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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
291

Role of the CTLA-4 C-terminus in regulating its intracellular trafficking

Kaur, Satdip January 2014 (has links)
CTLA-4 is an important inhibitor of T cell immune responses. The location of CTLA-4 in intracellular vesicles is the most dominating aspect of its biology, yet the significance of this at the functional level remains to be completely understood. I have therefore investigated the role of the CTLA-4 cytoplasmic domain in the intracellular trafficking of the receptor with particular emphasis on sorting signals encoded within this domain. We found that CTLA-4 was located in punctate intracellular vesicles in transfected cells, activated T cells and in regulatory T cells. CTLA-4 internalisation from the cell surface was clathrin dependent and was driven by the YVKM motif encoded within the cytoplasmic domain. Post-internalisation CTLA-4 colocalised with markers of late endosomes. Since the degradation process may serve as one of the mechanisms to regulate CTLA-4 expression we investigated this further and found that ubiquitination of intracellular lysine residues targets CTLA-4 to lysosomes. The ability of CTLA-4 to recycle was dependent on the YVKM motif and subtle changes in this motif reduced recycling efficiency. Moreover, in the absence of lysine residues CTLA-4 recycling was enhanced. CTLA-4 transendocytosis was conserved through evolution but the exact sorting signals required for this function remain to be identified. Overall this thesis emphasises the importance of the CTLA-4 cytoplasmic domain in regulating its intracellular trafficking.
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292

Studies of TNF-alpha in Alpha-One Antitrypsin Deficient and healthy subjects

Gane, Jennie Margaret January 2016 (has links)
TNF-α, a pro-inflammatory cytokine, is implicated in the immune response in chronic obstructive pulmonary disease (COPD) secondary to Alpha-One Antitrypsin Deficiency (A1ATD). This thesis firstly describes studies in monocytes from A1ATD-related COPD subjects, examining the effect of the rs361525 TNF-A single nucleotide polymorphism, previously associated with 100-fold greater TNF-α concentration in the sputum of affected patients. Secondly, the autocrine effects of TNF-α on monocytes from healthy subjects are considered, in particular the differential roles of its two receptors, TNF-α receptor 1 (TNFR1) and 2 (TNFR2), an important topic given recent interest in selective TNFR1 blockade in TNF-α associated diseases. Unexpectedly, TNF-α mRNA expression and secreted protein was not greater in A1ATD-related COPD subjects with the rs361525 polymorphism when compared to matched wild-type subjects. Reasons may include the cell type and stimulus used or inadequate power. In monocytes from healthy subjects, autocrine binding of TNF-α increased production of pro-and anti-inflammatory cytokines. Trends were observed for TNFR1 blockade to reduce both types of cytokine, for IL-10 to be reduced by TNFR2 blockade and for TNFR1 expression at the monocyte surface to be up-regulated by TNF-α-TNFR2 binding. Further studies are required to fully characterise the relative roles of TNFR1 and TNFR2 in monocytes.
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293

Heterogeneity of injury in vasculitis : influence of anti neutrophil cytoplasm antibody IgG subclass and endothelial susceptibility

Pankhurst, Tanya January 2010 (has links)
This study examined IgG subclass in ANCA associated vasculitis and glomerular endothelial cell (GEC) phenotype predisposes to injury. Using the flow model, interaction of neutrophils with normal immunoglobulin subclasses was compared to interaction with subclasses of ANCA IgG. Neutrophils were captured by normal IgG3>IgG1>IgG2/IgG4. Blockade of CD32 affected IgG3, CD16, IgG1/2. Neutrophils exposed to soluble ANCA IgG1/3 adhered to cytokine-activated endothelial cells, as did IgG4, not previously thought to bind constitutively expressed CD16/CD32. Fc blockade reduced binding. GEC were compared with human umbilical vein endothelial cells. Surface VCAM-1 was reduced on GEC and GEC demonstrated reduced leukocyte capture. RNA array analysis demonstrated a reduction in the GEC gene responsible for post translational modification of VCAM-1 to a sialoglycoprotein. VCAM-1 expression by GEC may be a protective mechanism to reduce inflammatory responses, potentially disrupted in disease. ANCA subclass and endothelial phenotype are important vasculitis pathogenesis: this may be useful in designing targeted therapy reducing overall immunsuppressive load. Additionally modification of specific adhesion molecule profiles on endothelial cells may enable alteration of conditions of one vascular bed whilst reducing impact on unaffected sites.
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294

The biology of antibiotic resistance plasmids

Saw, Howard Thien Hui January 2015 (has links)
Plasmids confer genes encoding clinically relevant antibiotic resistance. It was hypothesised that the AcrAB-TolC multidrug resistance efflux pump was required for clinically relevant levels of carbapenem resistance. However, carbapenemase-producing \(Salmonella\) TolC mutants were less susceptible to carbapenems. In the presence of the efflux inhibitor phe-arg- β-naphthylamide (PAβN), wildtype bacteria and 36/86 non-replicate clinical isolates of carbapenem-producing Enterobacteriaceae were ≥4-fold less susceptible to ertapenem. Experimental data suggested that OmpF repression conferred the increased carbapenem MICs. Two blaKPC-encoding plasmids have been isolated in the UK; pKpQIL-UK was found in K. \(pneumoniae\), but its variant, pKpQIL-D2 was also found in other species. Therefore, it was hypothesised that a region of pKpQIL-D2 either conferred a broader plasmid host range and/or a fitness benefit to the host bacterium. Fitness studies measuring growth rates, ability to form biofilm, conjugation frequency and plasmid persistence showed that both plasmids affected the host bacterium but in different ways. Compared to pKpQIL-UK, pKpQIL-D2 did not confer a significant fitness advantage to its host under the conditions tested. RNAsequencing showed both plasmids affected a different set of genes related to metabolism. The understanding of the factor(s) contributing to the persistence and dissemination of successful plasmids may help to control antibiotic resistance.
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295

The pleomorphic role of stromal cells in the formation and maintenance of tertiary lymphoid organs

Dias De Campos, Joana January 2016 (has links)
A large body of evidence supports the role of activated stromal cells in the persistence of inflammation. The switch from resting to pathogenic stroma appears to be associated with the development of tertiary lymphoid organs (TLOs) within sites of chronic inflammation. However little is known about the immunological function of the stromal component. We utilised a murine model of inducible TLO formation in inflamed salivary glands to investigate the role of activated stromal cells characterised by the expression of gp38 and FAP during TLO development. We demonstrated that during inflammation, stroma-derived ICOSL engages ICOS on T cells, necessary for the release of lymphotoxin α and consequent TLO formation. Whilst dissecting the role of stromal cells in this context, we demonstrate that gp38 expression is required for the upregulation of adhesion molecules involved in cell clustering. Depletion of gp38+FAP+ stromal cells led to a significant reduction in lymphoid chemokine production, a decreased number of infiltrating lymphocytes and severely compromised TLO formation. Collectively, we provide evidence that activated stromal cells express FAP, provide co-stimulatory signals, and are necessary for the establishment of viral-induced TLOs, highlighting a potential novel therapeutic target in TLO-associated autoimmune diseases.
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296

Regulation of C-type lectin-like receptors dectin-1 and CLEC-2 by tetraspanins

Tomlinson, Neil David January 2010 (has links)
Tetraspanins are a superfamily of glycoproteins that function as ‘organisers’ of membranes by clustering with each other to form tetraspanin-enriched microdomains, into which certain other receptors and signalling proteins are recruited and regulated. Tetraspanin microdomains have been implicated in a range of biological processes including cell signalling, adhesion, intracellular trafficking, cell-cell fusion and viral entry. The tetraspanin CD37 was recently shown to negatively regulate the C-type lectin-like receptor dectin-1, which is essential for innate immune responses to fungal pathogens. The aim of this thesis was to firstly develop a cell line model system to investigate the mechanism by which tetraspanins inhibit dectin-1, and to secondly extend this work to the dectin-1-related CLEC-2, which is essential for platelet thrombus formation and stability. Using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay in the Jurkat T-cell line, transient over-expression of CD37 was found to powerfully inhibit dectin-1 signalling following stimulation with its ligand, β-glucan. Over-expression of other tetraspanins also inhibited dectin-1 signalling, but did not globally inhibit receptor signalling because the platelet collagen receptor, GPVI, was unaffected. Similar to dectin-1, CLEC-2 signalling in response to its ligand, the snake venom toxin rhodocytin, was also abrogated following tetraspanin over-expression. However, stable tetraspanin over-expression only partially reduced signalling. Moreover, knockdown of the major Jurkat cell tetraspanin, CD81, and deletion of the major platelet tetraspanin, CD9, did not affect dectin-1 and CLEC-2 signalling, respectively. In summary, the importance of transient tetraspanin over-expression for dectin-1 and CLEC-2 inhibition, and the fact that any tetraspanin can inhibit, suggests that tetraspanin microdomains are disrupted by the presence of one over-expressed tetraspanin. This leads to a failure of dectin-1 and CLEC-2 signalling by a mechanism that is not clear, but suggests that tetraspanin microdomains are important for signalling by these C-type lectin-like receptors.
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297

Identifying lineage relationships in human T cell populations

Menckeberg, Celia Lara January 2011 (has links)
CD4\(^+\) and CD8\(^+\) T cell populations can be divided into subpopulations based on expression of surface markers CCR7 and CD45RA. The resulting populations are referred to as naive, central memory, effector memory and effector memory RA\(^+\) (EMRA). The aim of this study was to identify potential lineage relationships between these subpopulations for both CD4\(^+\) and CD8\(^+\) T cells through microarray analysis. The genes found to distinguish between these subpopulations include many molecules with known functions in T cell differentiation, including CCR7, CD45RA, granzymes, L-selectin and TNF receptors. Several genes from the tetraspanin family of proteins were found to be differentially expressed at mRNA and protein level; suggesting a possible role for these genes in CD4\(^+\) and CD8\(^+\) T cell activation, migration and lysosomal function. Other genes identified, such as LRRN3 and CXCR5 which were expressed highest on naive and CM T cells respectively, provide interesting gene targets to follow up on their function in these T cell populations. Microarray data was validated through Real Time PCR and suggests that both CD4\(^+\) and CD8\(^+\) T cells differentiate along a linear pathway of naive to central memory to effector memory. The transcriptional programmes responsible for these differentiation steps were distinct between CD4\(^+\) and CD8\(^+\) T cells, although additional elements were common to both subsets.
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298

The role of proteinase 3 in chronic obstructive pulmonary disease

Sinden, Nicola Jane January 2013 (has links)
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. In COPD, an imbalance is believed to exist between the activities of neutrophil serine proteinases (NSPs) such as neutrophil elastase (NE) and proteinase 3 (PR3), and their endogenous inhibitors such as alpha-1-antitrypsin (A1AT). Hence, a deficiency of A1AT predisposes to the development of COPD. Following their release from neutrophils, NSPs may bind to local inhibitors depending on their concentrations and affinities, to substrate such as lung elastin or to the neutrophil cell membrane where they remain active. This work has demonstrated that; NSPs bound to the proteinase “inhibitor” alpha-2-macroglobulin (A2M) remain active, and A2M:NE complexes are able to degrade elastin in vitro; NE bound to elastin is poorly inhibited by A1AT; and PR3 binding to the neutrophil cell membrane is greater when the local concentration of A1AT is reduced. The role of PR3 has not previously been studied in detail. However, PR3 activity was found to be present in sputum from clinically stable subjects with COPD or A1AT deficiency and was greater than NE activity. Hence, PR3 is likely to be important in the pathogenesis of COPD and could potentially be a target for therapeutic inhibitors.
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299

The role of antibody in cell-mediated immunity to Non-typhoidal Salmonella in African children and HIV-infected adults

O'Shaughnessy, Colette January 2013 (has links)
Nontyphoidal Salmonella (NTS) are a major cause of invasive disease in young children and HIV-infected adults in Sub-Saharan Africa. To develop a vaccine for NTS, an improved understanding of immunity to NTS is required. This thesis investigates the role of opsonic antibody in protection against NTS. First, we defined the optimal serum handling conditions to preserve complement function. We determined minimal titres of antibody and complement required for cell-mediated killing of Salmonella and found they are higher than for cell-free killing. We demonstrated impaired blood cell killing of NTS opsonised with sera from HIV-infected Africans. Developing a method to purify anti-LPS antibodies, we showed that high titres of anti-LPS antibodies in these sera inhibit cell-mediated killing while lower titres are opsonic and induce cell-mediated killing of NTS. For most children, antibody acquired during NTS bacteraemia effected cell-mediated killing of NTS. High antibody titres were not necessarily protective, but for some sera, dilution prior to opsonisation, induced killing. The sensitivity of Malawian NTS isolates to opsonic antibody varied, with resistance to cell-mediated and bactericidal killing correlating. Overall, this thesis emphasises the importance of opsonic antibody in protecting against NTS and supports the development of a vaccine which induces antibody to Salmonella.
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300

Inflammation and neutrophil recruitment in ageing subjects and patients with chronic obstructive pulmonary disease

Sapey, Elizabeth January 2010 (has links)
The neutrophil is central to the development of COPD. To enter lung, neutrophils must migrate accurately from the circulation to inflamed tissue. It is unclear which migratory stimuli are important and whether COPD neutrophils vary in their migratory behaviour, either to controls or patients with similar lung disease. COPD sputum and plasma samples were collected on 11 occasions over one month. Significant correlations were demonstrated between the inflammatory biomarkers and between inflammatory biomarkers and markers of disease. IL-8 correlated most strongly both with other inflammatory mediators, neutrophil counts and indices of disease. Neutrophils from healthy older subjects migrated with maintained speed but reduced accuracy to IL-8. Differences could not be accounted for by surface receptor expression or shedding, but inhibition of CXCR2 gave young neutrophils and old migratory phenotype, suggesting altered downstream signalling. COPD neutrophils migrated with increased speed and reduced accuracy compared with control groups. They formed less pseudopodia when migrating, and had reduced surface expression of CXCR1 and CXCR2. Inhibitory studies suggested that CXCR2 was the predominant receptor in migration to biological samples. Treating COPD cells with a PI3 Kinase inhibitor differentially altered their migration, reducing speed but increasing accuracy, so that cells now resembled those from controls.
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