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Rozprawy doktorskie na temat „Molecular immunology”

Autor: Grafiati
Data publikacji: 4 czerwca 2021
Data aktualizacji: 29 lipca 2024

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1

Johansson, Alina. "Molecular mechanisms behind TRIM28expression". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-252834.

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2

All-Ericsson, Charlotta. "Uveal melanoma : cytogenetics, molecular biology and tumor immunology /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-278-7.

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3

Eckert, Rachael. "Molecular Mechanisms of Neutrophil Migration". NCSU, 2007. http://www.lib.ncsu.edu/theses/available/etd-10312007-134315/.

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This work is an investigative look behind the mechanisms of neutrophil migration. Each of three chapters involves exploration into a different signaling pathway important for migration downstream of chemoattractant stimulation through inhibition of a kinase or disruption of the function of an effector and examination of the effects on migration, adhesion, and actin reorganization in primary human or equine neutrophils. Chapter II examines the requirement for the signaling molecule p38 Mitogen Activated Kinase (MAPK) in equine neutrophil chemotaxis through use of the p38 specific inhibitor SB203580. SB203580 reduced LTB4- and PAF-induced migration and disrupted the ability of cells to polarize, but did not affect b2 integrin-dependent adhesion or surface b2 integrin expression. Chapter III is a comprehensive inquiry into the regulation of the phosphorylation of serine 157 of the cytoskeletal protein Vasodilator-stimulated Phosphoprotein (VASP). The rapid and transient phosphorylation of VASP serine 157 corresponded with F-actin levels in chemoattractant-stimulated human neutrophils. fMLF-induced serine 157 phosphorylation was abolished by pretreatment with the PKA inhibitor H89 and the adenylyl cyclase inhibitor SQ22536. In contrast, fMLF-induced serine 157 phosphorylation was unaffected by PKC inhibitors, PKG inhibitors, and the CamKII inhibitor KN-62. Inhibition of adhesion did not alter fMLF-induced VASP phosphorylation or dephosphorylation. This study demonstrated that chemoattractant stimulation of human neutrophils induces a rapid and transient PKA-dependent and adhesion-independent VASP serine 157 phosphorylation. Chapter IV probed into the function of the actin binding protein and PKC substrate Myristoylated Alanine-Rich C-kinase Substrate (MARCKS) through utilization of a cell permeant peptide derived from the MARCKS myristoylated aminoterminus (MANS peptide). Treatment of isolated human neutrophils with 50 μM MANS, but not a scrambled control peptide, significantly inhibited their migration and adhesion in response to fMLF, IL8, or LTB4. MANS significantly reduced F-actin content in neutrophils 30s after fMLF-induced polymerization, but did not alter the ability of cells to polarize, spread, or upregulate surface b2 integrin expression. These data provided evidence that MARCKS, via its myristoylated aminoterminus, is a key regulator of neutrophil migration and adhesion.
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4

Wijewardana, Thula Gaurie. "Molecular immunology of bovine isolates of Pasteurella multocida type A". Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/24424.

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5

Chou, Richard M. "Use of Phage Display Libraries to Select For B-cell Receptor-specific Peptides of Chronic Lymphocytic Leukemia Cells". Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1346584096.

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6

Duarte, Nádia. "Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes". Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-601.

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Type 1 diabetes is an autoimmune disorder determined both by genetic and environmental factors. The Non-obese diabetic (NOD) mouse is one of the best animal models of this disease. It spontaneously develops diabetes through a process resembling the human pathogenesis. The strong association of NOD Type 1 diabetes to the MHC region and the existence of other diabetes susceptibility loci are also in parallel with the human disease. The identity of the genetic factors and biological function mediated by these loci remain, however, largely unknown. Like in other autoimmune diseases, defects in tolerance mechanisms are thought to be at the origin of type 1 diabetes. Accordingly, defects in both central and peripheral tolerance mechanisms have been reported in the NOD mouse model. Using a subphenotype approach that aimed to dissect the disease into more simple phenotypes, we have addressed this issue. In paper I, we analyzed resistance to dexamethasone-induced apoptosis in NOD immature thymocytes previously mapped to the Idd6 locus. Using a set of congenic mice carrying B6-derived Idd6 regions on a NOD background and vice-versa we could restrict the Idd6 locus to an 8cM region on the telomeric end of chromosome 6 and the control of apoptosis resistance to a 3cM region within this area. In paper II, further analysis of diabetes incidence in these congenic mice separated the genes controlling these two traits, excluding the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. These results also allowed us to further restrict the Idd6 locus to a 3Mb region. Expression analysis of genes in this chromosomal region highlighted the Lrmp/Jaw1 gene as a prime candidate for Idd6. Lrmp encodes an endoplasmatic reticulum resident protein. Papers III and IV relate to peripheral tolerance mechanisms. Several T cell populations with regulatory functions have been implicated in type 1 diabetes. In paper III, we analyzed NOD transgenic mice carrying a diverse CD1d-restricted TCR αVa3.2b9), named 24abNOD mice. The number of nonclassical NKT cells was found to be increased in these mice and almost complete protection from diabetes was observed. These results indicate a role for nonclassical NKT cells in the regulation of autoimmune diabetes. In paper IV, we studied the effects of introducing the diverse CD1d-restricted TCR (Va3.2b9) in immunodeficient NOD Rag-/- mice (24abNODRag-/- mice). This resulted in a surprising phenotype with inflammation of the ears and augmented presence of mast cells as well as spleenomegaly and hepatomegaly associated with extended fibrosis and increased numbers of mast cells and eosinophils in the tissues. These observations supported the notion that NKT cells constitute an “intermediary” cell type, not only able to elicit the innate immune system to mount an inflammatory response, but also able to interact with the adaptive immune system affecting the action of effector T cells in an autoimmune situation. In this context the 24abNODRag-/- mice provide an appropriate animal model for studying the interaction of NKT cells with both innate and adaptive components of the immune systemα.
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7

Basak, Sanjukta. "Studies of Hepatitis C virus immunology : translation and replication". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97903.

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Hepatitis C virus (HCV) has become a worldwide problem. Roughly 3% of world population are estimated to be infected with the virus, producing high rates of progressive liver disease, leading to cirrhosis and hepatocellular carcinoma. The present therapy, a combined administration of pegylated interferon-alpha (IFN) and ribavirin is costly and only successful in 50% of patients infected with HCV. It is also associated with serious side effects. Thus, there is an urgent need for better tolerated and more effective treatment modalities. A therapeutic vaccine may be the solution.
Recent efforts to produce efficient vaccines require not only the identification of potential viral antigens but also vaccine adjuvants or enhancers of immunity. Dendritic cells (DC) are being considered one such adjuvant for the activation of CD4+ and CD8+ T-cells. As potent antigen presenting cells, they are capable of capturing antigens, processing them into peptides, and presenting them on products of the MHC to T cells. For such reasons, peptide loading of antigens onto DCs to enhance T cell responses is becoming of increasing interest. Using cell penetrating peptides, or motifs capable of transporting cargo freely across cell membranes, we have developed a peptide based delivery system suitable for the transport of all HCV proteins into immature DCs. In our studies we demonstrated that 3.1% of immature DCs internalized the reporter cargo, eGFP. This system was then optimized to 53.81 % in target HeLa cells.
Another area of recent focus is the regulation of HCV translation and replication. Positive stranded viruses such as HCV use the genomic RNA as a common template for translation as well as for RNA replication, both proceeding in inverse directions. Thus, specific regulatory mechanisms must be in place in order to coordinate these two antagonistic processes. In this study, we investigated the role of HCV Core protein as a translational inhibitor and enhancer of replication. Using several transient and stable in vivo reporter assays, we showed that Core expression inhibited HCV IRES-mediated translation in trans, in a dose-dependent manner. Furthermore, HCV Core protein is able to dramatically inhibit HCV translation in the Huh7 replicon system, more so than the bicistronic reporter systems tested and subsequently increase total levels of replicon RNA by 1.5 log fold and thus, affect replication. We believe that Core may indeed be the sought regulator of translation and replication.
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8

Emani, Sirisha. "MOLECULAR CHARACTERIZATION OF T REGULATORY CELLS IN FIV-INFECTION". NCSU, 2006. http://www.lib.ncsu.edu/theses/available/etd-01192006-105756/.

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Naturally occurring CD4+CD25+ T regulatory cells (Treg) play important roles in maintaining immunologic self-tolerance in addition to controlling the magnitude of anti-microbial immune responses. However, the capacity of these CD4+CD25+ Treg cells to control immune responses both in vivo and in vitro is not well established. CD4+CD25+ Treg cell-mediated suppression can control autoimmune diseases; transplantation tolerance and graft verses host disease and, in contrast hinder tumor immunity and immunity to infectious agents. As Treg cells have been reported to be involved in several diseases, this study focused on molecular characteristics that enables them to maintain anergy and also resistance to programmed cell death along with the effect of FIV-infection on regulation of the above phenotypic characteristics. Our results show that feline CD4+CD25+ Treg cells are phenotypically and functionally anergic as indicated by elevated levels of the cyclin dependent kinase inhibitors, CdkI¡¦s, (p21cip1,p16ink4, and p27kip1) , and resistance to mitogen-induced proliferation compared to their counter parts CD4+CD25- T cells. Importantly, CdkI¡¦s are constitutively over-expressed only in FIV-infected cats. As expected Treg cells from FIV-infected cats that over-expressed CdkI¡¦s expressed low levels of the cyclins (mainly cyclins D) and phosphorylated retinoblastoma protein (pRb) that are responsible for cell cycle progression. We investigated the role of TGF?Ò signaling and found that TGF?Ò1 plus ConA stimulation was able to convert CD4+CD25- T cells to CD4+CD25+ T cells with functional and phenotypic characteristics including upregulation of CdkI¡¦s and bcl-2. The differential expression of CdkI¡¦s and bcl-2 between the two CD4+ T cell subsets may be linked to TGF?Ò-Smad pathway. Consistent with upregulation of CdkI¡¦s and bcl-2, we found that although natural and TGF?Ò1 converted CD4+CD25+ Treg cells are anergic, they are more resistant to activation induced cell death compared to CD4+CD25- T cells functionally which correlated with increased bcl-2 to bax ratio in Treg cells. Thus, the molecular characterization of this unique population of Treg cells may be essential for understanding their role and function for developing effective therapeutics and vaccination especially against chronic infections such as Acquired Immune Deficiency Syndrome (AIDS).
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9

Schauenburg, Andrea J. A. "Molecular mechanisms underlying pMHC-II recognition". Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/96291/.

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The immune system is a complex network of cells and molecules working together with the purpose of fending off potentially harmful pathogens. CD4+ T cells take key roles within this network by orchestrating a multitude of its players. They recognise pathogen or self-derived peptides (p) bound to molecules of the major histocompatibility class II (MHC-II) through their T cell receptor (TCR). Cytokines secreted in response to recognition aid antibody production and cytotoxic T cell activity, both critical for anti-viral immunity. In this thesis, TCR/pMHC-II interactions were investigated using a range of functional and molecular approaches in order to gain valuable insight into the mechanisms underlying successful antigen recognition. To aid these investigations, a versatile, insect cell based expression system for HLA-DR1 was successfully implemented to generate soluble protein for use in multimer stainings and biophysical assays. Two HLA-DR1 restricted peptides encoded within influenza heamagglutinin (HA) were confirmed as being highly conserved making them ideal targets for vaccine development and allowing identification of influenza specific CD4+ T cells. Furthermore, the various roles of peptide flanking residues (PFR) were investigated using two experimental models. In a HA derived peptide, C-terminal PFR proved essential for peptide binding stability to HLA-DR1 and in consequence, CD4+ T cell activation. Clonotyping of CD4+ T cells grown against peptides of varying PFR lengths showed that TCR gene selection was heavily influenced by PFR. A HIV gag24 derived peptide displaying an unusual secondary structure within its N-terminal PFR gave further insight into how seemingly small modifications to PFR can have wide reaching impact on CD4+ T cell activation. Both studies highlighted the need for more in depths investigations into this emerging field and the wide reaching impacts of this inherent feature of MHC-II restricted peptides. Overall, the results in this thesis added novel insight into the mechanisms underlying TCR/pMHC-II interactions.
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10

Huang, Bei. "Molecular interaction of the CD4 and MHC class II molecules : mapping the contact sites on CD4". Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42056.

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T cells expressing CD4 recognize antigens presented by class II following the contact of CD4 with non-polymorphic regions of class II. CD4 enhances T cell activation by acting as an adhesion molecule (co-ligand function), or by bringing the CD4 associated p56$ sp{lck}$ to the vicinity of the TCR (co-receptor function).
To dissect the molecular interactions which lead to CD4 function(s), wild-type (WT) and mutant CD4 molecules were expressed in the CD4-dependent 3DT52.5.8 T cell hybridomas. Results showed that multiple sites on CD4 encompassing the CDR1, the CDR3 regions of D1 and the FG loop of D2 are involved in class II interaction. The opposite face containing the CDR2 region also plays a role, either as another class II binding site, or the TCR docking site, or in another function of CD4. Co-receptor function requires a much larger site on CD4, compared to co-ligand function. A stretch of 15 amino acids which links D2 and D3 of CD4 appears to be very important for maintaining CD4 conformation, or to provide CD4 the flexibility required for its interaction with other cell surface molecules, including class II, the TCR, etc.
Crystallographic and functional studies have suggested that CD4 may dimerize, although biochemical evidence is lacking. To investigate the CD4 dimerization issue both human and mouse CD4 WT were co-expressed in 3DT52.5.8 cells. Surprisingly this led to a severe disruption of CD4 functions, although it has been shown that both human and mouse CD4 molecules are capable of interacting with human class II efficiently. As expected, co-expression of h-CD4 WT with class II-interaction-deficient CD4 mutants within the CDR1, CDR3 and the FG loop did not rescue CD4 functions. However, co-expression of CD4 WT with mutants from the CDR2 region resulted in an enhanced response. This result suggests that CDR2 mutants do not dimerize with WT molecule, therefore cannot behave as a dominant negative mutant, which is not the case for class II-interaction-deficient mutants from the CDR1, CDR3 and FG loop. Based on these results we suggest a model whereby dimerization involves, at least in part the CDR2 region. Final confirmation of this model awaits further structural data.
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11

Martin, Bradley N. "The Cellular and Molecular Mechanisms of ASC-dependent Inflammasomes in Neuroinflammation". Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459420965.

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12

Smith, Michael J. "Molecular modelling of MHC/peptide complexes". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297304.

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13

Wojciechowski, Wojciech. "Molecular mechanism of IFN-[gamma]-induced macrophage activation". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37667.

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Macrophages are considered as one of the early effector cells involved in the immunological response against infection. Following macrophages interaction with pathogens, macrophages become activated and attempt to eliminate the invader. Interferon gamma (IFN-gamma) is one of the most important activators of macrophage function. In macrophages IFN-gamma is promoting the expression of major histocompatibility complex class II (MHC-II) molecules and other proteins directly involved in the process of containing infection.
The effect of the Nramp1, on macrophage function is investigated in this thesis. Nramp1 has been shown to determine the resistance or susceptibility of mice to infections with several intracellular microorganisms, including Mycobacterium bovis BCG. Although the precise mechanism of Nramp1 action is unknown, there are several well-established effects associated with the Nramp1. In general, it has been shown that macrophages derived from mice susceptible to infections with M. bovis BCG are less efficient in the production of nitric oxide (NO), reactive oxygen intermediates (ROI), TNF-alpha, and MHC-II antigens in response to IFN-gamma.
Using macrophage cell lines derived from mice that are either resistant (B10R) or susceptible (B10S) to M. bovis BCG infection, we have demonstrated that lower levels of IFN-gamma-induced expression of MHC-II antigens is correlated with less efficient phosphorylation of the STAT1 protein in B10S macrophages compared to B10R macrophages. We have shown that low levels of MHC-II expression in B10S macrophages correlate with less efficient expression of CIITA (Class II Transactivator). We have observed that infection of macrophages with M. bovis BCG has an inhibitory effect on both CIITA and MHC-II expression in macrophages stimulated with IFN-gamma.
We have also studied the effect of lipopolysaccharide (LPS) on MHC-II expression in macrophages. We have found that the inhibitory effect of LPS on CIITA gene transcription does not involve changes in the binding of STAT1 to CIITA promoter IV. We have also demonstrated that unlike M. bovis BCG, the inhibitory effect of LPS on MHC-II expression is mediated by Toll-like receptor 4 (TLR4). In addition, we have shown that inhibitory effects of both LPS and M. bovis BCG depend on the adaptor protein MyD88.
We have also analyzed the regulation of IFN-gamma- or/and LPS-stimulated expression of TLR2 in macrophages. We have shown that regulation of TLR2 expression by IFN-gamma depends on TLR4 expression. We have also determined that the phenol extractable fraction present in the commercial preparations of endotoxins from Gram-negative bacteria is able to synergize with IFN-gamma and activate TLR4-deficient macrophages.
Overall, we believe that these studies significantly contribute to the understanding of the molecular mechanism of the process of macrophage activation.
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14

Gliddon, Daniel. "The molecular basis of bovine dendritic cell functions". Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272235.

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15

Wright, Ann Heather. "The molecular basis of leukocyte adhesion deficiency in six patients". Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239257.

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16

Peaker, Christopher James Gordon. "A molecular analysis of the B-cell antigen receptor complex". Thesis, University of Cambridge, 1995. https://www.repository.cam.ac.uk/handle/1810/275263.

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17

Shah, Vaibhav. "Molecular and functional analysis of beta-glucan-mediated microglial activation". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1229705831.

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18

Yasmin, Mahmuda. "Molecular biology of fulminant hepatitis B viruses". Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360121.

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19

Carmo, Alexandre V. X. M. do. "Molecular associations of proteins involved in signal transduction in T lymphocytes". Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260113.

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20

Das, Amitava. "Chronic Inflammation: Molecular and Nutritional Interventions of Metabolic Disorder and its Complications". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461254458.

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21

Al-Mot, Sawsan. "Molecular signatures as a new classification scheme for chronic rhinosinusitus". Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114268.

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Chronic Rhinosinusitis (CRS), an inflammation of the paranasal sinus cavities, is a common disorder of uncertain etiology that affects the upper airways and paranasal sinuses. Biopsy specimens had taken from CRS patients document disruption of the normal epithelial architecture, in addition to an intense infiltration of inflammatory cells, consisting mainly of eosinophils. Current clinical classification of CRS is based on the presence or absence of nasal polyposis; however, no consistent difference in histological aspect characterizes these two groups. Recently, we have identified distinct gene expression patterns in cultured epithelial cells obtained from surgical CRS subjects. These molecular signatures, which differ from clinical phenotype, may help better differentiate this disorder than clinical phenotype. In our current study we investigated the histological pattern associated with these two different molecular signatures in surgical biopsies obtained from CRS patients and control subjects. Cellular infiltrates were identified using immunohistochemistry (IHC) staining using three markers: neutrophil elastase (NE), CD68, Major basic protein (MBP). Macrophage activation status into classical and alternatively activated macrophages was verified by double-staining for CD68 and CD 206 markers. Results were reported both according to standard clinical criteria (CRSwNP and CRSsNP) and also according to their expression signature into two groups (CRS1, CRS2) and control subjects. Expression signatures were validated using immunohistochemical staining for the highest differentially expressed marker, CCL2. Results showed differences in the number of eosinophils, macrophages and neutrophils cells in CRS patients compared to the control subjects. Using conventional criterion, eosinophilia was higher in the CRSwNP group, but not greatly different for neutrophils or macrophages between the two groups. Using the molecular signatures to assign groups, eosinophilia was similar between both groups, however, there was a significant increase in the number of neutrophils and macrophages in CRS1 comparing to CRS2. The CRS2 group had a higher incidence of alternatively activated macrophages, supporting the concept of a less inflammatory, immunotolerant CRS2 phenotype. Validity of the molecular signature was supported by demonstration of increased levels of protein product of CCL2 expression in CRS1 compared to CRS2. Taken together, these results identify a molecular phenotype of CRS that is characterized by a marked neutrophilic infiltration, and a second one that is markedly less inflammatory, accompanied by alternative macrophage activation. This suggests that these expression signatures may identify novel mechanism-based phenotypes, which differ from the clinical phenotype, and can help in providing a better understanding of pathophysiologic mechanism and phenotypes of CRS.
La rhinosinusite chronique (RSC), une inflammation des sinus paranasaux, est un trouble commun avec une étiologie incertaine, qui affecte les voies respiratoires supérieures et les sinus paranasaux. Les biopsies des échantillons prélevés sur des patients atteints de RSC documentent la perturbation de l'architecture normale épithéliale, en plus d'une infiltration de cellules inflammatoires intense constituée principalement par des éosinophiles. La classification clinique actuelle de la RSC est basée sur la présence (CRSwNP) ou l'absence (CRSsNP) de polypose nasale, mais aucune différence consistente de l'aspect histologique caractérise ces deux groupes. Récemment, nous avons identifié des profils d'expression génique distincts dans des cultures de cellules épithéliales provenant de sujets atteints de la RSC ayant subis une chirurgie des sinus. Ces signatures moléculaires, qui diffèrent du phénotype clinique, peuvent aider à mieux différencier ce trouble que le phénotype clinique. Dans notre étude, nous avons étudié l'aspect histologique associé à ces deux différentes signatures moléculaires à partir de biopsies chirurgicales obtenus chez des patients atteints de la RSC et les sujets témoins. Les infiltrats cellulaires ont été identifiés par immunohistochimie (IHC), une coloration à l'aide de trois marqueurs: l'élastase de neutrophile (NE), le CD68 et la protéine basique majeure (MBP). L'état d'activation des macrophages dans les formes classiques et alternativement activés a été vérifié par une double-coloration pour les marqueurs CD68 et CD206. Les résultats ont été rapportés à la fois selon les critères cliniques habituels (CRSwNP et CRSsNP) et aussi en fonction de leur signature d'expression en deux groupes (CRS1, CRS2) et les sujets témoins. Les signatures d'expression ont été validées à l'aide de coloration immunohistochimique pour le marqueur le plus différentiellement exprimé, le CCL2.Les résultats ont montré des différences dans le nombre d'éosinophiles, macrophages et les cellules de neutrophiles chez les patients atteints de la RSC par rapport aux sujets témoins. Selon le critère classique, l'éosinophilie était plus élevée dans le groupe CRSwNP, mais pas très différent entre les deux groupes pour les neutrophiles ou les macrophages. En utilisant les signatures moléculaires pour assigner des groupes, l'éosinophilie était similaire entre les deux groupes, cependant, il y avait une augmentation significative du nombre de neutrophiles et de macrophages dans CRS1 comparativement à CRS2. Le groupe CRS2 avait une incidence plus élevée des macrophages alternativement activés, supportant le concept d'une inflammatoire basse, phénotype CRS2 immunotolérant. La validité de la signature moléculaire a été supportée par la démonstration du niveau accru de la protéine produite par l'expression de CCL2 dans CRS1 par rapport à CRS2.En somme, ces résultats mettent en évidence un phénotype moléculaire de la RSC qui se caractérise par une infiltration neutrophilique marquée, et une seconde qui est nettement moins inflammatoire, accompagnée par l'activation alternative des macrophages. Ceci suggère que ces signatures d'expression peuvent identifier de nouveaux mécanismes basés sur des phénotypes, qui diffèrent du phénotype clinique, et peuvent aider à fournir une meilleure compréhension du mécanisme physiopathologique et les phénotypes de la RSC.
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22

Birkenheuer, Adam Joseph. "Canine Babesiosis: Epidemiological, Molecular and Therapeutic Investigations". NCSU, 2004. http://www.lib.ncsu.edu/theses/available/etd-04192004-164025/.

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Canine babesiosis is an emerging infectious disease in the United States (US). An epidemic of Babesia gibsoni infections in the US was identified. An association between dog breed and B. gibsoni infections was detected. Babesia gibsoni-infected dogs were more likely to be American pit bull terriers and B. canis vogeli infected dogs were more likely to be greyhounds. An association between a recent dog bite and B. gibsoni infection was detected, implicating direct dog-to-dog transmission as a route of infection in the US. Several genes from canine Babesia spp. were characterized, including 18S ribosomal RNA (rRNA), internal transcribed spacer regions (ITS), cytochrome B (cytB), and rhoptry-associated protein-1 (RAP-1). These genetic data were used to develop a sensitive and specific diagnostic semi-nested polymerase chain reaction (PCR) test for canine babesiosis. Using this assay, a novel large Babesia organism was identified in a blood sample obtained from a clinical patient. Molecular and phylogenetic characterization of this large Babesia spp. determined that it was most closely related to B. bigemina. Lastly, an atovaquone and azithromycin drug combination was shown to be the first treatment to clear canine B. gibsoni infections.
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23

Redpath, Stella. "Effector functions of human IgG". Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363193.

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24

Moots, Robert J. "The fine specificity of HLA class I-restricted antigen recognition by cytotoxic T lymphocytes". Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315327.

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25

Ho, Minh-Minh. "Complement protein C1q modulates macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins". Thesis, California State University, Long Beach, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10131681.

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Foam cell formation from arterial intima macrophages and defective clearance of apoptotic foam cells drive the progression of the inflammatory disease atherosclerosis. The role of innate immune protein C1q in autoimmune disease and pathogen defense is well characterized, however its role in atherosclerosis remains largely uninvestigated. Prior studies have characterized the complement independent role of C1q in polarizing macrophages towards an anti-inflammatory phenotype during uptake of apoptotic cells and modified lipoproteins. To further understand the role of C1q in programming human monocyte-derived macrophages during foam cell formation, we used RNA-sequencing to elucidate pathways that are modulated by C1q during clearance of atherogenic lipoproteins. Expression of genes in JAK-STAT, PPAR, apoptotic, and TLR signaling pathways were modulated by C1q in this study. In addition, C1q suppressed STAT1 and PPAR transcriptional activity. This study identifies potential molecular mechanisms that support a beneficial role for C1q in early atherosclerosis.

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26

Alrammah, Hanaa. "The role of lysophosphatidylcholine acyltransferase-2 (LPCAT-2) in inflammatory responses". Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/11291.

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Sepsis is the overwhelming inflammatory response to infection, especially bacterial infection and associated bacterial products. It has major healthcare impacts, affecting an estimated 19-30 million persons/year worldwide with a mortality of 30-70%. Despite intense research, no specific therapy has been established for sepsis and in addition to the high mortality, the associated economic costs are very high. For example, recent data shows that the annual cost of patients with sepsis is more than $20 billion in the USA, and £2.5 billion in the UK. Therefore, novel targets and new therapies for sepsis are required which will have an important impact on both mortality and economic benefits. Recent work has demonstrated that the phopsholipid modifying enzyme, LPCAT, has a role in the regulation of inflammatory responses to bacterial infections. However, the mechanism of action in this regard is not well understood. This project aimed to identify the role of LPCAT-2 in inflammatory response to infections. This project has utilized the RAW264.7 murine macrophage cell line as an experimental model and LPS or Pam3CSK4 as infectious stimuli to investigate the role of overexpressing LPCAT-2 as well as silencing the over-expressed LPCAT-2 using siRNA technique. RAW264.7 cells transiently or stably transfected with the LPCAT-2 gene were used to study the role of LPCAT-2 in the inflammatory responses of macrophages. LPCAT-2 was successfully over-expressed in RAW264.7 cells and the overexpression was successfully confirmed with real time polymerase chain reaction (RT-PCR) and western blotting. The overexpression of LPCAT-2 significantly upregulated the pro-inflammatory cytokines TNF-α and IL-6, at both gene expression, and protein level, while the anti-inflammatory cytokine, IL-10, was down regulated in these cells. Moreover, overexpression of LPCAT-2 significantly decreased the expression of TLR4, peroxisome proliferator-activated receptors –gamma (PPARγ) and CD206 (a marker of M2 macrophages) while it significantly increased CD14, TLR2, COX-2 and iNOS (M1 markers). LPCAT-2 gene expression was also increased when PPARγ was blocked with the selective (PPAR-γ) antagonist T0070907. Importantly, silencing the transiently over-expressed murine LPCAT-2 resulted in a significant reduction in TNF-alpha and a significant increase in IL-10 gene expression. Both the transient and stably transfected RAW264.7 cells have been used to study the role of LPCAT-2 in regulating inflammatory responses in macrophages. The results have significantly added to knowledge of the role of LPCAT-2 in the inflammatory response and will aid in the development of novel therapies for inflammatory conditions such as sepsis.
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27

Jaigirdar, Shafqat Ahrar. "Investigating the molecular mechanisms of CD4 T cell persistence at inflamed peripheral tissues". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8952/.

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CD4 T cells play an important role in the initiation and maintenance of inflammation in numerous inflammatory diseases. Rheumatoid arthritis (RA) is one such autoimmune inflammatory condition where inflammation of the joint occurs. CD4 T cells are one of the key cells in RA pathogenesis due to their ability to activate or influence other cells in the joint including B cells, macrophages and osteoclasts, which collectively lead to joint destruction. The recruitment and function of CD4 T cells at inflamed tissues has been studied extensively. However, the signals that regulate CD4 T cell accumulation and persistence at peripheral inflamed sites are poorly understood. In this study, a novel in vivo model of inflammation was designed in the murine ear pinnae to study the signals which regulate CD4 T helper 1 (Th1) cell persistence at inflamed tissues. Congenically marked, in vitro polarised CD4 Th1 cells were adoptively transferred directly into inflamed or non-inflamed ear pinnae and their persistence and survival were studied using flow cytometry. Higher numbers of CD4 Th1 cells were found at the inflamed as compared to the non-inflamed site. Intravital microscopy was used to further study the behaviour of these cells. Th1 cells were found to be more mobile in inflamed compared to non-inflamed ear pinna. To investigate the molecular mechanism of this, either the ear pinnae or the T cells themselves were manipulated. Introducing cognate antigen at the inflamed site did not alter the number of recovered T cells, nor did the T cells proliferate at the site. Next, the survival of persistent CD4 Th1 cells was examined by investigating their expression of active caspases. Lower proportion of Th1 cells recovered from inflamed tissues were found to express active caspases compared to those from a non-inflamed site. Together these data suggest that local T cell activation is not required for persistence but rather, the increase in T cells at inflamed sites may be due to a combination of persistence and survival signals. The sphingolipid sphingosine-1-phosphate (S1P) has been implicated in driving both egress of T cells out of secondary lymphoid organs and their survival. To investigate whether S1P affects Th1 cell persistence and/or survival at inflamed tissues, Th1 cells were treated with S1PR agonists or antagonists, prior to transfer. Fewer Th1 cells were recovered from the inflammatory site of mice injected with antagonist treated cells. Additionally, S1PR agonism was sufficient to induce Th1 cell persistence at non-inflamed tissues. A trend towards increased expression of active caspases was also found in S1PR antagonist treated T cells recovered from inflamed ear pinnae compared to untreated controls. Finally, elevated levels of the S1P metabolising enzyme, SPHK1, was found in human RA joints compared to OA joints. In sum, I propose a novel function for S1P and its receptors in regulating the persistence of activated CD4 Th1 cells at inflamed tissue sites. Moreover, targeting S1P and its receptors at peripheral inflamed tissues could provide a novel target for the development of more effective anti-inflammatory therapeutics.
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28

Thomas, Laura. "The molecular basis for preservative resistance in Burkholderia cepacia complex bacteria". Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/14475/.

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Burkholderia cepacia complex bacteria can contaminate and survive in a variety of antimicrobial and preserved industrial products. Contamination may lead to economic loss for manufacturers and also potentially pose a risk to the health of vulnerable consumers. Understanding the interaction between Bcc bacteria and preservatives, and the molecular basis for their resistance, is essential in order to better target these organisms and to facilitate the implementation of improved preservative strategies which target resistance mechanisms. In the present study, multi-locus sequence typing analysis of a collection of 67 Bcc isolates from environmentalindustrial sources was used to expand the current knowledge of Bcc species diversity within this niche and identified B. lata (n=17) and B. cenocepacia (n=11) as predominant species groups. The relationship between Bcc species diversity, isolation source and preservative susceptibility was investigated using a collection of 83 genetically diverse Bcc strains from clinical, environmental and environmental-industrial isolation sources. Susceptibility to eight preservatives was not related to Bcc taxonomy, as susceptibility profiles varied both between and within species groups. However, Bcc isolates from environmental-industrial sources had a significantly higher minimum inhibitory and minimum bactericidal concentration (MIC and MBC) for the formaldehyde releasing agent DMDM hydantoin. This suggests that for this preservative agent, susceptibility was related to source and that the selection of highly tolerant Bcc bacteria had occurred within the niche. Isothiazolone, DMDM hydantoin, phenoxyethanol and methyl paraben preservatives were observed to be highly efficacious against Bcc bacteria when evaluated in growth medium at the maximum concentration regulated for use in rinse-off personal care products in EU-regulated countries. Benzethonium chloride and sodium benzoate preservatives had the weakest anti-Bcc activity at these levels but were effective against several strains. Combinations of preservatives, and preservatives with potentiating agents, were evaluated for synergistic anti- Bcc activity. The greatest anti-Bcc activity was observed when isothiazolone preservatives were combined with EDTA or phenoxyethanol, with each combination resulting in an additive effect. The competency of Bcc bacteria to adapt to preservatives was explored via the progressive sub-culture of B. lata strain 383 in subinhibitory preservative concentrations. This genome sequence strain represented a Bcc species commonly encountered in the environmental-industrial niche. Stable adaptive-resistance to isothiazolone and benzethonium chloride preservatives was developed. Phenoxyethanol, DMDM hydantoin and methyl paraben preservatives were recalcitrant to B. lata strain 383 adaptation. The preservative and antibiotic susceptibility profiles of the adapted B. lata strain 383 derivatives differed, suggesting the induction of agent-specific adaptive-resistance mechanisms had occurred. The B. lata 383-CMIT,-BIT, derivatives (adapted respectively to chloromethylisothiazolinone and benzisothiazolinone), demonstrated cross-resistance to isothiazolone preservatives and fluoroquinolone antibiotics. Sequence analysis of the topoisomerase genes in these derivatives revealed fluoroquinolone resistance was not mediated by target modification. Preservative-induced adaptive resistance was not associated with overall increased multi-drug resistance. The molecular basis for resistance to DMDM hydantoin and isothiazolone preservatives was investigated via the random transposon mutagenesis of B. lata strain 383 using pTnModOTp’. Several genetic pathways were identified as putative preservative resistance determinants, suggesting that resistance is multi-factorial. These included the detoxification of formaldehyde via a glutathione-dependent pathway; a type II general secretory system (A3244_A3233 genes); a homologue of an ABC-type efflux system involved in resistance to organic solvents (A3512_A3517 genes); homologues of multi-drug RND-type efflux systems EmrB/QacA-Emr-TolC; and bacterial defence mechanisms against oxidative stress. A transcriptomic microarray-based approach was used to profile global gene expression of B. lata strain 383 in response to sub-MIC of 0.00162% DMDM hydantoin and 0.00001498% of a methylisothiazolinone and CMIT blend, as well as isothiazolone-induced adaptive resistance. With a 1.5-fold change and P < 0.05 confidence level criterion applied, few significant changes were observed after a single sub-MIC exposure, and the differential expression of putative resistance determinants identified by transposon mutagenesis was not induced at these concentrations. Isothiazolone-induced adaptive-resistance involved a greater number of significant gene expression changes that were stable irrespective of the presence of the priming agent, with 126 up-regulated and 90 down-regulated genes. Transcriptomic analysis suggested that isothiazolone-induced adaptive resistance was multi-factorial in nature, and identified active efflux as a putative key resistance mechanism. A novel role for a RND-type efflux system (B1004_B1006 genes) was identified, and the up-regulation of the ABC-efflux system (A3512_A3517 genes) and bacterial defence mechanisms against oxidative stress corroborated the transposon mutagenesis findings. B. lata strain 383-CMIT demonstrated a four-fold reduction in MIC for the priming preservative (2.81E-04%) in the presence of 512 mg/L of the efflux inhibitor PAβN. Resistance mechanism targeted preservative strategies such as using efflux inhibitors may work to improve preservation.
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29

Dalziel, Catherine Ellen. "The molecular basis of adjuvant activity of pneumolysin". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5405/.

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Streptococcus pneumoniae is a major human pathogen and causes a significant burden of disease in both developed and developing countries. Currently, two pneumococcal vaccines are available, a polysaccharide conjugate vaccine for children <2 years of age and an adult polysaccharide vaccine for ‘at risk’ groups such as the elderly and immunocompromised. Unfortunately, due to the vast variation and highly recombinant nature of the pneumococcus vaccine escape through serotype replacement is significantly decreasing the efficacy of pneumococcal vaccines globally. New cost-effective and protective pneumococcal vaccines are urgently required. Pneumolysin (PLY) is a 53Kd cholesterol-dependent cytolysin that is largely conserved in all strains of Streptococcus pneumoniae, making it an ideal candidate for inclusion in a broad spectrum vaccine. It has been shown that PLY is not only a protective immunogen but also has potent adjuvant properties and stimulates both IgG and IgA antibody responses to antigens genetically coupled to the toxin (Douce et al., 2010). Both systemic and mucosal responses are induced when PLY is used as an adjuvant which may prevent colonization and therefore provide non-serotype specific herd immunity to Streptococcus pneumoniae. The cytolytic activity of PLY prevents its inclusion in a human vaccine; a non-lytic deletion mutant 76PLY was created for this purpose which retains adjuvanticity, albeit slightly reduced. The aim of this study was to elucidate the mechanism(s) of PLY/Δ6PLY adjuvanticity, it will be essential to have a basic model of adjuvant activity before PLY-based vaccines can be advanced to human clinical trials. This project used a combination of high-throughput methods such as protein pulldowns and gene expression profiling to examine the abilities of PLY, 76PLY and the truncation mutants D123PLY and D4PLY to bind to and be internalized by host cells and to differentially regulate gene expression. These studies highlighted specific and direct interactions between PLY variants and the host cytoskeleton that could mediate antigen/PLY uptake; they also revealed a pattern of gene expression that is similar to those of other adjuvants and could provide the basis for a model of adjuvanticity. Finally, through the use of reporter cell lines and transgenic TLR4-/- BMDM, the relationship between PLY and TLR4 has been further defined. A novel method for preparing vehicle controls provided evidence that the ligation of TLR4 in this system is PLY-dependent and is not an artefact caused by contaminating TLR ligands such as LPS. Once this was established it was possible to further investigate the role of TLR4 in the adjuvant activity of PLY, in particular the PLYdependent production of IL-1@. Through these studies a surprising role for TLR4 in in vitro PLY-dependent cytokine production was discovered. Additionally, it was found that complement has an essential role in the PLY-dependent production of IL-1@. The role(s) of complement and IL-1@ in the adjuvant activity were further investigated using an in vivo immunization model and the biological basis for the difference in adjuvant activity of PLY and 76PLY was defined.
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Ma, Hoi-tung, i 馬凱彤. "Studies on the elements in the innate immune system of the shrimp, Penaeus monodon: from recognition, activationto melanization". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42841501.

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Rahim, Rahimi Ali Akbar. "Molecular mechanisms for IL-10 induced CD14 expression in human monocytic cells". Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/26752.

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IL-10, an immunoregulatory cytokine with biological effects primarily on inhibition of inflammatory responses, has also been shown to stimulate a variety of functions including CD14 expression on human monocytic cells. CD14, a receptor for lipopolysaccharide (LPS), plays a critical role in the synthesis of proinflammatory cytokines by LPS-stimulated monocytic cells. Herein, I show that LPS-induced CD14 expression on monocytic cells may be mediated by endogenously produced IL-10. In this study, I have investigated the molecular mechanisms by which IL-10 enhances CD14 expression in normal human monocytes and a promyelocytic HL-60 cells as a model system. IL-10 induced the phosphorylation of PI3K and p42/44 extracellular signal-regulated kinase (ERK) MAPKs. By employing specific inhibitors for PI3K (LY294002) and ERK MAPKs (PD98059), I provide evidence that LY294002 either alone or in conjunction with PD98059 inhibited IL-10-induced phosphorylation of STAT1 and consequently CD14 expression. However; IL-10-induced STAT3 activation remained unaffected under these conditions. Furthermore, LY294002 and PD98059 inhibited the binding of STAT1 transcription factor to its binding site in the CD14 promoter. Finally, STAT1 siRNA inhibited IL-10-induced CD14 expression. Taken together, results show for the first time that IL-10-mediated CD14 upregulation may be mediated by STATI activation independently of STAT3. Furthermore, IL-10-activated STAT1 may be regulated through PI3K either alone or in concert with the ERK MAPKs.
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32

Wilson, Eleanor. "Characterising the molecular function of the Rho GTPase RhoJ in endothelial cells". Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5363/.

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RhoJ is an endothelial expressed Rho GTPase that localises to focal adhesions and regulates cell migration and tube formation. Previous work in our laboratory determined that RhoJ activation negatively regulates focal adhesion (FA) numbers, and interacts with the FA proteins GIT1 and β-PIX. The studies presented in this thesis aimed to characterise the role of RhoJ in modulating FA dynamics, further investigate its interactions with the GIT/PIX complex, and generate a RhoJ knockout mouse to determine its function in vivo. Silencing RhoJ led to prolonged FA disassembly in migrating human umbilical vein endothelial cells (HUVEC), while adhesions in cells expressing a dominant active (da) mutant of RhoJ disassembled more rapidly. Interactions between daRhoJ and GIT1, GIT2 and β-PIX were identified, and the localisation of any member of the RhoJ/GIT/PIX complex to FAs was found to be dependent on each of the other components. daRhoJ expression increased levels of GIT2 protein, while silencing RhoJ reduced GIT2 Tyr 392 phosphorylation. In vivo, the growth of subcutaneous tumours was reduced in RhoJ knockout mice compared to wild type controls. In conclusion, the data presented in this thesis show that RhoJ regulates FA disassembly, most likely in concert with the GIT/PIX proteins. This in turn influences endothelial cell migration and ultimately angiogenesis.
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33

鍾婉茹 i Yuen-yue Yvonne Chung. "Immunological and molecular studies of antigens from trichinellid nematodes". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1996. http://hub.hku.hk/bib/B31213054.

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Chung, Yuen-yue Yvonne. "Immunological and molecular studies of antigens from trichinellid nematodes /". Hong Kong : University of Hong Kong, 1996. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19668326.

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35

Levi, Michael. "The use of peptides for studying molecular events in HIV and HSV infection /". Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2784-7/.

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Bucsu, Eva. "Plasmodium chabaudi adami : vaccine antigens and antigenic variation /". Connect to thesis, 2003. http://repository.unimelb.edu.au/10187/2881.

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There is an abundance of information available on the molecular mechanisms of antigenic variation in Plasmodium falciparum. The variant antigen PfEMP1, which mediates antigenic variation as well as cytoadherence and rosetting, has been extensively characterised. Genes coding for the antigen belong to the gene family var, and several var genes have been cloned and characterised. The rodent malaria parasite P. chabaudi is a widely studied in vivo model for P. falciparum. The P. c. chabaudi AS parasite strain has been shown to exhibit antigenic variation and the variant antigen has been detected by surface fluorescence. As with P. falciparum, there is a link between antigenic variation and cytoadherence, however genes coding for the variant antigen in P. chabaudi have not been cloned to date. Therefore, potentially useful in vivo experiments on antigenic variation are restricted. In this thesis it is shown for the first time that the P. c. adami DS parasite strain also exhibits antigenic variation.
Chapter 3 describes efforts to locate genes coding for variant antigens in P. c. adami DS. The main strategy involved a genome survey, by sequencing and analysing randomly selected clones from a P. c. adami DS genomic library. DNA sequences were compared to Plasmodium spp. sequence databases to look for similarity to var genes or other genes encoding variant antigens. Of the 297 clones analysed none had significant sequence similarity to genes coding for variant antigens. However, in a small proportion of sequences some similarity to var genes was noted. Several genes of potential interest were identified, most importantly the gene coding for the vaccine candidate rhoptry associated protein 1 (RAP1), which was subsequently cloned and characterised. Further attempts to locate var gene homologues in P. c. adami involved amplification of P. c. adami genomic DNA using degenerate oligonucleotide primers corresponding to conserved regions of var genes. This strategy proved to be unsuccessful, most likely due to lack of sequence similarity between P. falciparum and P. c. adami genes. In several vaccination studies with the apical membrane antigen 1 (AMA1) of P. c. adami DS, mice were significantly protected against homologous parasite challenge. However, some mice developed late, low-level breakthrough parasitaemias. In Chapter 4, the characterisation of two such breakthrough parasitaemias is described. The ama1 genes of the breakthrough parasites were found to be identical to the ama1 gene of the parental parasites. Similarly, no alteration in AMA1 expression was observed. However, the breakthrough parasites were found to be more resistant than the parental parasites to the effects of passive immunisation with rabbit antisera to AMA1, RAP1 and possibly also MSP119. P. chabaudi infections in mice have been previously shown to consist of a primary parasitaemia followed by a short period of subpatency, and a recrudescent parasitaemia. In surface immunofluorescence studies with P. c. chabaudi, parasites of the recrudescence were shown to be distinct from parasites of the primary parasitaemia, with respect to antigens expressed on the surface of late trophozoite- and schizont-infected erythrocytes.
Chapter 4 describes similar surface immunofluorescence assays carried out with P. c. adami infected erythrocytes, and quantitation of fluorescence by flow cytometry. As with P. c. chabaudi, the recrudescent parasites were found to be antigenically distinct from the primary parasitaemia, indicating that antigenic variation had taken place. Because breakthrough parasites from the AMA1 vaccination trial were similar to recrudescences in peak and duration, we hypothesised that breakthrough parasitaemias, like recrudescent parasitaemias, occur as a result of antigenic variation. In Chapter 4 it was shown by surface immunofluorescence and flow cytometry using hyperimmune sera raised against different parasite populations, that breakthrough parasites express antigens on the surface of late trophozoite- and schizont infected erythrocytes that differ from those expressed by the parental and recrudescent parasites. These results support the hypothesis that switching of the variant antigen on the infected erythrocyte surface enables parasites to evade protective antibody responses directed against merozoite antigens.
Chapter 5 describes the cloning and characterisation of P. c. adami RAP1 which was identified in the process of the genomic survey described in Chapter 3, as well as P. berghei RAP1. Both rodent parasite orthologues of RAP1 were found to have 30% sequence similarity to P. falciparum RAP1, and 6 of 8 cysteines were conserved in the rodent parasite orthologues. However the three polypeptides vary significantly in size. P. c. adami RAP1 and P. berghei RAP1 consist of 691 aa and 604 aa respectively, whereas P. falciparum RAP1 consists of 783 aa residues. These size differences reflect very different N-terminal sequences prior to the first cysteine, whereas the cysteine-rich C-terminal regions are more conserved. Both P. falciparum RAP1 and P. c. adami RAP1 contain N-terminal repeats, however they bear no sequence similarity to each other. P. berghei RAP1 lacks N-terminal sequence repeats that are characteristic of P. falciparum and P. c. adami RAP1. The large cysteine-rich C-terminal region P. c. adami RAP1 (PcRAP1 C3) was expressed in E. coli as a hexa-his fusion protein. Rabbit antiserum to recombinant PcRAP1 C3 was used to characterise the expression and sub-cellular localisation of the RAP1 antigen. P. c. adami RAP1 was found to have a Mr of approximately 80,000 and was shown by immunofluorescence to localise to the merozoite rhoptries. Passive immunisation of mice with rabbit anti-RAP1 serum was shown to protect against fulminant parasitaemia and mortality. In a mouse vaccination trial using the recombinant PcRAP1 C3 polypeptide partial protection was conferred against homologous parasite challenge.
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37

Godec, Jernej. "Molecular Mechanisms of CD8+ T Cell Differentiation". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493424.

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CD8+ T cells are a crucial component of the adaptive immune system and are required for optimal protection from most pathogens and cancer. They function by secreting pro-inflammatory cytokines and by directly eliminating infected and malignant cells. In order to be effective, CD8+ T cells must be activated through a complex sequence of steps involving engagement of the antigen-specific T cell receptor (TCR) and other receptors, which orchestrate transcriptional, epigenetic, and metabolic changes that direct the differentiation of the responding cells. Following optimal activation, naive CD8+ T cells rapidly undergo clonal expansion and effector differentiation that enables prompt resolution of infection. Following pathogen clearance, a fraction of effector CD8+ T cells differentiate into long-lived memory CD8+ T cells that provide robust protection from re-challenge with the same microbe. However, in the context of persistent abundance of antigen and inflammation, such as in chronic infections and in cancer, the T cells instead become gradually more dysfunctional – a state known as T cell exhaustion. The overarching goal of this thesis is to identify the cardinal features and molecular mechanisms associated with three main states in which CD8+ T cells exist: T cell memory, T cell exhaustion, and T cell effector differentiation. I used two complementary approaches to examine CD8+ T cells at the different states in vivo. First, I used classical immunology techniques including knockout mice and cellular phenotypic analyses to examine the role of cell surface molecules PD-1 and CD39 on CD8+ T cells in the context of memory and exhaustion, respectively. Secondly, I developed a novel experimental platform that enables gene perturbation in naive CD8+ T cells in vivo during their differentiation. I used this approach to systematically interrogate the transcriptional programming of activated CD8+ T cells and to identify novel regulators of effector differentiation. In a proof of concept study, I used this system to further define how the transcription factor BATF regulates CD8+ T cell activation. Additionally, I used this experimental platform to systematically interrogate the functional role of a set of ~80 transcription factors in CD8+ T cell differentiation, and identified TGIF1 as a novel regulator of this process. The role of the co-inhibitory receptor PD-1 on CD8+ T was examined in mice using an acute respiratory infection model. PD-1 is a co-inhibitory receptor that is up-regulated on T cells following activation and recruits SHP1/2 phosphatases to directly antagonize signals through the TCR and this way inhibit the activation of T cells. It is down-regulated following the resolution of an acute infection but remains persistently expressed on CD8+ T cells in chronic infections and cancer. As such, PD-1 has been exhaustively studied for its contribution to the functional exhaustion of T cells. However, its role in acute infections remains less defined. We found that this receptor prevents over-activation and over-expansion of CD8+ T cells following initial differentiation, and is crucial for optimal differentiation of effector CD8+ T cells into functional memory cells. Exhausted CD8+ T cells express several markers distinctive of the state. Some, like PD-1, Tim-3, and Lag-3 are well known. However, genome-wide transcriptional studies identified numerous additional genes that are differentially expressed in the exhausted state. Thus, we hypothesized that additional markers may provide characteristic features of the exhausted cell state and may function in chronic infections. We investigated one such gene – ENTPD1 – that encodes for CD39. This cell surface molecule is an ectonucleotidase that hydrolyzes extracellular ATP into ADP and AMP, which can be further broken down to immunosuppressive adenosine by CD73. In the context of the immune system, CD39 has largely been studied on CD4+ regulatory T cells, which use CD39 as a mechanism to suppress immune responses. However, surprisingly, we found that CD8+ T cells can also express CD39, but its expression is largely restricted to terminally exhausted CD8+ T cells. These cells are most dysfunctional as measured by the most limited proliferative capacity and ability to produce pro-inflammatory cytokines. We have observed this biology in both human and mouse chronic viral infections. Additional studies further demonstrated the importance of CD39 and the purinergic pathway in regulating lethal immunopathology associated with chronic LCMV infection in mice. In addition to interrogating memory and exhaustion fates of CD8+ T cells, we also examined the initial regulatory programs involved in CD8+ T cell differentiation in vivo through gene silencing. Gene perturbation in naive T cells without prior cellular stimulation has been a continuous challenge in the field. To circumvent this limitation, we engineered a novel experimental platform that enables inducible gene knock-down in any immune cell in mice in vivo without prior manipulation of these cells. Initially, I validated this system by knocking down BATF and confirmed its essential role in CD8+ T cell responses to acute LCMV infection. Additionally, leveraging the inducible nature of the platform, I showed that BATF functions in the early stages of T cell activation but becomes dispensable once its transcriptional program is initiated. Several other transcription factors such as T-bet, Eomes, Bcl6, and Blimp-1 have been described to regulate CD8+ T cell differentiation. However, numerous additional transcription factors may function in this process based on their rapid up-regulation following T cell activation. I used the novel platform to systematically test the functional relevance of ~80 additional transcription factors in a pooled setting. These experiments identified several novel candidate regulators of this process. We validated one such gene – Tgif1 – to confirm its role in the effector CD8+ T cell differentiation following acute LCMV infection and provide clues to the potential mechanism in which it may function. The above projects have benefited significantly from genome-wide transcriptional datasets of cells at various states or of different genotypes that we generated or that originate from published studies. One particularly powerful approach to examine differences between different groups is gene set enrichment analysis (GSEA) that examines coordinate up- or down-regulation of sets of genes rather than assessing differential expression of specific genes. This is particularly important because changes in biological processes are often guided by relative small changes of groups of genes that act in concert rather than by a robust expression change of a single gene. This approach, however, is only informative if a relevant gene-set collection is used to analyze the data. Existing collections are largely centered around cancer biology and general biological processes but no extensive gene-set collection existed that contained information describing immune processes. Thus, we created ImmuneSigDB – the largest collection of immunology-focused gene sets to date by identifying, annotating, and reanalyzing ~400 published immunology studies. To show its broad use, we used it to examine the cross-species conservation of transcriptional responses in the immune system. We focused on analyzing transcriptional data from systemic responses to sepsis using GSEA and a novel approach, called leading edge metagene analysis. Using these approaches, we uncovered shared and species-specific biology in mouse and human transcriptional responses to sepsis. Deciphering CD8+ T cell biology is key for conceptualizing new medical interventions that may boost their activation, memory development, and rejuvenation from functional exhaustion. We have determined that PD-1 is essential for optimal CD8+ T cell memory responses, and that BATF is a key transcription factor initiating effector T cell transcriptional programming. We also identified CD39 as a new marker of terminally exhausted CD8+ T cells and uncovered a key role for purinergic signaling in regulating lethal immunopathology in LCMV Clone 13 infection in mice. Furthermore, we developed a new experimental platform that enables systematic interrogation of gene function in any hematopoietic cell type by inducible knock-down of genes and identified TGIF1 as a novel negative regulator of CD8+ T cell responses. We have also developed a new computational resource to improve analyses of transcriptional profiles in the immune system. Together, the body of work presented in this thesis advances our knowledge of major states of CD8+ T cell biology, uncovering both novel mechanisms underlying CD8+ T cell function, as well as highlighting potential novel therapeutic targets that may be transformative in creating better vaccines, treating infections, or fighting cancer.
Medical Sciences
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38

Portman, Jonathan Lewis. "Virulence Factor Regulation in Listeria monocytogenes". Thesis, University of California, Berkeley, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10620349.

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Listeria monocytogenes is a Gram-positive intracellular pathogen that is readily amenable to genetic manipulation and for which there are excellent in vitro and in vivo virulence models. These attributes have allowed a thorough examination of the molecular underpinnings of L. monocytogenes pathogenesis, however, there are still a number of major unresolved questions that remain to be answered. For example, it has been known for many years that L. monocytogenes rapidly changes its transcriptional profile upon access to the host cytosol, however the host cues and bacterial components that are involved in driving this change have remained continually unanswered. One large piece of evidence came when the long-sought co-factor for the primary virulence regulator, PrfA, was discovered to be the antioxidant tripeptide, glutathione. Glutathione was demonstrated to play a crucial role in the activation of PrfA in vivo— a finding that has since led to two important discoveries that are described herein. First, the activation of PrfA in vitro requires both exogenous glutathione and a metabolic licensing step that can be recapitulated by a chemically defined synthetic media. Second, glutathione also functions as a post-translational regulator of the pore-forming virulence factor, Listeriolysin O (LLO), by reversibly binding via an S-glutathionylation reaction and preventing membrane association of the LLO monomers. These discoveries elucidate numerous regulatory roles for glutathione during infection and describe how L. monocytogenes is able to sense and respond to critical host compartments to mount a successful infection.

Upon entry to the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator, PrfA. Here we report that robust virulence gene expression can be recapitulated by growing bacteria in a synthetic medium (iLSM) containing GSH or other chemical reducing agents. Bacteria grown under these conditions were 45-fold more virulent in an acute murine infection model and conferred greater immunity to a subsequent lethal challenge compared to bacteria grown in conventional media. During cultivation in vitro , PrfA activation was completely dependent on intracellular levels of GSH, as a glutathione synthase mutant (ΔgshF) was activated by exogenous GSH but not reducing agents. PrfA activation was repressed in iLSM supplemented with oligopeptides, but suppression was relieved by stimulation of the stringent response. These data suggest that cytosolic L. monocytogenes interpret a combination of metabolic and redox cues as a signal to initiate robust virulence gene expression in vivo.

Cholesterol-dependent cytolysins (CDCs) represent a family of homologous pore-forming proteins secreted by many Gram-positive bacterial pathogens. CDCs mediate membrane binding partly through a conserved C-terminal undecapeptide, which contains a single cysteine residue. While mutational changes to other residues in the undecapeptide typically have severe effects, mutating the cysteine residue to alanine has minor effects on overall protein function. Thus, the function of this highly conserved reactive cysteine residue remains largely unknown. We report here that the CDC Listeriolysin O (LLO), secreted by the facultative intracellular pathogen Listeria monocytogenes, was post-translationally modified by a S-glutathionylation at this conserved cysteine residue, and that either endogenously synthesized or exogenously added glutathione was sufficient to form this modification. When recapitulated with purified protein in vitro, this modification completely ablated the activity of LLO, and this inhibitory effect was fully reversible by treatment with reducing agents. A cysteine-to-alanine mutation in LLO rendered the protein completely resistant to inactivation by S-glutathionylation and retained full hemolytic activity. A mutant strain of L. monocytogenes expressing the cysteine-to-alanine variant of LLO was able to infect and replicate within bone marrow-derived macrophages indistinguishably from wild-type in vitro, yet was attenuated 4-6 fold in a competitive murine infection model in vivo. This study suggests that S-glutathionylation may represent a mechanism by which CDC family proteins are post-translationally modified and regulated, and help explain an evolutionary pressure behind the highly conserved undecapeptide cysteine.

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39

Mudenda, Lwiindi. "Identification of Dermacentor andersoni saliva proteins that modulate mammalian phagocyte function". Thesis, Washington State University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3717421.

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Ticks are obligate blood sucking parasites which transmit a wide range of pathogens worldwide including protozoa, bacteria and viruses. Additionally, tick feeding alone may result in anemia, dermatosis and toxin-induced paralysis. Dermacentor andersoni is a species of tick found in the western United States that transmits pathogens of public health importance including Rickettsia rickettsii, Francisella tularensis, and Colorado Tick Fever Virus, as well as Anaplasma marginale, a rickettsial pathogen that causes economic losses in both the dairy and beef industries worldwide. D. andersoni ticks are obligate blood sucking parasites that require a blood meal through all stages of their lifecycle. During feeding, ticks secrete factors that modulate both innate and acquired immune responses in the host which enables them to feed for several days without detection. The pathogens transmitted by ticks exploit these immunomodulatory properties to facilitate invasion of and replication in the host. Molecular characterization of these immunomodulatory proteins secreted in tick saliva offers an opportunity to develop novel anti-tick vaccines as well as anti-inflammatory drug targets. To this end we performed deep sequence analysis on unfed ticks and ticks fed for 2 or 5 days. The pooled data generated a database of 21,797 consensus sequences. Salivary gland gene expression levels of unfed ticks were compared to 2- and 5-day fed ticks to identify genes upregulated early during tick feeding. Next we performed mass spectrometry on saliva from 2- and 5-day fed ticks and used the database to identify 677 proteins. We cross referenced the protein data with the transcriptome data to identify 157 proteins of interest for immunomodulation and blood feeding. Both proteins of unknown function and known immunomodulators were identified. We expressed four of these proteins and tested them for inhibition of macrophage activation and/or cytokine expression in vitro. The results showed diverse effects of the various test proteins on the inflammatory response of mouse macrophage cell lines. The proteins upregulated some cytokines while downregulating others. However, all the proteins upregulated the regulatory cytokine IL-10.

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40

Chirieleison, Steven Morrow. "XIAP-MEDIATED INNATE IMMUNE SIGNALING IN INFLAMMATORY BOWELDISEASE". Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1499435128937345.

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41

Oldridge, Joanne. "Molecular and immunological characterisation of two vaccine dominant antigens of Schistosoma mansoni". Thesis, London School of Hygiene and Tropical Medicine (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307435.

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42

Wedderburn, Lucy Rachel. "Molecular analysis of T cell receptors : mapping T cell recognition and repertoire in two human immune responses". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261721.

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43

Chatterjee, Avijit. "Vitamin A and measles : cellular and molecular analysis". Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31206.

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Measles virus (MV) infects up to 40 million individuals each year, leading to one million deaths. MV can infect a wide variety of cell types including cells of the immune system. Although vitamin A (retinal) supplements can significantly reduce measles-associated mortality, the mechanism(s) remains unknown. We adopted a three-pronged approach to investigate vitamin A modulation of measles infection of human immune cells. We found that, at 1muM, both retinoic acid and retinol (ROH) with or without retinol binding protein (RBP) decreased MV production by 33% +/- 24% (p < 0.001), 37% +/- 20% (p < 0.001), and 23% +/- 17% (p < 0.04) respectively and peak inhibition with ROH:RBP occurred at 10-6 muM. Also, ROH:RBP treatment of U937 cells increased the viral fusion:nucleocapsid mRNA ratio by 1.6 +/- 0.3-fold (p < 0.05) thus altering optimal transcript ratios. Finally, MV-infection of U937 cells increases retinoic acid receptor alpha and retinoid X receptor alpha mRNA expression (2.0 +/- 0.74-fold and 2.1 +/- 0.33-fold; p < 0.05, respectively) while simultaneous treatment with ROH:RBP maintained or decreased levels of these two receptors compared to control, respectively. These data demonstrate that vitamin A can have substantial impact on MV replication and viral protein expression in human immune cells in vitro. These data also suggest that MV may have its profound impact on the immune system by manipulation of the retinoid signaling pathway and that supplemental retinoids may interfere with this action.
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44

Im, Jin Seon. "Molecular characterization of T cell receptors and non-MHC restricted T cell receptor binding peptides". Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/284969.

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T cells recognize antigenic peptides presented by MHC molecules on antigen presenting cells (APC) through T cell receptors (TCRs). Since TCRs are very similar to antibodies in structure and genetics, TCRs might have the potential to bind free antigens as antibodies do. Here, peptides which bound TCRs irrespective of MHC molecules have been identified by screening "one-bead one-peptide" combinatorial libraries. Peptides: VRENAR, RTGNYV, GKMHFK, KDAVKR and RKPQAI bound recombinant Jurkat single chain T cell receptors (scTcrs). GKMHFK, KDAVKR and RKPQAI were also specific for natural TCRs on the Jurkat cell surface. Molecular modeling implies that Glu96 in the CDR3 loop of TCR alpha chain is a candidate for the peptide interaction site. However, TCR-binding peptides did not induce biological effects on parental Jurkat cells. To extend this study to a biologically relevant system, diabetogenic T cells involved in insulin-dependent diabetes mellitus (IDDM) have been characterized. GAD(524-543) responding T cells showed restricted TCR variable gene usage, which utilized preferentially Vα17 and Vβ12. Three domain single chain T cell receptors (3D scTcr) were constructed as tools to investigate potential therapies for IDDM and to identify peptides which bind to TCR without association of MHC molecules. Functional analysis has demonstrated that GAD(524-543)-specific scTcrs retained the ability to bind GAD(524-543)/IAg7 complex. This work shows that recombinant scTcrs can bind cognate peptide presented by MHC molecules, therefore they can be used as substitutes for natural TCRs in screening "one-bead one-peptide" combinatorial libraries to identify TCR-binding peptide.
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45

Tabbaa, Omar Peter. "Stochastic and Multi-scale Modeling in Biology and Immunology". The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1416498545.

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46

Tessmer, Marlowe S. "Biological functions and molecular associations of the killer cell lectin-like receptor G1". View abstract/electronic edition; access limited to Brown University users, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3318364.

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47

Girard, Tanya. "Role of CD80 and CD86 cosignaling proteins functional domains in molecular structure and adaptive immune responses". Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103159.

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The initiation of adaptive immune responses requires the interactions of T cells with antigen presenting cells (APC) in the context of an immunological synapse (IS). Naive T cell responses are dependent on the engagement of CD28 and CTLA-4 by CD86 and CD80, respectively amplifying and dampening the antigen specific signal. CD80 and CD86 cosignaling molecules display three major domains: a membrane distal IgV-like domain, a membrane proximal IgC-like domain and an intracellular domain. Crystallographic data has shown that only the IgV domain of CD80 and CD86 physically interacts with CTLA-4. However, extensive mutational analyses have also implicated the IgC domain in receptor binding and in the overall function of these molecules. The role of CD80 and CD86 within the IS and their exact molecular structure remains to be elucidated. The work presented in this thesis employs wild type, mutant, deleted and chimeric forms of CD80 and CD86 to characterize the role of their domains in molecular structure, receptor binding and overall cosignaling function in an antigen specific cellular interaction system. CD80 and CD86 are shown to be associated to the AFC cytoskeleton. A highly conserved K4 motif within CD86 is shown to be a cytoskeletal association motif. Moreover, CD86 is shown to physically interact with ERM proteins. Only cytoskeleton-linked CD86 localizes at the IS and induce IL-2 production. CD80 and CD86 molecular organization is clearly established using cytometry-based fluorescence resonance energy transfer (FCET) and biochemical approaches. CD80 exists as a mixed monomeric and dimeric population and CD86 as a monomer in live cells. The crucial role of CD80 and CD86 IgC domain in multimerization is revealed. Importantly, the molecular structure of these molecules correlates with their binding properties and cosignaling function. A functional picture of CD80 and CD86 domains emerges where the IgV is responsible for receptor binding, the IgC domain impacts dimerization, and the intracellular domain functionally links these proteins to the cytoskeleton. The findings presented in this thesis certainly contribute to the general understanding of cosignaling protein interactions and functions and may facilitate the design of structure-based immunotherapeutics.
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48

McBerry, Cortez. "Cellular and Molecular Mechanisms of Immunoregulation In Vivo". University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1354296472.

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49

Wong, Raymond Kah-Meng. "Molecular characterization of the regulation of endothelial barrier function during inflammation". Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/279800.

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A major feature of inflammation is the extravasation of cellular and macromolecular components of blood into the interstitium to attack and fend off an offending stimuli, thus initiating healing. When prolonged and/or uncontrolled, this process can begin to produce deleterious effects and inadvertently damage tissue. Such instances are observed in pathologies, such as atherosclerosis, organ transplant rejection and reperfusion injury. It is therefore vital to understand the various mechanisms that initiate and control the process of extravasation. Since the endothelium is the key component between blood and the interstitium, its regulation is largely responsible for control of extravasation. TNFα and IFNγ are cytokines that function in orchestrating signals between different cellular players involved in inflammation. In this dissertation, the effects of these cytokines on endothelial permeability were explored using in vivo and in vitro methods. I investigated two ways whereby the endothelial barrier could be controlled. Firstly, the molecular mechanisms at intercellular junctions could be regulated, thus influencing permeability via the paracellular pathway. One such mechanism involves cadherins which are transmembrane homotypic Ca²⁺-dependent cell-cell adhesion molecules implicated in the control of junctional organization and therefore, paracellular permeability. Secondly, manipulation of signaling pathways by cytokines that induce endothelial apoptotic cell death could create cell-sized gaps in the endothelial barrier. The results of this work demonstrated that combined cytokine treatments: (i) induced focal areas of cadherin-5 relocalization which corresponded to regions of macromolecular extravasation in a rat in vivo model and (ii) induced the upregulation and junctionalization of N-cadherin, concomitant with downregulation and decreased junctionalization of cadherin-5 in cultured endothelial cells. Thus, combined cytokine regulation of endothelial cadherin function was found central in both accommodating an initial microvascular permeability increase upon cytokine induction of inflammation and in limiting the extent of paracellular gap formation (via its effects on N-cadherin) under chronic inflammatory conditions. Furthermore, despite in vitro evidence of endothelial apoptosis, the combined cytokines induced most endothelial cells to express protective, anti-apoptotic molecules (e.g. A1) and therefore contributed to preserving endothelial barrier integrity. Through these experiments, specific mechanisms for regulating the endothelial barrier during inflammation have been identified and are better understood.
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50

Sala, Hojman Ada. "Molecular mechanisms involved in the immunomodulation induced by LIF in cancer". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/398852.

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LIF is a pleiotropic cytokine that can act as an immunomodulatory factor in different biological processes, such as embryo implantation, organ transplantation tolerance and multiple sclerosis. Here, we have observed that in tumors expressing LIF, its blockade inhibits tumor growth, and that the anti-tumor effect of LIF neutralization is mediated by the polarization of tumor-associated myeloid cells (TAMCs). LIF sustains the expression of CCL22, MRC1 and CD163 in human healthy monocytes and in TAMCs from mouse syngeneic (non-small cell lung cancer, ovarian cancer and colorectal cancer) models, patient-derived xenograft models and organotypic cultures from glioblastoma. We show that LIF blockade down-regulates CCL22 secretion by TAMCs preventing regulatory T cell and inducing effector T and NK cell tumor infiltration, leading to an increase in tumor cell apoptosis and an anti-tumor response. A positive correlation between M2-like markers and LIF expression has been observed in glioblastoma patients, and high levels of these factors confer poor prognosis. Moreover, we have studied one of the multiple mechanisms through which LIF could modulate the inhibition of effector T and NK cells: the regulation of PD-1/PDL1 axis. We have seen that after anti-LIF treatment of tumor-bearing mice, the expression of PDL1 decreases in tumor cells and in TAMCs. Furthermore, a positive correlation between PDL1 and LIF expression has been observed in glioblastoma patients, and both proteins also correlate with CD44 expression, a marker for cancer-initiating cell (CIC) population. High levels of these three factors confer poor prognosis. Thus, we have found that LIF acts as an immune-suppressor in cancer recapitulating its normal function in other biological processes. LIF is a bridge between the innate and adaptive immune responses through the induction of CCL22 in TAMCs and subsequent regulation of regulatory and effector T and NK cells. Our results identify LIF as a promising immuno-oncology therapeutic target and establish the translational potential of anti-LIF agents.
LIF és una citoquina que actua corn un factor immunomodulador en diferents processos biologics, corn en la implantacio de l'embrio, en la tolerancia en trasplantaments d'argans i en I'esclerosi multiple. Hem observat que aquells tumors que expressen LIF, sofreixen una inhibicio del creixement tumoral en resposta al seu bloqueig. Aquest efecte esta mitjangat per la polaritzacio de les cel•ules mieloides associades al tumor (TAMCs) cap a un fenotip M2. LIF sustenta l'expressio de CCL22, MRC1 i CD163 en monacits alats de sang periferica de donants sans, en TAMCs de models singenics de ratolf (cancer de pulmo, ovari i colon), en models xenagrafts derivats de pacients i en cultius organotipics de glioblastoma. Demostrem que el bloqueig de LIF disminueix la secrecio de CCL22 de les TAMCs, prevenint la infiltracio tumoral de les cel•ules T reguladores (Tregs) i induint el reclutament de cel•ules T efectores (Teff) i de natural killer (NKs), el que comporta un augment en I'apoptosi de les cel•ules tumorals. Hem observat una correlacio positiva entre l'expressio de marcadors del fenotip M2 i LIF en pacients de glioblastoma. Alts nivells d'aquests factors confereixen un mal pronastic. D'altra banda, hem estudiat un dels mecanismes mitjangant el qual LIF podria modular la inhibicio de les Teff i NKs: la regulacio PDL1. Hem observat que despres de tractar els ratolins amb l'anticas anti-LIF, l'expressio de PDL1 disminueix tant en les cel•ules tumorals corn en les TAMCs. A mes, hem trobat una correlacio positiva entre l'expressio de PDL1 i LIF en pacients amb glioblastoma, i ambdues protenes correlacionen amb CD44, un marcador d'una poblacio enriquida amb cel•ules iniciadores de tumor (CICs). Alts nivells d'aquests tres factors confereixen un mal pronastic. Aixf doncs, hem demostrat que LIF actua corn un supressor immunologic en processos tumorals, recapitulant la seva funcio normal en altres processos biologics. LIF es un pont entre la resposta immunolagica innata i I'adaptativa a traves de la induccio de la secrecio de CCL22 de les TAMCs, i la posterior regulacio de les Tregs, Teff i NKs. Els nostres resultats identifiquen LIF corn una diana terapeutica immuno-oncolagica prometedora i estableixen el potencial translacional d'agents inhibidors de LIF.
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