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Hemic and Immune Systems Commons

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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 ...


Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence 2018 University of Massachusetts Medical School

Trisomy Silencing By Xist Normalizes Down Syndrome Cell Pathogenesis Demonstrated For Hematopoietic Defects In Vitro, Jen-Chieh Chiang, Jun Jiang, Peter E. Newburger, Jeanne B. Lawrence

Open Access Articles

We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used ...


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 ...


The Dynamic Roles Of Mesenchymal Stem Cells In Colon Cancer, Shan Wang, Zhiguo Miao, Qiyuan Yang, Yimin Wang, Jinzhou Zhang 2018 Henan Institute of Science and Technology

The Dynamic Roles Of Mesenchymal Stem Cells In Colon Cancer, Shan Wang, Zhiguo Miao, Qiyuan Yang, Yimin Wang, Jinzhou Zhang

Open Access Articles

Colon cancer is still one of the most common causes of cancer in human and is characterized by lymphocyte infiltrates and originates from the epithelial cells found in the lining of colon or rectum of the gastrointestinal tract. Mesenchymal stem cells (MSCs) are composed of the multipotent stem cell group of stroma and can be differentiated as various cell lineages, such as fibroblasts, osteoblasts, and adipocytes. MSCs provide mechanical and structural support and have potential functions during tumor growth and metastasis. The efficacy of MSC-based therapies is partly dependent on the migration and homing of MSCs to tumors and metastatic ...


Extracellular Vesicles In Oral Squamous Carcinoma Carry Oncogenic Mirna Profile And Reprogram Monocytes Via Nf-Kappab Pathway, Fatemeh Momen-Heravi, Shashi Bala 2018 Columbia University

Extracellular Vesicles In Oral Squamous Carcinoma Carry Oncogenic Mirna Profile And Reprogram Monocytes Via Nf-Kappab Pathway, Fatemeh Momen-Heravi, Shashi Bala

Open Access Articles

Extracellular vesicles (EVs) are carriers of different biomacromolecules that participate in cellular signaling and disease pathogenesis. Although it has been shown that EVs can play an active role in cellular communication and different stages of cancer progression, the role of EVs in oral squamous cell carcinoma (OSCC) cancer pathogenesis, especially in the crosstalk of cancer cells with immune cells is unknown. Here, we present a detailed analysis of findings regarding the profile of EVs in OSCC and the role of EVs and associated miRNAs in the crosstalk of malignant cells with monocytes. We demonstrate that EVs are detectable in significantly ...


Use Of Structural Equation Models To Predict Dengue Illness Phenotype, Sangshin Park, Anon Srikiatkhachorn, Siripen Kalayanarooj, Louis Macareo, Sharone Green, Jennifer F. Friedman, Alan L. Rothman 2018 Brown University

Use Of Structural Equation Models To Predict Dengue Illness Phenotype, Sangshin Park, Anon Srikiatkhachorn, Siripen Kalayanarooj, Louis Macareo, Sharone Green, Jennifer F. Friedman, Alan L. Rothman

Open Access Articles

BACKGROUND: Early recognition of dengue, particularly patients at risk for plasma leakage, is important to clinical management. The objective of this study was to build predictive models for dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) using structural equation modelling (SEM), a statistical method that evaluates mechanistic pathways.

METHODS/FINDINGS: We performed SEM using data from 257 Thai children enrolled within 72 h of febrile illness onset, 156 with dengue and 101 with non-dengue febrile illnesses. Models for dengue, DHF, and DSS were developed based on data obtained three and one day(s) prior to fever resolution (fever ...


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 ...


Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. McCormick 2018 University of Massachusetts Medical School

Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. Mccormick

Open Access Articles

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted ...


Il-16/Mir-125a Axis Controls Neutrophil Recruitment In Pristane-Induced Lung Inflammation, Siobhan Smith, Hardy Kornfeld, Caroline A. Jefferies 2018 Royal College of Surgeons in Ireland

Il-16/Mir-125a Axis Controls Neutrophil Recruitment In Pristane-Induced Lung Inflammation, Siobhan Smith, Hardy Kornfeld, Caroline A. Jefferies

Open Access Articles

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute "SLE-like" lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was ...


Peptide Antigen Concentration Modulates Digital Nfat1 Activation In Primary Mouse Naive Cd8(+) T Cells As Measured By Flow Cytometry Of Isolated Cell Nuclei, Michael P. Gallagher, James M. Conley, Leslie J. Berg 2018 University of Massachusetts Medical School

Peptide Antigen Concentration Modulates Digital Nfat1 Activation In Primary Mouse Naive Cd8(+) T Cells As Measured By Flow Cytometry Of Isolated Cell Nuclei, Michael P. Gallagher, James M. Conley, Leslie J. Berg

Open Access Articles

Circulating naive T cells exist in a quiescent state. After TCR contact with the cognate peptide presented by APCs in secondary lymphoid structures, T cells undergo a period of rapid transcriptional changes that set the stage for fate-determining effector or memory programming. We describe a novel method to analyze TCR signaling pathway activation in nuclei isolated from primary mouse naive T cells after stimulation with natural peptide Ags. We prelabeled cells with cell tracking dye to easily distinguish CD8(+) T cell nuclei from APC nuclei by conventional flow cytometry. Using this approach, we observed clear digital activation of NFAT1 transcription ...


Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio 2018 Albert Einstein College of Medicine

Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio

Open Access Articles

Transport of tissue-derived lymphatic fluid and clearance by draining lymph nodes are pivotal for maintenance of fluid homeostasis in the body and for immune-surveillance of the self- and non-self-proteomes. Yet a quantitative analysis of nodal filtration of the tissue-derived proteome present in lymphatic fluid has not been reported. Here we quantified the efficiency of nodal clearance of the composite proteomic load using label-free and isotope-labeling proteomic analysis of pre-nodal and post-nodal samples collected by direct cannulation. These results were extended by quantitation of the filtration efficiency of fluorophore-labeled proteins, bacteria, and beads infused at physiological flow rates into pre-nodal lymphatic ...


The N-Terminal Region Of Photocleavable Peptides That Bind Hla-Dr1 Determines The Kinetics Of Fragment Release, Maria P. Negroni, Lawrence J. Stern 2018 University of Massachusetts Medical School

The N-Terminal Region Of Photocleavable Peptides That Bind Hla-Dr1 Determines The Kinetics Of Fragment Release, Maria P. Negroni, Lawrence J. Stern

Open Access Articles

Major Histocompatibility Complex class II (MHC-II) molecules bind peptides and present them to receptors on CD4+ T cells as part of the immune system's surveillance of pathogens and malignancy. In the absence of peptide, MHC-II equilibrates between peptide-receptive and peptide-averse conformations. The conversion between these forms has been postulated to be important in regulating cellular antigen presentation but has been difficult to study. In order to generate the MHC-II molecule HLA-DR1 in the peptide-receptive form, we designed and tested a series of photocleavable peptides that included the UV-sensitive 3-amino-3-(2-nitrophenyl)-propionate amino acid analog. They were intended to bind ...


Efficacy Of A Respiratory Syncytial Virus Vaccine Candidate In A Maternal Immunization Model, Jorge C. G. Blanco, Lioubov M. Pletneva, Lori McGinnes Cullen, Raymonde O. Otoa, Mira C. Patel, Lurds R. Fernando, Marina S. Boukhvalova, Trudy G. Morrison 2018 Sigmovir Biosystems Inc.

Efficacy Of A Respiratory Syncytial Virus Vaccine Candidate In A Maternal Immunization Model, Jorge C. G. Blanco, Lioubov M. Pletneva, Lori Mcginnes Cullen, Raymonde O. Otoa, Mira C. Patel, Lurds R. Fernando, Marina S. Boukhvalova, Trudy G. Morrison

Open Access Articles

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Maternal immunization is an option to increase maternal antibody levels and protect infants from infection. Here we assess the efficacy of virus-like particle (VLP) vaccine candidates containing stabilized pre-fusion (pre-F) or post-fusion (post-F) conformations of the RSV F protein and the attachment RSV G protein in a maternal immunization model using cotton rats. VLP vaccines containing RSV F and G proteins strongly boost pre-existing RSV immunity in dams preventing their perinatal drop in immunity. Boosting is stronger for the pre-F VLP than for the post-F VLP or ...


Ebola: Africa, James Goodwin 2018 Augustana College, Rock Island Illinois

Ebola: Africa, James Goodwin

Global Issues in Public Health

In this paper, I talk about the Ebola Hemorrhagic Fever. Ebola is a rare virus that spreads through the immune system and can be fatal. Ebola is a pathogen from Africa, specifically West Africa. There has been almost 32,000 cases since 1976. Symptoms include, Fever, Headache, Muscle pain, Fatigue, Diarrhea, Vomiting, Stomach pain, and Bleeding/Bruising. Transmission happens during close or direct contact. World Health Organization has been making efforts to handle outbreaks such as the outbreak in 2014. World Health Organization mobilized and set up relief efforts. Education is a key idea for my thoughts on how we ...


Conservation And Divergence In Modules Of The Transcriptional Programs Of The Human And Mouse Immune Systems, Tal Shay, Vladimir Jojic, Broad Institute of MIT and Harvard, Harvard Medical School, Stanford University, ImmGen Consortium, Kavitha Narayan, Katelyn E. Sylvia, Joonso Kang 2018 Broad Institute of MIT and Harvard

Conservation And Divergence In Modules Of The Transcriptional Programs Of The Human And Mouse Immune Systems, Tal Shay, Vladimir Jojic, Broad Institute Of Mit And Harvard, Harvard Medical School, Stanford University, Immgen Consortium, Kavitha Narayan, Katelyn E. Sylvia, Joonso Kang

University of Massachusetts Medical School Faculty Publications

Studies in mouse have shed important light on human hematopoietic differentiation and disease. However, substantial differences between the two species often limit the translation of findings from mouse to human. Here, we compare modules of co-expressed genes in human and mouse immune cells based on compendia of genome-wide profiles. We show that the overall modular organization of the transcriptional program is conserved. We highlight modules of co-expressed genes in one species that dissolve or split in the other species. Many of the associated regulatory mechanisms - as reflected by computationally inferred trans regulators, or enriched cis-regulatory elements - are conserved between the ...


The Systemic Quantification Of Immune Cell Populations In Various Murine Models: How Age, Tumor Burden, And Immunotherapy Affect The Immune Response, Kavita Sinha 2018 University of Connecticut

The Systemic Quantification Of Immune Cell Populations In Various Murine Models: How Age, Tumor Burden, And Immunotherapy Affect The Immune Response, Kavita Sinha

Honors Scholar Theses

Immunotherapy as a form of cancer treatment has become increasingly popular in the past few decades. Researchers have worked to figure out how to best use the body’s natural defense mechanism, the immune system, to fight off and destroy cancer cells. In particular, the goal has been to manipulate checkpoint blockades such as CTLA-4 and PD-1 in order to take the breaks off of the immune system, allowing for a prolonged immune response to the cancer. This work has led to the development of human versions of anti-CTLA4 antibodies (ipilimumab, tremelimumab) and anti-PD1 antibodies (pembrolizumab and Nivolumab) that are ...


Micro Rnas From Dna Viruses Are Found Widely In Plasma In A Large Observational Human Population, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Tianxiao Huan, Lauren Clancy, Ravi Shah, Emelia J. Benjamin, Daniel Levy, Evelyn A. Kurt-Jones, Kahraman Tanriverdi, Jane E. Freedman 2018 University of Massachusetts Medical School

Micro Rnas From Dna Viruses Are Found Widely In Plasma In A Large Observational Human Population, Milka Koupenova-Zamor, Eric O. Mick, Heather A. Corkrey, Tianxiao Huan, Lauren Clancy, Ravi Shah, Emelia J. Benjamin, Daniel Levy, Evelyn A. Kurt-Jones, Kahraman Tanriverdi, Jane E. Freedman

Open Access Articles

Viral infections associate with disease risk and select families of viruses encode miRNAs that control an efficient viral cycle. The association of viral miRNA expression with disease in a large human population has not been previously explored. We sequenced plasma RNA from 40 participants of the Framingham Heart Study (FHS, Offspring Cohort, Visit 8) and identified 3 viral miRNAs from 3 different human Herpesviridae. These miRNAs were mostly related to viral latency and have not been previously detected in human plasma. Viral miRNA expression was then screened in the plasma of 2763 participants of the remaining cohort utilizing high-throughput RT-qPCR ...


Exploiting Glycan Topography For Computational Design Of Env Glycoprotein Antigenicity, Wen-Han Yu, Peng Zhao, Monia Draghi, Claudia Arevalo, Christina B. Karsten, Todd J. Suscovich, Bronwyn Gunn, Hendrik Streeck, Abraham L. Brass, Michael Tiemeyer, Michael Seaman, John R. Mascola, Lance Wells, Douglas A. Lauffenburger, Galit Alter 2018 Massachusetts Institute of Technology

Exploiting Glycan Topography For Computational Design Of Env Glycoprotein Antigenicity, Wen-Han Yu, Peng Zhao, Monia Draghi, Claudia Arevalo, Christina B. Karsten, Todd J. Suscovich, Bronwyn Gunn, Hendrik Streeck, Abraham L. Brass, Michael Tiemeyer, Michael Seaman, John R. Mascola, Lance Wells, Douglas A. Lauffenburger, Galit Alter

Open Access Articles

Mounting evidence suggests that glycans, rather than merely serving as a "shield", contribute critically to antigenicity of the HIV envelope (Env) glycoprotein, representing critical antigenic determinants for many broadly neutralizing antibodies (bNAbs). While many studies have focused on defining the role of individual glycans or groups of proximal glycans in bNAb binding, little is known about the effects of changes in the overall glycan landscape in modulating antibody access and Env antigenicity. Here we developed a systems glycobiology approach to reverse engineer the complexity of HIV glycan heterogeneity to guide antigenicity-based de novo glycoprotein design. bNAb binding was assessed against ...


Immunodeficient R2g2 Mouse Strain Yields Spleens With Unusual Cytoarchitecture And Sympathetic Innervation, Nicholas Mason Britt, Madeleine Kate Miller, Donald B. Hoover Ph.D., John B. Schweitzer M.D. 2018 East Tennessee State University

Immunodeficient R2g2 Mouse Strain Yields Spleens With Unusual Cytoarchitecture And Sympathetic Innervation, Nicholas Mason Britt, Madeleine Kate Miller, Donald B. Hoover Ph.D., John B. Schweitzer M.D.

Appalachian Student Research Forum

The nervous system and immune system contact one another through two-way communication in order to establish and preserve homeostasis. The sympathetic neurotransmitter norepinephrine has an impact on how the immune system responds by affecting regional blood flow and activation of adrenergic receptors on leukocytes. Former studies showed that immune cells are capable of releasing nerve growth factor allowing for the establishment and continuation of sympathetic nerves in targeted tissues. From this gathered information, it was hypothesized that sympathetic nerves would prove to be less frequent in spleens from the immunodeficient R2G2 mouse strain (Envigo) when compared to 129P3/J (129 ...


Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. McCauley, Ann Dauphin, William E. Diehl, Jeremy Luban 2018 University of Massachusetts Medical School

Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. Mccauley, Ann Dauphin, William E. Diehl, Jeremy Luban

University of Massachusetts Medical School Faculty Publications

Drugs that inhibit HIV-1 replication and prevent progression to AIDS do not eliminate HIV-1 proviruses from the chromosomes of long-lived CD4+ memory T cells. To escape eradication by these antiviral drugs, or by the host immune system, HIV-1 exploits poorly defined host factors that silence provirus transcription. These same factors, though, must be overcome by all retroviruses, including HIV-1 and other primate immunodeficiency viruses, in order to activate provirus transcription and produce new virus. Here we show that Vpx and Vpr, proteins from a wide range of primate immunodeficiency viruses, activate provirus transcription in human CD4+ T cells. Provirus activation ...


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