that regulates myeloid-specific genes by activating distal enhancers. This study addresses the functional importance of a potential enhancer of IL-1β, and how PU.1 regulates its activity state. A putative enhancer RNA (eRNA) was transcribed from the enhancer, and eRNA knock-down with antisense oligonucleotides inhibited IL-1β production. Furthermore, enhancer-promoter interactions in stimulated macrophages were detected via chromatin conformation capture (3C) analysis. The role of PU.1 was examined in PU.1-overexpressed B16-BL6 cells, which responded to LPS and expressed IL-1β mRNA ...


The Effect Of Wild Blueberry Anthocyanins And Phenolic Acids On Innate Immunity: The Compliment System, Vasiliki Papakotsi 2018 University of Maine

The Effect Of Wild Blueberry Anthocyanins And Phenolic Acids On Innate Immunity: The Compliment System, Vasiliki Papakotsi

Electronic Theses and Dissertations

Ingestion of berries containing polyphenols is associated with lower risk of inflammatory, metabolic, cardiovascular and degenerative diseases. Diet has been shown to modulate the activation of the complement system, a set of over 50 proteins present in the circulation and tissues that reacts in response to damage or microbial encounter and is critical for the maintenance of homeostasis. Imbalanced activation is tightly correlated with inflammation and various pathologies. Wild blueberries are a rich source of anthocyanins and phenolic acids, which can be found in plasma shortly after consumption. Given the involvement of both complement and polyphenols in the modulation of ...


Sodium Pyruvate Alters The Immune Response To Influenza A Virus Infection In Macrophages, Hazzar Abysalamah 2018 Missouri State University

Sodium Pyruvate Alters The Immune Response To Influenza A Virus Infection In Macrophages, Hazzar Abysalamah

MSU Graduate Theses

ABSTRACT

Pyruvate is the end product of glycolysis. It can either be transported into the mitochondria for use in the TCA cycle or be used to regenerate NAD+ during fermentation or aerobic glycolysis (also called the Warburg Effect). I recently discovered that addition of sodium pyruvate to the culture medium during infection of macrophages with influenza A virus affects the production of cytokines involved in immune signaling. While infection of macrophages with influenza A virus resulted in high levels of cytokines (IL-6, IL-1β, and TNF-α) in the absence of sodium pyruvate, the addition of sodium pyruvate significantly impaired cytokine production ...


Identification And Characterization Of Human Monoclonal Antibodies For Immunoprophylaxis Against Enterotoxigenic Escherichia Coli Infection, Serena Giuntini, Matteo Stoppato, Maja Sedic, Ejemel Monir, Jessica R. Pondish, Danielle Wisheart, Zachary Schiller, William D. Thomas Jr., Eileen M. Barry, Lisa Cavacini, mark S. klempner, Yan Wang 2018 University of Massachusetts Medical School

Identification And Characterization Of Human Monoclonal Antibodies For Immunoprophylaxis Against Enterotoxigenic Escherichia Coli Infection, Serena Giuntini, Matteo Stoppato, Maja Sedic, Ejemel Monir, Jessica R. Pondish, Danielle Wisheart, Zachary Schiller, William D. Thomas Jr., Eileen M. Barry, Lisa Cavacini, Mark S. Klempner, Yan Wang

Open Access Articles

Background. Enterotoxigenic Escherichia coli (ETEC) cause diarrheal illness in infants in the developing world and travelers to endemic countries including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea.

Methods. Mice transgenic for ...


From Olfaction To Immunity: Characterization Of Nasal Immunity In Bony Fish, Ali Sepahi 2018 University of New Mexico

From Olfaction To Immunity: Characterization Of Nasal Immunity In Bony Fish, Ali Sepahi

Biology ETDs

The olfactory system is a common route pathogen entry in vertebrates. As a consequence, the nasopharynx-associated lymphoid tissue (NALT) needs to rapidly clear infections without compromising the sense of olfaction. NALT is present in teleost fish but its cellular and molecular mechanisms of action have not been investigated to this date. This dissertation focuses on three aims: 1. investigating the role of CCL19-like as a primordial chemokine in vertebrate nasal immunity, 2. determining the presence of tissue microenvironments within the olfactory organ (OO) of rainbow trout, and 3. understanding the immune contributions of olfactory sensory neurons (OSNs) in teleosts against ...


Production Of A Candidate Recombinant Protein Vaccine For Mannheimia Haemolytica In Lettuce And Tobacco Chloroplasts, Coby K. Martin 2018 The University of Western Ontario

Production Of A Candidate Recombinant Protein Vaccine For Mannheimia Haemolytica In Lettuce And Tobacco Chloroplasts, Coby K. Martin

Electronic Thesis and Dissertation Repository

The cattle industry worldwide is ravaged by bovine respiratory disease (BRD), a bacterial disease caused by Mannheimia haemolytica. Recent efforts to design vaccines against M. haemolytica focus on a virulence factor, leukotoxin, in addition to surface lipoproteins. Plant-based protein production is a safe and inexpensive alternative to traditional methods. Edible vaccines deliver antigens to pharyngeal tissues, which can provide local immunization against M. haemolytica prior to its progression into the lungs. In this project, a chimeric protein containing M. haemolytica antigens was produced in tobacco chloroplasts as a candidate edible vaccine for BRD. Attempts were made to transform lettuce chloroplasts ...


Total Body Cd4+ T Cell Dynamics In Treated And Untreated Siv Infection Revealed By In Vivo Imaging, Michele Di Mascio, Sharat Srinivasula, Insook Kim, Gorka Duralde, Alexis St. Claire, Paula DeGrange, Marisa St. Claire, Keith A. Reimann, Erin E. Gabriel, Jorge Carrasquillo, Richard C. Reba, Chang Paik, Henry C. Lane 2018 National Institute of Allergy and Infectious Diseases

Total Body Cd4+ T Cell Dynamics In Treated And Untreated Siv Infection Revealed By In Vivo Imaging, Michele Di Mascio, Sharat Srinivasula, Insook Kim, Gorka Duralde, Alexis St. Claire, Paula Degrange, Marisa St. Claire, Keith A. Reimann, Erin E. Gabriel, Jorge Carrasquillo, Richard C. Reba, Chang Paik, Henry C. Lane

Open Access Articles

The peripheral blood represents only a small fraction of the total number of lymphocytes in the body. To develop a more thorough understanding of T cell dynamics, including the effects of SIV/SHIV/HIV infection on immune cell depletion and immune reconstitution following combination antiretroviral therapy (cART), one needs to utilize approaches that allow direct visualization of lymphoid tissues. In the present study, noninvasive in vivo imaging of the CD4+ T cell pool has revealed that the timing of the CD4+ T cell pool reconstitution following initiation of ART in SIV-infected nonhuman primates (NHPs) appears seemingly stochastic among clusters of ...


Fas Ligand Promotes An Inducible Tlr-Dependent Model Of Cutaneous Lupus-Like Inflammation, Purvi Mande, Bahar Zirak, Wei-Che Ko, Keyon Taravati, Karen L. Bride, Tia Bumpus Brodeur, April C. Deng, Karen A. Dresser, Zhaozhao Jiang, Rachel Ettinger, Katherine A. Fitzgerald, Michael D. Rosenblum, John E. Harris, Ann Marshak-Rothstein 2018 University of Massachusetts Medical School

Fas Ligand Promotes An Inducible Tlr-Dependent Model Of Cutaneous Lupus-Like Inflammation, Purvi Mande, Bahar Zirak, Wei-Che Ko, Keyon Taravati, Karen L. Bride, Tia Bumpus Brodeur, April C. Deng, Karen A. Dresser, Zhaozhao Jiang, Rachel Ettinger, Katherine A. Fitzgerald, Michael D. Rosenblum, John E. Harris, Ann Marshak-Rothstein

University of Massachusetts Medical School Faculty Publications

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet ...


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