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1
Warnatsch, Annika. "Impact of proteasomal immune adaptation on the early immune response to viral infection." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16775.
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Im Kampf gegen eine Virusinfektion spielen CD8+ T Zellen des adaptiven Immunsystems eine besondere Rolle. Sie patroullieren im Körper und entdecken spezifische Virusepitope, welche mittels MHC Klasse I Molekülen auf der Oberfläche infizierter Zellen präsentiert werden. Wird eine virus-infizierte Zelle erkannt, kann diese schnell und effizient eliminiert. Für die Generierung viraler Peptide, welche auf MHC Klasse I Komplexe geladen werden, ist das Ubiquitin-Proteasom-System von essentieller Bedeutung. Kürzlich wurden weitere Funktionen des Immunoproteasoms aufgedeckt wie zum Beispiel der Schutz gegen oxidativen Stress. Innerhalb der vorliegenden Arbeit konnte die Fähigkeit des Immunoproteasoms gegen eine Akkumulation oxidativ geschädigter Proteine zu schützen mit der Generierung von MHC Klasse I Liganden kombiniert und neu interpretiert werden. Es konnte gezeigt werden, dass während einer Virusinfektion in Nicht-Immunzellen die Produktion reaktiver Sauerstoffspezies durch die alternative NADPH Oxidase Nox4 eine bedeutende Rolle spielt. Die Aktivierung von Nox4 resultiert in der Akkumulation oxidativ geschädigter Proteine. Innerhalb von zwei Stunden nach dem Eintreten von Viruspartikeln in die Zellen wurden strukturelle Virusproteine oxidiert und anschließend ubiquityliert. Die gleichzeitige, virus-induzierte Expression von Immunoproteasomen führte zu einem schnellen und effizienten Abbau ubiquitylierter Virusantigene. Infolgedessen konnten immundominante Virusepitope vermehrt freigesetzt werden. Folglich wurde ein soweit unbekannter Mechanismus gefunden, welcher Substrate für das Proteasom zur Generierung von MHC Klasse I Liganden bereitstellt. Zusammenfassend konnte innerhalb dieser Arbeit gezeigt werden, dass das Immunoproteasom den Schutz vor oxidativen Stress mit der Generierung antigener Peptide verbindet, wodurch eine effektive adaptive Immunantwort etabliert werden kann.An efficient immune control of virus infection is predominantly mediated by CD8+ T cells which patrol through the body and eliminate infected cells. Infected cells are recognized when they present viral antigenic peptides on their surface via MHC class I molecules. To make antigenic peptides available for loading on MHC class I complexes, the ubiquitin proteasome system plays a crucial role. Moreover, the induction of the i-proteasome is known to support the generation of MHC class I ligands. Recently, new functions of the i-proteasome have been discovered. Evidence is increasing that the i-proteasome is involved in the protection of cells against oxidative stress. Within this thesis the characteristic of the i-proteasome to protect cells against the accumulation of oxidant-damaged proteins could be linked to its role in improving the generation of MHC class I ligands. It could be demonstrated that during a virus infection in non-immune cells the production of reactive oxygen species by the alternative NADPH oxidase Nox4 is of critical importance resulting in the accumulation of potentially toxic oxidant-damaged proteins. Indeed, within two hours of infection structural virus proteins were oxidized and subsequently poly-ubiquitylated. The concomitant formation of i-proteasomes led to a rapid and efficient degradation of ubiquitylated virus antigens thereby improving the liberation of immunodominant viral epitopes. In conclusion, a so far unknown mechanism to fuel proteasomal substrates into the MHC class I antigen presentation pathway has been revealed. A new protein pool consisting of exogenously delivered viral proteins provides proteasomal substrates in the very early phase of a virus infection. Within the scope of this thesis the i-proteasome has been shown to link the protection against oxidative stress, initiated directly by pathogen recognition, with the generation of antigenic peptides. Together, an effective adaptive immune response is triggered.
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Kühl, Thomas. "Pathogenic impact of immune-related cells in Batten disease." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/pathogenic-impact-of-immunerelated-cells-in-batten-disease(ff86b71b-e859-4d91-a378-421eab71ae97).html.
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The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are inherited neurodegenerative diseases of children. In all types of NCL glial activation, the innate immune response of the brain, precedes neurodegeneration. However, it is unclear whether adaptive immune responses are also involved in these diseases, or if they directly contribute to disease pathogenesis. Therefore, we examined the role of adaptive immune cells in mouse models of Infantile NCL (Ppt1-/- mice) and Juvenile NCL (Cln3-/- mice) by identifying, localising, and subsequently genetically removing immune components. Characterising the adaptive immune response within Ppt1-/- and Cln3-/- mice, we revealed evidence for progressive CNS infiltration by different classes of T-cells in both forms of NCL. To analyse the pathogenic impact of these lymphocytes, we crossbred PptP/- mutants with mice deficient in Rag-1, which lack T- and B-lymphocytes. Disease progression was significantly delayed in immune deficient PptP/ /Rag-1-/- mice, which displayed ameliorated neuroinflammation and neuron loss. We also crossed our Infantile and Juvenile NCL mouse models with mice deficient in sialoadhesin (Sn), a binding protein found on macrophages and microglia, and is involved in pro-inflammatory T-cell regulation. Disease progression was also slowed down, with significantly increased neuron survival in both Sn deficient NCL mice. However, contrasting effects on glial activation were observed between Ppt1~/-/ ’ Sn~/-and Cln3-/-/Sn-/- mice. Whereas glial activation was only marginally attenuated in Cln3-/-/Sir/- mice, significantly decreased microglial activation and enhanced astrocytosis were observed in Ppt1-/-/Str/- mice. These latter findings suggest an unexpected link between macrophage-expressed Sn and astrocytosis in Taken together, our findings prove that adaptive immune cells and sialoadhesin each appear to contribute to disease progression in Infantile and Juvenile NCL mice. Therefore, both immune components could prove to be suitable therapeutic targets for these fatal disorders.
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Post, Frank A. "Mycobacterial strain diversity : impact on the host immune response." Doctoral thesis, University of Cape Town, 2003. http://hdl.handle.net/11427/2717.
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Zhao, Wei. "Impact of the innate immune response on mammary epithelia." [Ames, Iowa : Iowa State University], 2009.
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Daniłowicz-Luebert, Emilia. "Impact of helminths and helminth products on immune responses." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16683.
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Helmintheninfektionen induzieren in ihren Wirten Typ 2 (Th2) Immunantworten, welche parasitäre Larvenstadien hemmen und/oder zur Abstoßung von intestinalen Würmern führen. Th2-Antworten können auch gegenüber Umweltallergenen ausgebildet werden und allergische Reaktionen vermitteln. Mastzellen (MZ) spielen eine herausragende Rolle für die Wirtsantwort gegen Parasiten. Die Ergebnisse der vorliegenden Arbeit zeigen, dass eine Infektion von MZ-defizienten Mäusen mit Helminthen zu einer reduzierten Produktion von IL-25, IL-33 und TSLP, einer beeinträchtigten Etablierung von Th2 Immunantworten und einer erhöhten Wurmlast führt. Diese Parameter konnten allerdings nach einem erfolgreichen Transfer von Knochenmark aus Wildtypmäusen wiederhergestellt werden. Die vorliegende Arbeit beschreibt somit eine wichtige Funktion von Mastzellen für die Initialisierung von Th2 Immunantworten. Des Weiteren konnte gezeigt werden, dass ein Cystein-Protease-Inhibitor - AvCystatin sowohl Parameter von Atemwegsentzündung und -hyperreaktivität als auch Lieschgraspollen (Phl p 5b)-spezifische Immunantworten in einem klinisch relevanten Mausmodell für Atemwegsentzündung inhibiert. Gleichzeitig führte die Behandlung mit AvCystatin zu einem Anstieg von IL-10 und erhöhten Frequenzen von CD4+CD25+Foxp3+ T Zellen. Die in vivo Effekte von AvCystatin wurden unabhängig von der Protease-inhibitorischen Aktivität des Immunmodulators oder dessen Fähigkeit zur Oligomerisation vermittelt. AvCystatin unterdrückte zudem die Allergen-spezifische Produktion von IL-13 und induzierte in vitro unter Verwendung mononukleärer Zellen aus dem peripheren Blut (PBMCs) von Graspollen allergischen Patienten einen IFN-gamma vermittelten Th1 shift. Zusammenfassend tragen die Ergebnisse der Arbeit zu einem besseren Verständnis für die frühen Ereignisse von Th2 Immunantworten bei und zeigen, dass Helminthenmoleküle Bystandereffekte auf Immunantworten vermitteln können, die gegen andere Antigene gerichtet sind.Helminth infections induce protective type 2 (Th2) immune responses in the host leading to arrested larval development and/or intestinal worm expulsion. Moreover, Th2 immune responses are initiated against harmless environmental allergens and mediate development of allergic disease. Among multiple mechanisms implicated in host responses to parasites and allergens, mast cells (MCs) play a pivotal role. The present study shows that MC-deficient mouse strains following infection with two gastrointestinal helminths had dramatically reduced early production of the tissue-derived cytokines IL-25, IL-33, and TSLP, which resulted in impaired induction of Th2 immune responses as well as increased parasite burden. These parameters were restored after transfer of WT bone marrow. These data reveal an important role for MCs in orchestrating type 2 immune responses. Parasites have developed various strategies to modulate the immune system via induction of a range of regulatory mechanisms. In this study AvCystatin, the filarial cysteine inhibitor, was found to inhibit airway inflammation and hyperreactivity induced by a clinically relevant allergen of timothy grass pollen (Phl p 5b). AvCystatin increased levels of the regulatory cytokine IL-10 and total numbers of CD4+CD25+Foxp3+ T cells. The immunomodulatory effect in vivo was found to be independent of AvCystatin’s protease inhibitor activity or oligomerization. Finally, AvCystatin suppressed allergen-specific production of IL-13 and created a shift towards Th1 immunity by increased levels IFN-gamma of human peripheral blood mononuclear cells (PBMCs) from grass pollen allergic patients. The findings contribute to a better understanding of the early events that dictate the priming of type 2 immune responses. Furthermore, helminth product-induced suppression may also have effects on bystander responses to unrelated antigens, thus, suggesting a promising preventive and therapeutic concept in the treatment of aberrant inflammations.
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Blaimer, Stephanie [Verfasser], and Edward K. [Akademischer Betreuer] Geissler. "Impact of innate and adaptive immune cells in tumor immune surveillance / Stephanie Blaimer ; Betreuer: Edward K. Geissler." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1210729202/34.
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Banerjee, Piu. "Immune mechanisms in atopic eczema and the impact of therapy." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391635.
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Pike, Lewis James. "Salmonella vaccines : the impact of antigenic location on immune responses." Thesis, University of York, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313867.
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Weaver, Wade G. "Impact of VHSV M Protein on the Innate Immune System." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1481191320713471.
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Howells, Anwen. "The impact of innate immune cells on immunopathology in dengue." Thesis, University of Oxford, 2014. https://ora.ox.ac.uk/objects/uuid:0a251372-4d0e-416d-ad3c-8e07e6729e1b.
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Dengue virus (DENV) is an arthropod-borne virus and has become a worldwide problem with steadily rising annual infection rates. Patients present with a range of symptoms from mild fever to, in some cases, life-threatening hemorrhagic fever and shock syndrome. The most severe cases require emergency hospital care and currently, there is no effective drug treatment or vaccine for dengue. As severe symptoms appear post-peak viremia, immuno-pathology is thought to be the cause and a potential trigger of this is differential activation of the immune response upon recognition of DENV. This could be due to a combination of factors including varying receptors, signalling pathways and immune regulation mechanisms. In order to understand DENV infection better, it is imperative to study the mechanisms of activation and control of immune responses triggered by the virus. Very early events in viral infection (after 10 min stimulation) were studied aiming to identify proteins involved in differential activation of immune responses. Phosphorylated proteins were isolated from cells post-stimulation and analysed by mass spectrometry. More than 200 proteins were differentially regulated by phosphorylation in response to DENV stimulation as compared to Mock, Influenza A virus and LPS stimulation. The effect of two specific proteins, namely Calpain-2 and Importin-5, identified to be differentially phosphorylated was investigated further. Calpain-2 was seen to be vital in the efficient production of progeny virions and the transcription of Mx1, an anti-viral interferon stimulated gene. Importin-5 is known to transport DENV NS5 into the nucleus during infection and was seen to co-precipitate with many host proteins. In summary, it is imperative that novel treatments and vaccines are developed for dengue as it is one of the worldâs most prevalent arthropod-borne viruses. It was discovered here that many proteins undergo phosphorylation/de-phosphorylation in response to DENV stimulation to a differing degree than other stimuli. Calpain-2 plays a vital role DENV infection, potentially influencing the potency of immune response. Importin-5 associates with various host proteins during DENV infection, potentially altering their function or the function of Importin-5 itself. Research into targeted inhibition of Calpain-2 function or Importin-5 interaction with DENV NS5 could lead to a successful anti-viral treatment for DENV infection.
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Schlundt, Claudia. "Impact of the adaptive immune system in bone fracture healing." Doctoral thesis, Humboldt-Universität zu Berlin, 2017. http://dx.doi.org/10.18452/18195.
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Knochengewebe besitzt die einzigartige Fähigkeit sich nach einem Bruch komplett zu regenerieren. Dennoch zeigen 10-15% der Patienten einen gestörten Heilungsverlauf. Das Immunsystem spielt eine entscheidende Rolle in der Frakturheilung. Im Rahmen der hier präsentierten Doktorarbeit wurde der Einfluss der CD4+ regulatorischen T-Zellen (Treg) auf die Knochenheilung untersucht. In einem Maus-Osteotomie-Modell wurde die zeitliche und räumliche Verteilung ausgewählter Immun- und Knochenzellen im osteotomierten Knochen untersucht. Dabei konnte gezeigt werden, dass Immunzellen im gesamten Heilungsverlauf in der Frakturzone zu finden waren und oft eine direkte Kolokalisation mit den Knochenzellen aufwiesen. Diese Ergebnisse zeigen deutlich die starke Interaktion beider Systeme. Ein adaptiver Transfer muriner Treg vor Setzen der Osteotomie diente als immunmodulatorischer Ansatz zur Verbesserung des Frakturheilungsprozesses. Tiere mit einem unerfahrenen Immunsystem (SPF-Haltung) zeigten eine verbesserte Heilung nach Treg-Transfer. Mäuse mit einem erfahrenen Immunsystem (semi-sterile Haltung) zeigten einen kontroversen Heilungserfolg: eine Hälfte der Mäuse heilte signifikant besser und die andere Hälfte signifikant schlechter. Die Schlechtheiler zeigten eine höhere Ratio von CD8+ Effektoren zu Treg im Vergleich zu den Gutheilern. In einer darauffolgenden Proof-of-concept-Studie konnte gezeigt werden, dass eine prä-OP definierte Ratio von CD8+ Effektoren zu Treg mit dem Heilungserfolg nach Osteotomie korrelierte.
Im Rahmen dieser Doktorarbeit konnte ein potentiell positiver Einfluss von CD4+ Treg auf den Frakturheilungsprozess bestätigt werden. Dennoch wurde auch der enorme Einfluss des prä-OP Immunstatus auf den Heilungserfolg deutlich. Für die Klinik ist es also im Rahmen einer Immuntherapie umso wichtiger Patienten-basierte Therapieformen zu entwickeln, bei denen der individuelle Immunstatus eines jeden Patienten vor Anwendung der Therapie berücksichtigt wird.Bone tissue possesses the remarkable capacity to fully regenerate after injury. However, in 10-15% of patients, unsuccessful bone repair is still a present problem. Components of the adaptive immune system play an indispensable role in bone regeneration. The here presented PhD thesis focused on the interaction of CD4+ regulatory T cells (Treg) during fracture healing. In a murine osteotomy model, the spatiotemporal distribution of immune and bone cells was analyzed within the healing bone. Cells of the immune system were detectable throughout the whole healing cascade in the injured area und showed often a direct co-localization with bone cells. These results highlight the interconnectivity of immune and bone cells during regeneration. By adoptive transfer of murine CD4+ Treg prior to osteotomy, an immunomodulatory approach to improve bone healing was conducted. Mice possessing an unexperienced immune system (SPF housing) showed a consistent improved healing outcome after adoptive Treg transfer. However, mice with a more experienced immune system (semi-sterile housing) receiving an adoptive Treg transfer demonstrated a controversial healing outcome: half of the mice showed a significantly improved and the other half a significantly poorer healing outcome. In the mice with a poorer healing outcome, a higher ratio of CD8+ effector T cells and Treg was observed. In a following proof of concept study, a pre-osteotomy defined ratio of CD8+ effector T cells and Treg could predict the healing outcome after adoptive Treg transfer and osteotomy. A potential positive impact of Treg in bone repair was confirmed in this study. However, the tremendous impact of the environment and thereby of the immune status prior to immunomo-dulation was also clearly demonstrated. Hence, for the clinic, it is even more important to develop and to apply patient based immunomodulatory treatment approaches considering the individual immune status of each patient prior to treatment.
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Anwar, S. "Impact of helminth infection on antimycobacterial immune responses in UK migrants." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2017. http://researchonline.lshtm.ac.uk/4398419/.
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Tuberculosis and helminth infections are co endemic in many parts of the world. This geographical overlap has led to the hypothesis that helminth infections could exacerbate the effects of Mycobacterium tuberculosis (Mtb) infection. Anthelmintic treatment has been observed to be associated with improved mycobacterial cellular responses and decreases in the frequency of Treg cells. The consequence of this immunomodulation may affect the ability of the host to restrict the growth of mycobacteria or mycobacterial killing. This study aims at investigating the modulations of the immune response profile of latent tuberculosis (LTBI) and helminth co-infected patients and whether these modulations are associated with a decrease in mycobacterial growth inhibition using a mycobacterial growth inhibition assay (MGIA).UK migrants attending University College Hospital London, UK with eosinophilia or suspected/diagnosed helminth infection (Strongyloides spp and Schistosoma spp) and/or LTBI were bled at recruitment (before anthelmintic treatment) and 4 months after completing anthelmintic treatment. Helminth infected patients displayed poor growth inhibition on MGIA which was improved after anthelmintic treatment which indicated this immunomodulation might be helminth mediated. The percentage of CD4+ T cells expressing IFNg, TNFa and IL-2 were quantified by flow cytometry in PPD and ESAT-6/CFP-10 stimulated PBMC and anthelmintic treatment was observed to increase the frequency of CD4+IFNg response. LTBI-helminth coinfection was associated with significantly elevated levels of proinflammatory and lower levels of anti-inflammatory cytokines after they were treated. IP- 10 was significantly upregulated and MCP-1 was significantly downregulated in LTBIhelminth coinfected patients after anthelmintic treatment. The effect of IL-10 and TGFb on MGIA were observed and suggested an immunoregulatory role in helminth infected patients. Gene expression analysis by qRT-PCR showed varied responses and showed significant fold changes of CXCL-10, arginase 1 and CD163 after the treatment. MGIA and multiple immune parameters have shown that helminth infection can modulate a variety of Mtb specific immune responses.
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Lascar, R. M. "Impact of human immunodeficiency virus on hepatitis B-specific immune responses." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445941/.
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Prior infection with hepatitis B virus (HBV) is a common occurrence in HIV infected subjects and an increasing cause of morbidity and mortality. The CD8 T cell response is crucial for the long-term control of the virus in patients resolving acute hepatitis B. I first examined the effect of HIV related immunodepletion on HBV-specific immune responses in patients who resolved HBV. A cross-sectional study showed a reduction in HBV-specific CD8 responses in HBV immune patients with HIV infection compared to those without. Longitudinal study of a subgroup of patients examined whether this attrition could be reversed by effective antiretroviral therapy. The introduction of highly active antiretroviral therapy (HAART) resulted in recovery of some HBV-specific CD8 and CD4 responses, in association with restoration of CD4 counts. These data provided a mechanism for the observed impairment of HBV control in the setting of HIV infection and support the ability of HAART to reconstitute functionally active responses. I also studied the HBV-specific cellular immune responses in HIV negative patients who resolved acute hepatitis B without symptoms, a group which has never been studied immunologically, but represents a significant proportion of hepatitis cases acquired in adulthood. In the last chapter I focused on the chronic hepatitis B carriers co-infected with HIV and the impact of HIV and HBV treatment. I showed that reconstitution of some HBV-specific T cell responses can also occur in HIV-positive patients after a reduction in HBV load. This potential to recover T cell responses provides support for the addition of anti-HBV therapy in the treatment of co-infected patients.
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Burton, Catherine Teresa. "The impact of treatment strategies on immune responses in HIV-1 infection." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407980.
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Bartlett, David B. "Impact of physical activity on immune function and inflammation in the elderly." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5003/.
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Physiological ageing is accompanied with an increase in systemic inflammatory mediators (inflammageing), a functional decline of the immune system (immunesenescence), altered endocrine function (adrenopause) and reduced physical activity which predisposes the elderly to increased risk of disease. Little is known about the interplay between physical activity, inflammageing, adrenopause and immunesenescence and what impact interventions may have in the elderly. This thesis identified the consequences of inflammageing and its association with immunesenescence and the impact physical activity plays on limiting the severity of inflammageing. Cytomegalovirus drives immunesenescence but was not associated with inflammageing. Instead inflammageing was associated with reduced physical activity and increased body fat. Furthermore, inflammageing and adrenopause was associated with increased frailty and mortality risk over a ten-year period. Accelerometer defined physical activity levels in healthy elders revealed a reduced inflammatory profile and improved neutrophil migration towards interleukin-8. Acute exercise revealed an enhanced inflammatory profile indicative of positive tissue adaptation. Furthermore there was a reduced ratio of cortisol to dehydroepiandrosterone-sulphate which was accompanied by enhanced neutrophil and monocyte bactericidal function. Subsequently ten-weeks of high-intensity interval training, which was more than half the time commitment of regular aerobic training, revealed similar reduced inflammation and improved neutrophil and monocyte bactericidal capacity.
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Warnatsch, Annika [Verfasser], Richard [Akademischer Betreuer] Lucius, Hartmut [Akademischer Betreuer] Hengel, and Elke [Akademischer Betreuer] Krueger. "Impact of proteasomal immune adaptation on the early immune response to viral infection / Annika Warnatsch. Gutachter: Richard Lucius ; Hartmut Hengel ; Elke Krueger." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://d-nb.info/1037389131/34.
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Barry, Julianne Cecile. "Immune cell phenotype and function : impact of type 2 diabetes, obesity, and exercise." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/64071.
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McCabe, R. H. "Towards a predictive model for pollutant impact on marine invertebrate cellular immune function." Thesis, Swansea University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.638040.
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The aim of this project was to develop predictive models for the impact of environmental pollution on marine invertebrate cellular immune function, through the analysis of the effects of season and selected organic chemicals on Mytilus edulis cellular immunity. In addition, the seasonal variation in Arenicola marina and Asterias rubens cellular immune function was studied to assess the suitability of these species as bioindicators of pollution. To achieve these aims, the blood cells of M. edulis and A. marina were initially classified into 3 and 5 subpopulations, respectively, based on the morphology and differential staining patterns of fixed cells, whereas the coelomocytes of A. rubens were classed as a single population. The phagocytic ability of M. edulis and A. marina blood cells was impaired during periods of spawning and the stability of lysosomal membranes decreased following these periods. Neutral red retention and phagocytosis assays were also employed to investigate the effects of organic chemicals, with known structural properties, on M. edulis cellular immune function, in order to identify structure-activity relationships. The chemicals studied were the amphiphilic cations, chlorpromazine (CP), clozapine (CZ) and chloroquine (CQ), the PAH, phenanthrene (PH) and the nitro-aromatic, methylene green (MG). Chlorpromazine and MG caused the greatest reductions in haemocyte lysosomal membrane integrity and phagocytic ability out of the 5 chemicals studied, which was believed to result, in part, from the inhibition of oxidative phosphorylation, thus limiting ATP available for the lysosomal retention of NR and phagocytosis, and the generation of radicals by CP and MG, which, in turn, may damage cell membranes. Finally, the NR retention and phagocytosis assays, developed in this project, were employed in field studies to compare the cellular immune function of M. edulis and A. marina sampled from 'polluted' and 'unpolluted' sites in South-West Wales. A. marina proved tolerant to oil pollution, presumably due to their ability, like other polychaetes, to metabolise oil hydrocarbons. In contrast, M. edulis cellular immunity was reduced at an industrialised, 'polluted' site compared with an 'unpolluted', rural site, and this trend correlates with tissue hydrocarbon burden.
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Neal, Stephanie Mary. "Adoptively transferred maternal colostral cells impact immune status and development in dairy calves." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/51629.
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Mortality and decreased weight gain resulting from infection and disease in dairy calves is a problem within the dairy industry. Colostrum is the sole source of maternal immunity for the calf, having a substantial impact on health and survival. To date, colostrum quality is determined by concentration of antibodies. Colostrum also contains proteins and cells, which may enhance immune development in the neonate. Our goals were to determine the impact of colostral immune cells on (1) immune status during the first month of life and (2) immune development over time. To determine the impact of adoptively transferred colostral immune cells, calves were fed either whole colostrum (WC) or cell-free colostrum (CFC) at birth. During the first month of life, calves fed CFC had decreased numbers of CD4+ T cells when compared to WC-fed calves. However, CFC-fed calves had a greater percentage of monocytes during the first month of life. To determine the influence of colostral immune cells on immune development, cellular blood parameters were measured in response to two series of vaccinations (A and B). After vaccination series A, CFC-fed calves had decreased numbers of B cells when compared to WC-fed calves. After vaccination series B, CFC-fed calves had decreased levels of interleukin-2 gene expression and numbers of CD4+ and gamma delta T cells when compared to WC-fed calves. This study demonstrates that colostral immune cells impact immune status and development in dairy calves.Master of Science
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Park, Myeongseon. "Dissecting the impact of macrophage migration inhibitory factor (MIF) on host immune response." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/97565.
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Macrophage migration inhibitory factor (MIF) has been implicated in mediating both innate and adaptive immune responses in inflammatory and infectious diseases. The sequence and structure of MIF is highly conserved across the avian phylogeny, which underlies high sequence homology and functional similarities between turkey and chicken MIFs. Turkey MIF (TkMIF) inhibited cell migration and promoted cell proliferation with production of inflammatory mediators, comparable to the biological properties of chicken MIF (ChMIF), thus indicating the biological cross-reactivity between turkey and chicken MIFs. This study identified the cell surface receptor(s) that could bind ChMIF and the biological roles triggered by such interactions. In addition to CD74, a previously identified receptor, CXCR4 also interacts with ChMIF. Moreover, the formation of receptor complexes was shown between CXCR4 and CD74. MIF signaling through CXCR4 and CD74 led to cell chemotaxis and proliferation activity as well as intracellular calcium influx. Intriguingly, Eimeria MIF (EMIF), a homologue secreted following parasitic infection, also interacted with CD74 leading to comparable biological functions to those of ChMIF. Given such observations, we hypothesized that CXCR4 and CD74 are receptors for ChMIF leading to the functional consequences similarly manifested by EMIF interaction with the corresponding receptors. EMIF, predominantly secreted from the invasive merozoite stage, may help the parasite exploit the host immune response by interacting with common ChMIF receptors. This may lead to functional mimicry thus provoking the question of whether EMIF would modulate the biological functions of ChMIF to manipulate the host defense that allows more efficient invasion of the host. To evaluate this concept, a transgenic E. tenella lacking MIF was generated by in vivo passage of E. tenella transfected with a CRISPR plasmid targeting EMIF. Although not fully disrupted, reduction of EMIF expression was observed in the transgenic E. tenella itself as well as in inoculated cells, which resulted in enhanced survival of host cells. Herein, we achieved a better characterization of the functional roles of both avian and parasite MIFs underlying the interaction with common host receptors, along with the essential role of parasite MIF promoting host cell death during parasitic infection.PHD
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Hellgren, Sofie. "Impact of cryopreservation and characterization of peripheral blood mononuclear cells and subsets in healthy donors by multicolor flow cytometry analysis." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-413035.
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Introduction: Immune therapy plays a larger role in cancer treatment these days, but in order to find new therapies and improve already existing ones, more knowledge about the immune system is needed. The peripheral blood contains many different cell types, some extensively studied, some less well-known. By using multicolor flow cytometry, the immune status of an individual can be displayed in relatively short time. Aim: The aim of this study was to develop a multicolor flow cytometry method in order to examine the distribution of 31 cell types, with a focus on immune regulatory cells, in peripheral blood in healthy donors, as well as examine the impact of cryopreservation on the different subsets. Methods: After isolating the mononuclear cells from peripheral blood using Ficoll separation, each sample (n = 19) were analyzed with three flow cytometry panels. The remaining cells were cryopreserved in -190°C and later thawed and analyzed the same way as the fresh samples were. Results: The cell distribution in fresh samples were mostly consistent with other studies. While the percentage of many cell types remained unchanged after thawing, the total percentage of T helper cells and some subsets were decreased in frozen samples, leading to a decrease in total T cells. Furthermore, the percentage of total monocytes were increased and the distribution of monocyte subsets were altered in frozen samples, among others. Conclusion: This study confirms the results of other studies of the human immune system and provides valuable knowledge about the impact of cryopreservation.
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Lira, Pedro Israel Cabral de. "Impact of zinc supplementation on the morbidity and growth of low birthweight infants in northeast Brazil." Thesis, London School of Hygiene and Tropical Medicine (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321777.
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Richey, Gary K. "The Impact of Psychosocial Variables on Immune System Functioning in a Sample of HIV-Positive Males." DigitalCommons@USU, 1992. https://digitalcommons.usu.edu/etd/6062.
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This study addressed the issue of the relationship between psychological well-being and immune function in a sample of HIV seropositive homosexual and bisexual males. A control group of HIV seronegative gay males was included. The study assessed the relationship between various psychological independent variables and immune system functioning over a 24-month time period for the seropositive subjects. Data on depression, coping style, psychosocial stress, and psychomatic symptoms were collected at baseline, as well as data on depression at 12 months and CD4 counts at 6-month intervals over a 2-year period. Preliminary analyses comparing HIV seropositive to HIV seronegative subjects showed differences on four of eight coping style scales, as well as on all of the psychogenic attitudes scales reflecting stress levels.
There were no effects of eight coping styles on immune system functioning for the seropositives. However, there were significant relationships among four of six psychogenic attitudes scales (chronic tension, premorbid pessimism, future despair, and somatic anxiety) and immune system functioning for the seropositives. There were also significant effects of three scales measuring psychosomatic symptoms (Allergic Inclination, Gastrointestinal Susceptibility, and Cardiovascular Tendency) for the seropositives. However, there was no effect of level of depression on immune system functioning.
The final chapter discusses the findings given the existing body of research. The emphasis is on the need to develop interventions targeting stress levels among persons with AIDS, as well as on conducting further research utilizing carefully constructed longitudinal research designs.
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Wu, Xi-Yang. "Studies on the impact of probiotic bacteria on enteric microbial diversity and immune response." Access electronically, 2006. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20061205.102712/index.html.
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Nóbrega, Cláudia Rubina Freitas Pereira de. "Infection of the thymus by micobacteria: potential impact on the immune response to infection." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/19397.
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Nóbrega, Cláudia Rubina Freitas Pereira de. "Infection of the thymus by micobacteria: potential impact on the immune response to infection." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/19397.
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Pieper, Natalia [Verfasser], and Annette [Akademischer Betreuer] Paschen. "Impact of IFN-γ resistance & MAPK inhibition on the immune surveillance of malignant melanoma - relevance for immune-based therapies / Natalia Pieper ; Betreuer: Annette Paschen." Duisburg, 2019. http://d-nb.info/1201274095/34.
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Nguyen, Trang Van. "Rotavirus vaccines and impact of maternal antibodies and cytokines on neonatal immune responses in swine." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1124135253.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xxv, 449 p.; also includes graphics (some col.). Includes bibliographical references (p. 376-449). Available online via OhioLINK's ETD Center
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Freund, Isabel [Verfasser], and Ralf [Akademischer Betreuer] Bartenschlager. "Impact of nucleotide modifications on immune stimulatory effects of RNA / Isabel Freund ; Betreuer: Ralf Bartenschlager." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177044579/34.
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Assmus, Lisa Mareike [Verfasser]. "Impact of chronic liver inflammation on adaptive immune responses to viral infection / Lisa Mareike Assmus." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1229989099/34.
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Ullah, Matti. "Immune Checkpoints in Peritoneal Carcinomatosis : HLA-G, PD-L1 & the Impact of Cancer Therapies." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS288.
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Carcinomatose péritonéale est un terme utilisé pour désigner la dissémination métastatique généralisée du cancer dans la cavité péritonéale. Il se caractérise par l’accumulation de liquide appelé « ascite » et est considéré comme étant au stade terminal du cancer, car il est difficile à traiter. L'ascite accumulée dans la PC comprend des cellules tumorales, cytokines et cellules immunitaires. Les cellules cancéreuses expriment des protéines spécifiques qui les aident à supprimer les cellules immunitaires et à survivre, appelées points de contrôle immunitaires. Des points de contrôle immunitaires sont présents pour réguler le système immunitaire et sont cruciaux contre la tolérance de soi. PD-1 / PD-L1 et CTLA-4 sont des voies de contrôle immunitaire bien établies adaptées au cancer pour échapper à l'immunité. Récemment, HLA-G a été reconnu comme un point de contrôle et il a été constaté que la survie globale était diminuée dans plusieurs types de cancers solides.Au cours de ma thèse, nous avons évalué l'expression de HLA-G dans la carcinomatose ovarienne. Nous avons constaté que les cellules cancéreuses dans l'ascite de presque tous les patients atteints de carcinomatose ovarienne exprimaient HLA-G. De plus, des taux croissants de sHLA-G1 et de HLA-G5 ont été trouvés dans les ascites. Cette présence de sHLA-G s'est révélée être corrélée positivement avec les Tregs et en corrélation négative avec les cellules T cytotoxiques (CD8) et les cellules NK. De plus, nous avons constaté que les ascites peuvent induire l’expression de HLA-G dans des «Hospicells» via des cytokines inflammatoires. Parmi les cytokines inflammatoires, le TGF-β et IL-1β ont une importance capitale dans l’induction de HLA-G. En outre, nous avons constaté que IL-1β implique la voie NF-κB. Dans une cohorte distincte de carcinomatose péritonéale, composée de patients atteints de PC d'origine différente, nous avons constaté que le groupe de cellules cancéreuses dans l'ascite avait une expression génique hétérogène de PD-L1, CTLA-4 et HLA- G. En outre, nous avons constaté que tous les patients présentaient des taux solubles de HLA-G et PD-L1 dans leur ascite. Cependant, seulement 5 patients présentaient des taux de CTLA-4 solubles dans leur ascite. De plus, nous avons trouvé une très forte corrélation positive entre le niveau de gène de PD-L1 et de CTLA-4, alors qu'aucune corrélation n'a été trouvée pour HLA-G avec PD-11 et CTLA-4 suggérant que HLA-G agit indépendamment des deux points de contrôle immunitaires. En outre, nous avons évalué l'expression de ces points de contrôle immunitaires par des nodules de cancer présents sur la membrane péritonéale. Nous avons trouvé une faible expression de HLA-G et PD-L1, mais la moitié des échantillons étaient fortement positifs pour sHLA-G. Nous avons également constaté que le sHLA-G pouvait être absorbé par l'ascite par la couche mésothéliale. Cette sHLA-G absorbée peut fournir un environnement immunosuppresseur pour la fixation des grappes de cellules cancéreuses à la membrane péritonéale. In vitro, nous avons constaté que l'ascite peut exercer une action immunosuppressive et retarder la lyse des cellules cancéreuses par les cellules immunitaires.De plus, nous avons constaté que la différenciation des cellules cancéreuses se traduit par une augmentation des propriétés immunosuppressives par une expression accrue de HLA-G ou PD-L1. En outre, l'expression de HLA-G et PD-L1 dépend de la phase du cycle cellulaire. Les cellules cancéreuses, si elles sont bloquées dans les cellules mitotiques, expriment des niveaux élevés de HLA-G et de PD-L1, tandis qu'une expression plus faible a été observée en phase G1. Par conséquent, nous suggérons d’éviter l’utilisation d’inhibiteurs de la mitose car ils pourraient augmenter la suppression immunitaire du cancer. De plus, le Ki-67 étant directement lié à l'index mitotique, nous suggérons de développer une échelle de Ki-67 pour évaluer le profil d'immunosuppresseur des patients cancéreuxPeritoneal carcinomatosis (PC) is a term used for widespread metastatic dissemination of cancer to the peritoneal cavity. It is characterized by the accumulation of fluid called “ascites” and is considered a terminal stage of cancer, as it is hard to treat. The overall survival rate for untreated patients is six-months. However, owing to modern techniques like HIPEC, the survival rate can be increased up to five years. The ascites accumulated in PC, consists of tumor cells, cytokines and immune cells. Cancer cells express specific proteins to suppress immune cells activity and their attack, known as immune checkpoints. PD-1/PD-L1 and CTLA-4 are well established immune checkpoint pathways adapted by cancer in evading immunity. Recently, HLA-G has been recognized as an immune checkpoint and has been found to decrease overall survival in several types of solid cancers. We evaluated the expression of HLA-G in ascites from ovarian carcinomatosis. We found that HLA-G is expressed by cancer cells in ascites from all of the patients(n=16) with ovarian carcinomatosis. Moreover, increased levels of sHLA-G1 and HLA-G5 were found in ascites. This presence of sHLA-G isoforms was found to be positively correlated with Tregs and negatively correlated with cytotoxic T-cells (CD8) and NK-cells suggesting the role of HLA-G in immune suppression. Further, we found that ascites can induce the expression of HLA-G in “Hospicells” via inflammatory cytokines. Among the inflammatory cytokines, TGF-β and IL-1β are of crucial importance in HLA-G induction with IL-1β being more potent compared to TGF-β. Further, we found that IL-1β induces HLA-G expression through NF-κB pathway.In a separate cohort of peritoneal carcinomatosis(n=27), consisting of patients with cancer from a different origin, we found that cancer cell cluster in ascites (n=23) had a heterogeneous gene expression of PD-L1, CTLA-4 and HLA-G. Further, we found that all of the patients presented soluble levels of HLA-G in their ascites. However, one patient was negative for soluble PD-L1 and only 5 patients presented soluble CTLA-4 levels in their ascites. This heterogeneity explains why some of the patients respond to immune therapy while others don’t. This also suggests the need for prescreening patients before immune therapy. Moreover, we found a very strong positive correlation (rs=0.793) between gene level of PD-L1 and CTLA-4, while no correlation was found for HLA-G with PD-L1 and CTLA-4 suggesting that HLA-G acts independently of both the immune checkpoints. Also, we evaluated the expression of these immune checkpoints by cells in peritoneal tissue (n=20). We found low expression of HLA-G and PD-L1, but the majority of the samples were found strongly positive for sHLA-G presence. This sHLA-G can provide an immune-suppressive environment for the attachment of the cancer cell clusters to the peritoneal membrane to form cancer nodule. Additionally, we developed an in-vitro cytotoxicity assay to show that the ascites can provide the immune-suppressive action by interfering with immune cell interaction and delaying the lysis of cancer cells by the immune cells.In parallel, we found that the differentiation of the cancer cells results in increased expression of immune checkpoints like HLA-G or PD-L1. This may render these cells more immune resistant and can protect against immune attack. However, in-vivo mice model is needed to study the oncogenic potential of these differentiated cells. Further, we report that the expression of HLA-G and PD-L1 is dependent on the cell cycle phase. The cancer cells, if blocked in mitotic phase express high levels of HLA-G and PD-L1, while lowest expression was observed in G1-phase. Therefore, we suggest avoiding the use of mitotic inhibitors as it may increase the immune suppression of cancer. Moreover, as Ki-67 is directly related to the mitotic index, we suggest developing a Ki-67 scale to evaluate the immune-suppressive profile of cancer patients
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Arakelian, Tsolère. "Impact of Targeting the Autophagy Related Gene Beclin 1 on the Immune Landscape of Melanoma." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS193.
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L'immunothérapie basée sur le blocage des points de contrôle immunitaire (ICBs) est un traitement prometteur pour les patients atteints de mélanome ; cependant, seule une petite sous-population en tire un bénéfice à long terme. Un des défis pour améliorer l'efficacité et étendre le bénéfice des ICBs aux patients non répondeurs est de concevoir des approches innovantes permettant de transformer les tumeurs dites "froides ou désertes pour les cellules immunitaire" en tumeurs dites "chaudes ou infiltrées par les cellules immunitaires" qui sont éligibles aux ICBs. Nous avons étudié l'impact du ciblage du gène de l'autophagie Beclin1 sur le paysage immunitaire des tumeurs de mélanome B16-F10. Nos résultats ont démonté que ce ciblage inhibait significativement la croissance tumorale B16-F10 et augmentait l'infiltration des leucocytes CD45+. Le phénotypage immunitaire a révélé une augmentation de l'infiltration de cellules NK (Natural Killer) actives, de macrophages inflammatoires et résidents de type 1, de cellules dendritiques et de lymphocytes T CD8+ actifs. L’inhibition de la croissance tumorale Becn1- n'était plus observée par la déplétion des CD8+ de l'hôte, soulignant ainsi leur rôle dans le contrôle du développement de ces tumeurs. Nos résultats ont démontré que La régulation du paysage immunitaire des tumeurs Becn1- était associée à une modulation du réseau de cytokines/chémokines dans le microenvironnement tumoral (TME). Ainsi, les tumeurs Becn1- présentaient une signature de cytokines inflammatoires (comprenant CCL5, CXCL10 et IFNg) qui pourrait être responsable de l'établissement de microenvironnement inflammatoire permissif aux cellules CD8. Nous avons révélé que la surexpression de l'IFNg dans le TME des tumeurs Becn1- était responsable de l'induction de PD-L1 sur les cellules tumorales par la voie d'activation JAK/STATs. En conclusion, cette étude met en évidence Beclin1 comme une cible majeure, capable d'induire l'infiltration des cellules effectrices immunitaires dans les mélanomes en induisant une signature inflammatoire. Elle fournit également la preuve de concept pour combiner des inhibiteurs d'autophagie avec les ICBs comme une approche de pointe pour améliorer leur efficacitéImmune Checkpoint Blockades (ICBs)-based immunotherapy has emerged as a promising treatment for melanoma patients; however only a small subset of patients reaps a long term benefit. One of the major challenges to enhance the efficacy and extend the benefit of ICBs to non-responder patients is to design innovative approaches allowing the switch of “immune desert cold tumors” to “immune infiltrated hot tumors" which are eligible for ICB-based therapies. Here, we investigated the impact of targeting the early autophagy gene Beclin1 on the immune landscape of B16-F10 melanoma tumors. We found that targeting Beclin1 (Becn1-) significantly inhibited B16-F10 tumor growth and increased the infiltration of CD45+ leukocytes into the tumor bed. Immune phenotyping revealed an increased infiltration of active Natural Killer (NK) cells, inflammatory and resident type 1 macrophages, dendritic cells, and active CD8+ T lymphocytes. The inhibition of Becn1- tumor growth was no longer observed by depleting host CD8+ T cells, thus highlighting their major role in the control of Becn1- B16-F10 tumor development. We showed that Beclin1-dependent regulation of the immune landscape was associated with profound modulation of the cytokine/chemokine network in the tumor microenvironment (TME). Importantly, we revealed that Becn1- tumors displayed an inflammatory cytokine signature (comprised, but not restricted to, CCL5, CXCL10 and IFNg) that could be responsible for the switch from cold non T-inflamed to hot T-inflamed tumors. Mechanistically, we reported that the overexpression of IFNg in Becn1- TME was responsible for the induction of Programed Death ligand-1 (PD-L1) on tumor cells through the activation of JAK/STATs pathway. Overall, this study highlights Beclin1 as a valuable target, able to drive immune effectors cells into the melanoma tumors by inducing an inflammatory signature. This study provides the proof of concept for combining drugs inhibiting early autophagy process along with ICBs as a cutting-edge approach to improve their efficacy
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Sjöberg, Veronika. "Immune response of the small intestinal mucosa in children with celiac disease : impact of two environmental factors, resident microbiota and oats." Doctoral thesis, Umeå universitet, Klinisk immunologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-71030.
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Celiac disease (CD) is an immune-mediated enteropathy caused by permanent intolerance to dietary gliadin in wheat gluten and related prolamines in barley and rye. The pathogenesis of CD is still unknown and several different environmental factors have been associated with CD, such as dysbiosis of the microflora. In this translational study we investigated the immune status and the interplay of T-cells and Tregs in the mucosa of children with CD and controls, as well as the immune status in treated CD patients, provoked by either dietary oats, CD associated bacteria or gluten. The major findings in the studies were: First, indicators of extrathymic T-cells maturation (ETCM), i.e., the RAG1 enzyme required for recombination of the T cell receptor (TCR) genes and the preTα-surrogate chain in the immature TCR, were both expressed at lower levels in CD patients compared to controls. In addition, IELs expressing RAG1 were less abundant in CD patients compared to controls. The levels of these two indicators stayed low in treated CD patients as well, suggesting that impaired capacity of ETCM is an inherent feature of CD patients. Second, IL-17A, a cytokine involved in both inflammation and anti-bacterial responses was increased in active CD. The major cellular source was CD8+IELs. Furthermore, ex vivo challenge of biopsies from treated CD patients with gluten and with CD-associated bacteria induced an IL-17A response. The CD-associated bacteria also influenced the magnitude of the IL-17A response to gluten. Third, we investigated the effect of dietary oats on local immune status in the intestinal mucosa by comparing CD patients receiving GFD with and without oats. 22 different mRNAs for immunity effector molecules and tight junction proteins were analyzed. We found that expression of two down-regulatory cytokines, two activating NK-receptors and the tight-junction protein claudin-4 normalized in patients on a standard GFD while they did not normalize in patients on a GFD with oats. Fourth, we analyzed the expression level of mRNAs for chemokines, cytotoxic effector molecules, NK-receptors and their ligands in IELs and epithelial cells. Expression levels of several of these genes follow disease activity, suggesting massive recruitment of immune cells by both cell types accompanied by increased IEL-mediated cytotoxicity in the epithelium of inflamed mucosa. In this thesis we have identified three potential risk factors for development of CD: 1) an inherent lower level of ETCM in the small intestinal mucosa than in controls. This could lead to decreased generation of regulatory T cells and less capacity to tolerate gluten and adapt to the local milieu in the mucosa. 2) Dysbiosis of the resident microbiota with increased IL-17A production that could promote local inflammation and immune cell infiltration as well as antibacterial reactions. 3) Dietary oats may provoke a local immune response in a sub-population of CD patients. These patients should probably avoid oats in their GFD but larger studies are needed.
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Gondorf, Fabian [Verfasser]. "Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis / Fabian Gondorf." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080561307/34.
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Richards, Hannah Elizabeth. "Investigation of the impact of CD4+CD25+ regulatory T cells on immune responses induced in vivo." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/54679/.
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CD4+CD25+ regulatory T cells (Treg) are known to inhibit T cell responses however their site of action and whether they suppress other immune responses has not been well characterised. Using a model of tumour rejection involving a melanoma cell line expressing Fas ligand (B16FasL) the effect of Treg on these responses has been studied. NK cells and macrophages were found to play a critical role in rejection of B16FasL. Depletion of Treg enhanced tumour rejection, whilst adoptive transfer of Treg inhibited tumour rejection, indicating that Treg suppress innate immune responses. Experiments performed to identify the Treg target indicated that Treg inhibit the cytolytic activity of NK cells. Furthermore, depletion of Treg enhanced the inflammatory infiltrate within 24 hours, which consisted of elevated numbers of neutrophils, indicating that Treg not only inhibit innate immune responses, but also act rapidly. Another aim of this project was to identify whether Treg act in lymphoid organs or at the tumour site. T cells from transgenic mice, in which lymph node horning receptor CD62L expression is maintained upon activation (LAP), were predicted not to enter inflamed tissue. However, experiments showed that T cells from LAP mice could enter inflamed lungs following influenza infection. Characterisation of memory T cell responses indicated that LAP mice exhibit delayed viral clearance, despite comparable cell numbers, cytolytic activity, and levels of CD 107a and IFNy. Control transgenic mice in which CD62L can be shed, showed no defect in viral clearance indicating that inability to shed CD62L in LAP mice did not affect T cell migration but compromised anti-viral immunity. Although not suitable to study location of Treg action, this data indicated that CD62L shedding is important for memory T cell responses.
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Ibbett, Paul. "The impact of systemic immune system activation on the retina : implications for age-related macular degeneration." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/418420/.
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Age-related macular degeneration (AMD) is a neurodegenerative disease of the retina and the leading cause of blindness in the UK. Genetic studies and mouse models demonstrate a clear role for local immune activation in AMD pathology, but it is not clear whether systemic inflammation can contribute to AMD pathology. Systemic inflammation, particularly due to bacterial infection, has been shown to exacerbate neurodegeneration in Alzheimer’s and Prion disease. There is also evidence that patients who have been exposed to chronic bacterial infections (i.e. periodontitis, pneumonia) are at increased risk of AMD development. Consequently, this thesis tests the hypothesis that systemic inflammation can contribute to the progression of AMD by exacerbating local inflammation in the retina, leading to earlier development of blindness. Systemic bacterial (Salmonella) infection induced retinal microglial activation, Müller cell activation, T cell recruitment and pro-inflammatory cytokine production in mice. When subsequent peripheral immune stimulation was induced by LPS, retinal inflammation was reduced, indicating a protective mechanism. However, during ongoing local retinal inflammation induced by immune complexes, systemic inflammation exacerbated the recruitment of immune cells to the subretinal space. No retinal degeneration was observed in this model, so a novel laser-induced model of acute outer retinal atrophy was developed showing RPE dysfunction, photoreceptor loss, functional deficits and inflammation mimicking aspects of human geographic atrophy. This model could be used to investigate the interaction of systemic inflammation and degeneration, gaining insights into AMD pathobiology. In AMD patients, increased aqueous humour IL-8 was identified compared to age-matched controls but no differences in serum cytokine levels were observed at baseline or in whole blood cultured with various immune stimuli. Data from mouse experiments indicate that systemic infections can induce chronic retinal inflammation and, during local inflammation, immune cell recruitment to the subretinal space - the site of AMD pathology. Meanwhile, human data demonstrates that local inflammation in AMD patients does not arise due to an exaggerated systemic inflammatory response to infections.
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Ott, Christopher Philip. "Impact of Dietary Beta-glucan Supplementation on Performance and Immune Response of Broiler Chickens During Challenge." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/75170.
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Coccidiosis is a costly parasitic disease to the poultry industry with multiple prevention methods being explored to control its impact. One approach under development is the use of -glucans, which are carbohydrates from cell walls of various plant species. The first study evaluated the feeding effects of algae- derived -glucans on performance and responses of broilers during a coccidiosis challenge. Cobb 500 broilers (n=1280) were fed a control diet, control supplemented with 150 g/MT Algamune (BG), 100 g/MT Algamune ZPC (BGZn), or 0.01% Salinomycin (Sal). On d 15, challenged birds received mixed Eimeria inoculum. Measurements were taken on d 7, 14, 21, and 28, and lesion scores assessed on d 21. The challenge resulted in reduced BW, and higher feed conversion ratio (FCR) was observed in the challenged birds with Sal and BGZn. Escherichia coli (E. coli) is normally commensal to the gastrointestinal tract, but certain serotypes cause disease in domestic poultry. A subsequent study was conducted to evaluate the feeding effects of algae-derived glucan (1,3 -glucan) on performance of broiler chickens during an E. coli challenge. Cobb 500 broilers (n=900) were fed a control diet, control + 25 mg/kg of -glucan, or control + 100 mg/kg of -glucan. On d 0, litter was sprayed with E. coli inoculum. Measurements were taken on d 7, 14, 21, and 28. -glucan supplementation increased BW gain andlowered FCR. The results from these studies offer some insight to the effects of -glucans on poultry and their potential to offset negative effects caused by infectious challenges.Master of Science
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Dungey, Maurice. "Exercise in haemodialysis patients : impact on markers of inflammation." Thesis, Loughborough University, 2015. https://dspace.lboro.ac.uk/2134/17157.
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End-stage renal disease patients have a greatly increased risk of cardiovascular disease partly attributed to the elevated levels of systemic inflammation observed in uraemia. One of the key mechanisms underlying inflammation appears to be the immune dysfunction that afflicts almost every aspect of the uraemic immune system. As a consequence patients experience immunosuppression and reduced responsiveness to antigen as well as a simultaneous over-activation leading to a pro-inflammatory environment. In addition, the haemodialysis (HD) treatment itself induces a proinflammatory response but may provide an otherwise opportune time to complete supervised exercise.
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Balthazar, Monique Stephanie. "THE IMPACT OF POPULATION CHARACTERISTICS AND HEALTH BEHAVIORS ON THE IMMUNOLOGIC FUNCTION OF PEOPLES LIVING WITH HIV/AIDS IN A MIDWESTERN CITY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396649416.
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Povey, Sonia. "Eating for Resistance : The Impact of Macro-Nutrients on Immune Function and Pathogen Resistance in Spodoptera exempta." Thesis, Lancaster University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524768.
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Harre, Ulrike [Verfasser], and Falk [Akademischer Betreuer] Nimmerjahn. "The impact of IgG sialylation on the osteoclastogenic activity of immune complexes / Ulrike Harre. Gutachter: Falk Nimmerjahn." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2015. http://d-nb.info/1076399061/34.
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Tsai, Ming-Han Chloe. "The impact of HLA-driven escape mutation on viral replicative capacity and immune control in HIV infection." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:398b1b9b-c8e8-49db-826d-cdbc915317a8.
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Despite the introduction of antiretroviral therapy, the HIV/HIV epidemic remains an unsolved global health problem. Amongst all the host defence mechanisms, HLA class I molecules have shown the strongest genetic association with delayed disease progression, in particular HLA-B alleles. Numerous studies have shown that the HLAmediated CD8+ T cell responses play a central role in the immune control of HIV. Yet our understanding of HLA-mediated immune control of HIV remains incomplete, even when considering the best-defined epitopes restricted by the protective HLA alleles at a population level. The studies I have conducted and describe herein focus on two well-charaterised protective HLA-B molecules, HLA-B*81:01 and HLA-B*27:05; a third protective molecule, HLA-B*52:01, that has not been well-studied hitherto; and finally the most prevalent HLAB allele in many Asian populations such as Taiwan, HLA-B*40:01, which has an apparently neutral effect on viral replication. This thesis is centred on the Gag-specific immune response, since previous studies have shown the benefits of CD8+ T-cell responses targeting this conserved and immunogenic region of the HIV proteome, in particular the p24 capsid protein. I have investigated here HLA footprints driven by CD8+ T-cell pressure on HIV that are evident in the viral sequences of individuals expressing these HLA molecules. These footprints include novel escape and putative compensatory mutations. The impact of these variants on viral replicative capacity (VRC) and on HIV disease outcome clinical outcomes was examined via fitness assays. These studies identified several escape mutations that effectively cripple HIV. The distinct compensatory pathways available to the virus to mitigate the fitness cost of particular escape mutations were evaluated. In the course of these analyses I have demonstrated the critical influence of the viral backbone, including HIV clade, in combination with particular viral variants, on VRC. Computational modelling analysis has been applied to facilitate understanding of the mechanism by which certain mutants affect the stability of interactions between HLA and viral capsid protein. This thesis offers novel insights into immune control of the key HIV subtypes â B- and C-clade â and of the most severely affected populations â in Africa (South Africa) and Asia (India and Taiwan) â within the global epidemic. This work helps to better define the viral mutation landscape that is essential both for future vaccines designed to corner the virus, and for successful HIV cure strategies.
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Juarez, Molina Claudia Ivette. "Population-specific HLA impact in immune control of HIV in Mexico and non-Mexican HIV infected cohorts." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2a6242d2-91bf-4029-9067-a922cbf1d8e4.
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HIV-1 persists to be a major health problem worldwide. A prophylactic or therapeutic vaccine offers the best hope to restrain the HIV-1 epidemic, however a consistent correlate of immune protection is yet to be found. HLA class I expression and their restricting HIV-1 specific CD8+ T cell responses have been shown to play a vital role in the control of HIV-1 infection. The interactions between HIV-1 and CD8+ T cell responses are complex and the mechanisms involved in the success or failure to control viraemia remain uncertain. Thus, the aim of these studies was to help define what CD8+ T cell responses a vaccine needs to induce to achieve durable immune control of HIV-1 infection. Focusing initially on HLA-B*35, an allele that has consistently been associated with rapid HIV-1 disease progression in the context of B clade infection, this study shows substantial differences in markers of HIV-1 disease outcome associated with different HLA-B*35 subtypes. Preliminary data suggest that effective targeting of a single epitope in Gag may be associated with HLA-B*35 mediated control of HIV-1 disease progression. Increased breadth of the Gag- specific CD8+ T cell responses is found to be associated with decreasing viral loads. These data therefore support the Gag hypothesis, and suggest that targeting of certain regions of the HIV-1 genome may have a positive effect in disease outcome, even for individuals carrying “detrimental” alleles. The extensive diversity of the HIV-1 genome and rapid viral adaptation are the main chal- lenges to vaccine design. Previous studies have suggested that effective CD8+ T cell responses drive selection of escape mutations that reduce viral replication capacity (VRC). There is also evidence that certain escape mutations can be transmitted from one host to another allow- ing for its accumulation in a population. The second study looked at the impact of HLA driven evolution of HIV-1 in VRC at a population level. This study compared two ART-naïve HIV-1 B clade infected cohorts, in Mexico and Barbados, in which protective HLA alleles (HLA- B*27/57/58:01/81:01) are expressed at 10% and 35% respectively, to analyze differences in VRC at a population level. Viral loads (VL) were found to be significantly higher in Mexico compared to Barbados and median CD4+ T cell counts significantly lower. Analysis of VRC in a subset of subjects in each cohort matched by CD4+ T cell counts between 300-500 cells/μl revealed that VL and VRC was significantly higher in the Mexican subset. This VRC difference was associated with accumulations in Barbados of eight previously described Gag escape mutation where fitness cost has previously been implicated. Accumulation remained significant in mismatched subjects. These data suggest that VLs and disease progression rates may differ between distinct populations as a result of the frequency of protective alleles in the respective populations, and that CD4+ T cell count-based guidelines to initiate antiretroviral therapy (ART) may need to be modified accordingly, to optimize the effectiveness of treatment-for-prevention strategies and reduce HIV-1 transmission rates to the absolute minimum. The final project aimed to improve the HIV-1 replication fitness assays currently used in the context of C clade infection. In order to achieve this, we attempted to design a clade C infectious molecular clone for the testing of gal-pol gene regions. However, the clones produced were not replication competent. Sequence analysis showed a large quantity of stop codons, most located within env which may explain the lack of infectivity. Chapter 5 describes the methodology used in the construction of the clade C isolate and suggests future work. Although we were unsuccessful in producing a replication competent virus, the construction of a C clade backbone which replicates efficiently remain an aim due to its importance for research directed to the analysis of genetic determinants of C clade virus. Data presented in this thesis suggest that vaccine-induced immune responses should aim to focus on vulnerable regions of the virus. These are conserved regions that can not escape without a high fitness cost and with a complex and difficult selection of compensatory mutations. Although much work remains to be done to achieve an effective CD8+ T cell based vaccine, hope remains that the induction of HIV control may be possible.
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Wanjiku, Samuel Mburu. "Impact of inflammation-induced oxidative stress on the integrity of immuno-haematopoietic cells and potential ameliorating interventions in an in vitro HIV model." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/95467.
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Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: Chronic inflammation and immune activation are hallmarks of HIV infection, resulting in chronic oxidative stress with over-utilization of antioxidant defences, which may contribute to the loss of immune cells and faster disease progression. Low levels of antioxidants in HIV- infected individuals have been associated with frequent opportunistic infections and an increased risk of mortality. HIV infection is also associated with on-going and aberrant activation of both the innate and adaptive immune systems. An important aspect of innate immune stimulation is derived from the leakage of lipopolysaccharide (LPS) across the damaged mucosal lining of the gut in early HIV infection. The impact of this innate immune stimulation on the adaptive arm of the immune system, as represented in this study by levels of CD4+ T-cell activation and death, have not been explored previously in untreated HIV infection. Using an integrated approach of immune activation, inflammation, oxidative stress and ameliorating antioxidant intervention for the first time, this thesis reports the impact of inflammatory induced-oxidative stress on CD4+ T-cells in an in vitro HIV model. In a preliminary study, baseline levels of neutrophil respiratory burst as an in vitro indication of immune stimulation were investigated. The relationships between baseline total antioxidant status (TAS), Red blood cell (RBC) antioxidant enzyme activities (catalase, superoxide dismutase & glutathione peroxidase), lipid peroxidation and glutathione redox ratio and other markers of disease in asymptomatic, untreated HIV infection were also explored. The design and optimization of an assay that could determine the effects of LPS-induced oxidative stress on CD4+ T-cells, was a critical part of this study. The development of this assay enabled the measurement of the effects of selected antioxidant interventions N-acetyl cysteine (NAC) and vitamin C, on LPS-induced CD4+ T-cell activation and death. The results were also correlated with CD4 count, viral load and markers of inflammation (fibrinogen & D-dimers) in HIV-infected and uninfected groups. Neutrophils from HIV-infected persons at rest showed a ―primed‖ response to low stimulating agent, bacterial N-formyl peptides (fMLP), which was significantly (P = 0.04) higher than uninfected individuals. There was increased oxidative stress as evidenced by increased catalase activity, malondialdehyde (MDA) and conjugated dienes (CDs) with a corresponding decrease in antioxidant capacity in HIV-infected individuals with lower CD4 count. NAC in combination with vitamin C, significantly (P = 0.0018) reduced activation of CD4+ T-cells to a greater degree than with either antioxidant alone. NAC and vitamin C individually and in combination significantly (P = 0.05, P = 0.012 and P<0.0001) decreased the expression of the markers of apoptosis, Annexin V and 7-amino-actinomycin (7-AAD). Importantly, the antioxidant combination decreased MDA values and significantly (P = 0.01) increased the glutathione redox ratio in the HIV-infected group. Based on these results, the respiratory burst and LPS-induced activation may be important contributing factors in inflammatory-associated oxidative stress in HIV infection and contribute to the depletion of CD4+ T-cells in the asymptomatic stage of HIV infection. These results also indicate the potential inhibitory effects of NAC and vitamin C in combination as agents that may limit immune activation and inflammation-induced oxidative stress. Importantly, the study showed that at this asymptomatic stage, CD4+ T-cells of the HIV-infected group responded similarly to stimulation as the HIV negative group, indicating that antioxidant defences were still functional and that appropriate early intervention at this stage may be protective against oxidative damage to the immune cells. To the best of our knowledge, this study is the first to use an integrated approach involving not only plasma levels of antioxidant status, but also RBC antioxidant enzyme activities, oxidative damage (lipid peroxidation), inflammation, cellular levels of immune activation and potential ameliorating interventions in evaluating the problem of inflammation-induced oxidative stress in HIV infection. Based on the results of this study, it is envisaged that an insight into the immune activation, inflammatory and oxidative stress status of patients will enable long-term profiling of each patient with a view to individualized therapy. This approach may have a direct impact on patient care in resource-limited settings such as sub-Saharan Africa.
AFRIKAANSE OPSOMMING: Chroniese inflammasie en immuunaktivering is kenmerke van MIV-infeksie. Dié twee prosesse lei tot chroniese oksidatiewe stres en oorbenutting van antioksidant verdedigingstelsels, wat lei tot die verlies van die immuun selle en vinniger siektevordering. Lae vlakke van antioksidante in MIV-positiewe individue stem ooreen met gereelde opportunistiese infeksies en 'n verhoogde risiko van mortaliteit. MIV-infeksie word ook geassosieer met langdurige en abnormale aktivering van beide die ingebore en aanpasbare immuunstelsels. 'n Belangrike aspek van ingebore immuun stimulasie in die raamwerk van vroeë MIV-infeksie, is die lekkasie van LPS oor die beskadigde slymvlies voering van die dunderm. Die impak van die ingebore immuun stimulasie op die aanpasbare arm van die immuunstelsel, soos aangetoon in hierdie studie deur die vlakke van CD4 T-sel aktivering en apoptose, is nog nie voorheen ondersoek in onbehandelde MIV-infeksie nie. Met behulp van 'n oorspronklike, geïntegreerde benadering van immuun aktivering, inflammasie, oksidatiewe stres en 'n lae vlak van antioksidant intervensie, lewer hierdie tesis verslag oor 'n in vitro model van inflammasie-geïnduseerde oksidatiewe stres op CD4 T-selle. In 'n voorlopige studie, is basislyn vlakke van die neutrofiel respiratoriese uitbarsting as 'n in vitro aanduiding van immuunstimulasie ondersoek. Die verhoudinge tussen basislyn totale antioksidant status (TAS), rooi bloed sel (RBC) antioksidant ensiemaktiwiteit (katalase, superoksied dismutase, en glutatioon peroksidase), lipied peroksidasie en glutatioon redoks-verhouding, asook ander merkers van siektevordering in asimptomatiese, onbehandelde MIV-infeksie is ook ondersoek. Die ontwerp en optimisering van 'n toets wat die effek van LPS-geïnduseerde oksidatiewe stres op CD4 T-selle kan bepaal, was 'n kritieke deel van hierdie studie. Die ontwikkeling van hierdie toets het ook die meting van die effek van toevoeging van twee geselekteerde anti-oksidante, N-asetiel sisteïen (NAC) en vitamien C, op LPS-geïnduseerde CD4 T-sel aktivering en apoptose ondersoek. Die resultate is ook gekorreleer met CD4-telling, virale lading en merkers van inflammasie (fibrinogeen en D-dimere) in groepe met en sonder MIV-infeksie. Neutrofiele van asimptomatiese persone met MIV infeksie, het 'n 'voorbereide' reaksie gehad teen ‗n lae stimulerende agent, bakteriële N-formiel peptied (fMLP), wat beduidend (P = 0,04) hoër was as in individue sonder MIV infeksie. Daar was verhoogde oksidatiewe stres soos bewys deur verhoogde katalase aktiwiteit, malondialdehied (MDA) en gekonjugeerde diëne (CDs), saam met 'n ooreenstemmende afname in anti-oksidant kapasiteit in MIV-positiewe individue met laer CD4-tellings. NAC in kombinasie met vitamien C, het die aktivering van CD4 T-selle beduidend verminder (P = 0,0018), 'n effek wat groter was in vergelyking met elke antioksidant alleen. NAC en vitamien C alleen, en in kombinasie het beduidend die uitdrukking van die merkers van apoptose, Annexin V en 7-AAD verminder (P = 0,05, P = 0.012 en P<0,0001). Wat belangrik is, is dat die afname in MDA waardes as gevolg van antioksidante in kombinasie, 'n beduidende styging in die glutatioon redoks verhouding in die MIV-positiewe groep tot gevolg gehad het. Hierdie resultate het aangetoon dat die respiratoriese uitbarsting en LPS-geïnduseerde aktivering belangrike bydraende faktore mag wees in inflammasie-verwante oksidatiewe stres in MIV-infeksie, wat kan bydra tot die uitputting van CD4 T-selle in die asimptomatiese stadium van MIV-infeksie. Hierdie resultate dui ook aan dat die moontlike inhiberende effekte van NAC en vitamien C in kombinasie, immuun aktivering en geïnduseerde oksidatiewe stres kan beperk. Van belang is die feit dat hierdie studie bewys het dat in die asimptomatiese stadium van MIV-infeksie, CD4 T-selle weens stimulasie dieselfde gereageer het as dié van mense sonder MIV infeksie. Dit het aangedui dat antioksidant verdediging in hierdie stadium nog funksioneel was, en dat 'n toepaslike vroeë intervensie op hierdie stadium beskermend teen immuun-sel oksidatiewe skade kan wees. Tot die beste van ons kennis, is hierdie studie die eerste om 'n geïntegreerde benadering te gebruik, waar plasma vlakke van antioksidant status saam met RBC antioksidant ensiemaktiwiteit, oksidatiewe skade (lipied peroksiidasie), inflammasie, sellulêre vlakke van immuunaktivering, en potensiële beskermende ingrypings ondersoek is in die evaluering van die probleem van oksidatiewe stres in MIV-infeksie wat tot inflammasie lei. Gebaseer op dié resultate, word dit in die vooruitsig gestel dat 'n insig in die status van immuunaktivering, inflammasie, en oksidatiewe stress van pasiënte, dit moontlik sal maak vir langtermyn- beplanning om vir elke pasiënt individuele terapie voor te skryf. Hierdie benadering kan 'n direkte impak op die sorg van pasiënte in hulpbron-beperkte gebiede soos sub-Sahara Afrika hê.
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Mays, Jacqueline Wiesehan. "Psychosocial stress modulation of the murine anti-viral immune response during a primary influenza infection and the impact on immunologic memory." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1241712390.
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Chachage, Mkunde Seithy [Verfasser], and Michael [Akademischer Betreuer] Hoelscher. "Immune system modulation by infections with Helminths and HIV-1 : Impact on pathogen-specific T cellresponses, regulatory T cells and systemic immune activation / Mkunde Seithy Chachage. Betreuer: Michael Hoelscher." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1049393228/34.
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Groh, Janos [Verfasser], and Rudolf [Akademischer Betreuer] Martini. "Pathogenic impact of immune cells in mouse models of neuronal ceroid lipofuscinosis / Janos Michael Groh. Betreuer: Rudolf Martini." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/103768785X/34.
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Sam, Leila. "Impact of Parkinson’s Disease- Linked- Lrrk2 Mutation (Lrrk2G2019S) on the Innate Immune Response During Infection with Listeria Monocytogenes." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41190.
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Mutations in the Leucine-rich repeat kinase 2 (Lrrk2) gene are associated with familial and sporadic cases of Parkinson’s disease but are also found in inflammatory-related disorders such as Crohn’s disease, systemic lupus erythematosus, tuberculosis and leprosy. There is also evidence that LRRK2 is highly expressed in immune cells, particularly in macrophages, and has been functionally linked to pathways pertinent to immune cell function such as modulating the course of infections, cytokine release, autophagy and phagocytosis. Indeed, G2019S mutation in Lrrk2 is the most common mutation in Parkinson’s disease. Accordingly, we hypothesized that G2019S mutation in Lrrk2 might enhance the activation of the innate immune system. We tested our hypothesis by performing challenge experiments in a mouse model of Listeria monocytogenes, and by measuring the activation of bone marrow derived macrophages (BMDMs) following in vitro infection with the bacterium.
We found that Lrrk2G2019S mutant mice controlled L. monocytogenes better than WT mice. The mechanism behind the better control of L. monocytogenes by the G2019S mutation of Lrrk2 was investigated in BMDMs following in vitro infection with L. monocytogenes. Interestingly, we found that Lrrk2G2019S mutation enhances the production of TNF-α, IL-1β and IL-10 by infected BMDMs. The impact on TNF-α and IL-1β was specifically due to the G2019S mutation of Lrrk2 since there was no impact on the expression of these cytokines in Lrrk2 knockout macrophages. Western blotting experiments revealed that the G2019S mutation of Lrrk2 enhances MAPK signaling (TAK1, p38 and ERK). Modulation of the expression of the pro-inflammatory cytokines, TNF-α and IL-1β by G2019S mutation of Lrrk2 occurred via p38 MAPK activation. The impact on IL-10 expression occurred through increased ERK activation by the G2019S mutation of Lrrk2. We did not observe any impact of G2019S mutation of Lrrk2 on the activation of NF-κB and JNK MAPK pathways.
Increased expression of IL-1β by G2019S mutation of Lrrk2 revealed increased inflammasome signaling. Inflammasome signaling in response to L. monocytogenes was mainly mediated by the AIM2- and partly by NLRP3- inflammasome and was dependent on activation of caspase-1. We found that Lrrk2G2019S mutation enhanced the expression of NLRP3 and caspase-1.
Finally, we found that the expression of reactive oxygen species (ROS) following infection with L. monocytogenes was augmented by G2019S mutation of Lrrk2, and this can be an important mechanism that promotes the enhanced clearance of the bacterium in vivo.
Overall, these results present new insights into the signaling mechanisms through which the G2019S mutation of Lrrk2 augments innate immune response which leads to better control of infection.
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Hatmi, Saloua. "Impact du déficit hydrique sur les réponses de défense et la sensibilité de la vigne à Botrytis cinerea : rôle de la dégradation des polyamines." Thesis, Reims, 2013. http://www.theses.fr/2013REIMS035.
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La vigne est sujette à de nombreuses contraintes biotiques et abiotiques face auxquelles elle devra optimiser ses stratégies de défense, en favorisant parfois des interconnections entre les réponses adaptatives au stress abiotique et la gestion de la réponse immune face à un pathogène. Dans cette étude nous avons évalué l'effet du stress hydrique (par privation d'eau) sur différentes réactions adaptatives au stress, mais aussi sur des réponses de défense et sur la sensibilité des feuilles et des baies de la vigne à Botrytis cinerea. Ces réactions ont été suivies en utilisant des boutures végétatives de deux cépages : cv. Meski (MSK), tolérant à la sécheresse et cv. Chardonnay (CHR), sensible. La relation entre les réponses au stress hydrique et la réponse immune a également été recherchée au moyen de feuilles de vitroplants et de baies isolées de Chardonnay exposées à des osmotica : le polyéthylène glycol (PEG) et une forte concentration en saccahrose (SUC). Les résultats montrent que le stress hydrique/osmotique conduit à des modifications physiologiques et biochimiques importantes dans les feuilles et les baies mûres de vigne. L'amélioration de la tolérance chez MSK est associée à une faible inhibition de l'activité photosynthétique, une altération du profil des acides aminés et un catabolisme actif des polyamines (PAs) comparé au CHR. Ces résultats suggèrent un rôle potentiel des déviations métaboliques observées dans les processus de tolérance de la vigne au stress osmotique. La tolérance du MSK au déficit hydrique est également corrélée à une forte induction des réponses de défense accumulation de resvératrol et e-viniférine, expression de certains gènes de défense dont STS, Gluc (PR-2), Chit-4c (PR-3) et PR-5 dans les feuilles, ainsi qu'à une faible sensibilité à B. cinerea.Ces résultats suggèrent un lien étroit entre la tolérance au déficit hydrique et la capacité de la vigne à exprimer davantage ses mécanismes de défense et à résister mieux à B. cinerea. Des expériences pharmacologiques ont montré qu'en situation de stress hydrique/osmotique, le catabolisme des PAs, via des diamine- et PA-oxydases, est impliqué dans la régulation de l'homéostasie des PAs et de l'expression des réactions de défense. L'application du stress osmotique avant l'infection des feuilles par B. cinerea potentialise l'accumulation des PAs en réduisant fortement leur dégradation. Ces effets sont corrélés à une réduction de l'amplitude des réponses de défense après infection, et à une sensibilité accrue à B. cinerea. Ces résultats rendent compte (1) de l'importance des stress abiotiques dans la régulation de la réponse immune chez la vigne et sa résistance à B. cinerea et (2) du fait que le niveau des réponses de défense osmo-induites et la résistance au pathogène sont tributaires, au moins en partie, de certains mécanismes adaptatifs au stress, comme c'est le cas ici des voies de dégradation des polyaminesGrapevine is often exposed to both biotic and abiotic stresses, and it will optimize defense strategies by favoing sometimes the cross-talk between adaptive responses to abiotic stress and immune response against pathogen challenge. In this study we evaluated the effect of water stress (by withholding water) on different adaptive responses, and also on defense responses and sensitivity of grapevine leaves or berries to Botrytis cinerea. These reactions were monitored using vegetative cuttings of two varieties: Meski (MSK) a drought tolerant cultivar and Chardonnay (CHR) as a sensitive one. The relationship between the responses to water stress and the immune response was also assessed using detached leaves from vitroplantlets and detached ripe berries from Chardonnay exposed to osmotic agents: polyethlene glycole (PEG) and a high concentration of sucrose (SUC). The results show that water/osmotic stress leads to significant physiological and biochemical changes in grapevine leaves and ripe berries. The improved tolerance of MSK to drought is associated with a weak inhibition of photosynthetic activity, altered amino acid profile and an activation of polyamine (PA) catabolism, compared to the sensitive plant CHR. These results suggest a potential role of metabolic deviations observed in the process of osmotic stress olerance. MSK tolerance to water deficit is also correlated with a strong induction of defense responses, such as accumulation of resveratrol and e-viniferin, enhanced expression of defense-related genes, including STS , Gluc (PR-2), Chit-4c (PR-3) and PR-5, and a low susceptibility of leaves to B. cinerea. These results suggest a close connection between water stress tolerance and the ability of grapevine to express more their defense mechanisms and then to resist better to the pathogen B. cinerea. Pharmacological experiments showed that experiencing water/osmotic stress, PA oxidation through diamine- and PA-oxidases is involved in the regulation of PA homeostasis and the expression of defense reactions in both leaves and berries. The application of osmotic stress before leaf infection by B. cinerea potentiates PA accumulation probably by reducing PA degradation. These effects are correlated with a reduction of defense responses after B. cinerea infection, as well as to an increased susceptibility to B. cinerea.These results highlight (1) the importance of abiotic stress in regulating the immune response in grapevine plants and resistance to B. cinerea and (2) that the level of defense responses induced by osmotic and the resistance of grapevine to the pathogen are dependent, at least in part, on some adaptive mechanisms to stress, as it is the case here for polyamine degradation pathways
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Beckett, Amy Elizabeth. "Defining the impact of colonisation with Shiga toxin positive E. coli O157 on adaptive immunity in cattle." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33097.
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Shiga producing E. coli (STEC) O157 is a zoonotic pathogen. In humans STEC O157 causes bloody diarrhoea and potentially fatal renal failure. Cattle are the major reservoir, where bacteria are limited to the intestinal tract and do not cause clinical signs of disease. Previous studies indicate that shiga toxins produced by STEC O157, suppress STEC-specific cellular immune responses in vivo. This study aimed to initially examine the humoral immune response in cattle following natural challenge and the effects of a toxoid vaccination on this humoral STEC specific-immune response. We determined a statistically significant suppression in Tir specific IgA in STEC O157 positive cattle compared to O157 negative cattle but not in super shedding cattle. Following toxoid vaccination we determined a significant increase in flagellin specific IgG1 antibody levels in toxoid vaccinated animals despite lower numbers of positive faecal samples compared to placebo vaccinated controls. These results suggest that shiga toxins produced by STEC O157 are actively suppressing the STEC specific immune response in natural colonisation. To clarify this suppression further calves were orally challenged with STEC O157 (either a PT21/28 Stx2c+, PT32 Stx2c+ or PT21/28 Stx2a+Stx2c+ strain) and their STEC specific immune responses monitored. STEC specific systemic antibody responses were variable and weak in some cases. STEC specific local antibody responses were only significantly increased following challenge with the PT21/28 Stx2a+Stx2c+ challenge. Transcripts for genes associated with immune responses, and in particular B cell activation, at the terminal rectum were analysed by reverse transcriptase quantitative PCR. Suppression of IL2RA transcripts was observed in calves challenged with PT21/28 Stx2a+Stx2c+ compared to control calves but not with the other two STEC O157 strains tested. This study also aimed to determine the effects of cattle colonisation with STEC O157 on the immune response to a non-bacterial T-cell dependent antigen, ovalbumin (OVA). Cattle were orally challenged with either a PT21/28 Stx2c+, PT32 Stx2c+ or PT21/28 Stx2a+Stx2c+ strain or unchallenged. Calves were subcutaneously immunised with OVA five days post challenge, on two separate occasions with a two week interval. Lymphocytes from lymph nodes local to the immunisation site demonstrated significantly increased OVA-specific proliferation and OVA-specific activation of CD4+ and CD8+ cells in calves that were challenged with the PT21/28 Stx2c+ strain (but not with the other two challenge strains), compared to unchallenged controls. These results indicate that colonisation with STEC O157 can alter local adaptive immune responses to non-bacterial antigens in a strain dependent manner, unexpectedly enhancing the immune response rather than suppressing it. Circulating T cell responses were unaffected. In conclusion this study provides some further evidence of adaption of the host immune response by STEC O157, which is strain dependent, and variable. It seems unlikely from the data in this study that STEC O157 colonisation is having a major impact on the responses of cattle to other vaccines or infections in the field.