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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The Role of the Wiskott-Aldrich Syndrome Protein in Regulating T Cell Programmed Cell Death Mechanisms and Implications for Autoimmunity in the Wiskott-Aldrich Syndrome

Marjanovic, Sophia Y. 04 February 2016 (has links)
<p> The development of autoimmunity in the setting of immunodeficiency has been a paradoxical observation. Many primary immunodeficiency diseases (PIDDs) are associated with autoimmunity. Wiskott-Aldrich Syndrome (WAS), a PIDD caused by defects in the Wiskott-Aldrich Syndrome protein (WASp), has an extremely high percentage of autoimmunity associated among WAS patients (40%). We hypothesized that defects in cell death mechanisms underlie the autoimmunity in WAS. In T cells, since TCR activation involves WASp, and TCR activation is necessary for restimulation induced cell death (RICD), we investigated whether WASp regulates this mechanism of peripheral tolerance. We found that older WASp deficient mice develop autoimmmunity with immune complex nephritis. WASp deficient T cells have a cell-intrinsic defect in RICD and have reduced secretion of secretory granules as well as high molecular weight FasL (HMW FasL). WASp is also required for cytotoxicity of CD4+ T cells, but does not affect the killing of target cell by CD8+ T cells. This was not simply due defects in FasL secretion or CTL granule secretion because Rab27a or FasL deficiency resulted in different defects in target cell killing. The defects we have found in T cell death mechanisms may contribute to the development of autoimmunity in WASp deficient mice and patients with WAS.</p>
2

The Multiple Roles of Id2 and Id3 in Invariant NKT Cell Development and NKT Lymphoma Formation in Mice

Li, Jia January 2014 (has links)
<p>Invariant NKT (iNKT) cells represent a unique group of &alpha;&beta; T cells that have been classified based on their exclusive usage of the invariant V&alpha;14J&alpha; 18 TCR&alpha; &ndash;chain and their innate&ndash;like effector function. Thus far, the transcriptional programs that control V&alpha;14J&alpha;18 TCR&alpha; rearrangements and the population size of iNKT cells remain incompletely defined.</p><p> E protein transcription factors have been shown to play multiple roles in T cell development including lineage commitment, receptor gene recombination, proliferation and lineage choice. Inhibitor of DNA&ndash;binding (Id) proteins are the natural inhibitors of E protein transcription factors. The goal of this dissertation is to examine E protein functions in the development of iNKT cells in the mouse after combined deletion of genes encoding E protein inhibitors Id2 and Id3. </p><p> We revealed important roles of Id proteins and E proteins in regulating iNKT cell development. Deletion of Id2 and Id3 in T cell progenitors resulted in a partial block at the pre&ndash;TCR selection checkpoint and a dramatic increase in numbers of iNKT cells. This increase in iNKT cells is accompanied with a biased rearrangement involving V&alpha;14 to J&alpha;18 recombination at the double&ndash;positive stage and enhanced proliferation of iNKT cells. We further demonstrate that a 50 percent reduction of E proteins can cause a dramatic lineage shift from iNKT cells to innate&ndash;like gd T cells in Id2 and Id3 double&ndash;deficient mice. Collectively, these findings suggest that Id2&ndash; and Id3&ndash;mediated inhibition of E proteins controls iNKT development by restricting lineage choice and population expansion.</p><p> Our study also uncovered a novel role of Id proteins in development of NKT lymphoma. Id deficient NKT cells gradually progresses into NKT lymphoma, a rare form of tumor with no clearly defined etiology. Id and E proteins have been demonstrated to be involved in multiple lymphoma and cancer subtypes, but their role in the development of NKT lymphomas is unexplored. Adoptive transfer experiments confirmed that the malignant cells are able to invade healthy tissues. cDNA Microarray analysis of NKT lymphoma and pre&ndash;malignant NKT cells revealed alterations in several cytokine signaling pathways during tumor progression. These findings indicate that regulation of E proteins by Id2 and Id3 may play important roles in the development of NKT lymphoma. To our knowledge, this study represents the first mouse model in which NKT lymphoma develops at such high frequency and fast kinetics. Our double knockout mice provide a unique model to study mechanisms of human NKT lymphoma progression.</p> / Dissertation
3

Migratory properties of IL-2 and IL-15 activated Natural Killer Cells in Dendritic Cells and tumor microenvironments

Sow, Ibrahim 27 April 2016 (has links)
Recent work on Natural Killer (NK)-Dendritic cell (DC) crosstalk has focused on how NK-DC interaction can lead to NK activation, DC activation, NK-DC reciprocal activation, apoptosis and other effector functions. The significance of the NK-DC crosstalk in both physiological and pathological conditions is well documented. However, the way in which NK-DC interaction helps in NK recruitment has not been studied in detail. Using a conventional Trans-well (TW) assay and a microfluidic (MF) platform in vitro, we recently reported on the migratory properties of IL-2 activated NK cells in response to conditioned media, CM, from immature or LPS-stimulated mature DC. In this present study as well, I employed the trans-well and the Microfluidic device to compare the migration of different cytokine activated NK towards the Conditioned media generated from DC activated with different Toll like receptor ligands, TLRLs. I observed that different TLRLs stimulated DC elicit strong NK chemotaxis but at different recruitment potentials. Also, the different cytokine activated NK cells showed different migration capacity towards the different CM generated from DC. I accounted for the differential migration pattern between the IL-2 and IL-15 NK on the differential expression of CXCR3. Good understanding of how NK-cell migratory properties are regulated in physiological and pathological microenvironments will provide further (good) insights into the development of NK cell based therapeutic against cancer. / May 2016
4

Methods and Mechanisms of Mitigating Mast Cell Activation in Anaphylaxis

Ang, Wei Xin Gladys January 2016 (has links)
<p>A great number of people suffer from allergic disorders, some of which can be serious and life threatening. Unfortunately, there are limited ways to treat or prevent these maladies, in part due to our limited understanding. This dissertation addresses a novel mechanism of rapid desensitization, a procedure used to achieve temporary tolerance to allergens to prevent anaphylaxis, a severe allergic reaction involving mast cell degranulation. Specifically, we found that desensitization results in the aberrant reorganization of the actin cytoskeleton in mast cells, preventing calcium mobilization and inhibiting degranulation. Additionally, we found that a bacterial-derived phosphatase, YopH-TAT, could be potentially used for the treatment of allergic diseases, as it efficiently blocked mast cell activation by inhibiting tyrosine phosphorylation.</p> / Dissertation
5

IL-10-producing Regulatory B Cell Development in Human Autoimmune Disease

Kalampokis, Ioannis January 2016 (has links)
<p>B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of costimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of “regulatory B cells” has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported with interleukin-10 (IL-10) being the most studied. IL-10-producing regulatory B cells predominantly localize within a rare CD1dhiCD5+ B cell subset in mice and the CD24hiCD27+ B cell subset in adult humans. This specific IL-10-producing subset of regulatory B cells have been named “B10 cells” to highlight that the regulatory function of these rare B cells is primarily mediated by IL-10, and to distinguish them from other regulatory B cell subsets that regulate immune responses through different mechanisms. B10 cells have been studies in a variety of animal models with autoimmune disease and clinical settings of human autoimmunity. There are many unsolved questions related to B10 cells including their surface phenotype, their origin and development in vivo, and their role in autoimmunity.</p><p>In Chapter 3 of this dissertation, the role of the B cell receptor (BCR) in B10 cell development is highlighted. First, the BCR repertoire of mouse peritoneal cavity B10 cells is examined by single cell sequencing; peritoneal cavity B10 cells have clonally diverse germline BCRs that are predominantly unmutated. Second, mouse B10 cells are shown to have higher frequencies of λ+ BCRs compared to non-B10 cells which may indicate the involvement of BCR light chain editing early in the process of B10 cell development in vivo. Third, human peripheral blood B10 cells are examined and are also found to express higher frequencies of λ chains compared to non-b10 cells. Therefore, B10 cell BCRs are clonally diverse and enriched for unmutated germline sequences and λ light chains.</p><p>In Chapter 4 of this dissertation, B10 cells are examined in the healthy developing human across the entire age range of infancy, childhood and adolescence, and in a large cohort of children with autoimmunity. The study of B10 cells in the developing human documents a massive transient expansion during middle childhood when up to 30% of blood B cells were competent to produce IL-10. The surface phenotype of pediatric B10 cells was variable and reflective of overall B cell development. B10 cells down-regulated CD4+ T cell interferon-gamma (IFN-γ) production through IL-10-dependent pathways and IFN-γ inhibited whereas interleukin-21 (IL-21) promoted B cell IL-10 competency in vitro. Children with autoimmunity had a contracted B10 cell compartment, along with increased IFN-γ and decreased IL-21 serum levels compared to age-matched healthy controls. The decreased B10 cell frequencies and numbers in children with autoimmunity may be partially explained by the differential regulation of B10 cell development by IFN-γ and IL-21 and alterations in serum cytokine levels. The age-related changes of the B10 cell compartment during normal human development provide new insights into immune tolerance mechanisms involved in inflammation and autoimmunity.</p><p>These studies collectively demonstrate that BCR signals are the most important early determinant of B10 cell development in vivo, that human B10 cells are not a surface phenotype defined developmental B cell subset but a functionally defined regulatory B cell subset that regulates CD4+ T IFN-γ production through IL-10-dependent pathways and that human B10 cell development can be regulated by soluble factors in vivo such as the cytokine milieu. The findings of these studies provide new insights into immune tolerance mechanisms involved in human autoimmunity and the potent effects of IL-21 on human B cell IL-10 competence in vitro open new horizons in the development of autologous B10 cell-based therapies as an approach to treat human autoimmune disease in the future.</p> / Dissertation
6

Antigen Drives Regulatory B10 Cell Development and Function

Candando, Kathleen January 2016 (has links)
<p>B cells mediate immune responses via the secretion of antibody and interactions with other immune cell populations through antigen presentation, costimulation, and cytokine secretion. Although B cells are primarily believed to promote immune responses using the mechanisms described above, some unique regulatory B cell populations that negatively influence inflammation have also been described. Among these is a rare interleukin (IL)-10-producing B lymphocyte subset termed “B10 cells.” B cell-derived IL-10 can inhibit various arms of the immune system, including polarization of Th1/Th2 cell subsets, antigen presentation and cytokine production by monocytes and macrophages, and activation of regulatory T cells. Further studies in numerous autoimmune and inflammatory models of disease have confirmed the ability of B10 cells to negatively regulate inflammation in an IL-10-dependent manner. Although IL-10 is indispensable to the effector functions of B10 cells, how this specialized B cell population is selected in vivo to produce IL-10 is unknown. Some studies have demonstrated a link between B cell receptor (BCR)-derived signals and the acquisition of IL-10 competence. Additionally, whether antigen-BCR interactions are required for B cell IL-10 production during homeostasis as well as active immune responses is a matter of debate. Therefore, the goal of this thesis is to determine the importance of antigen-driven signals during B10 cell development in vivo and during B10 cell-mediated immunosuppression. </p><p>Chapter 3 of the dissertation explored the BCR repertoire of spleen and peritoneal cavity B10 cells using single-cell sequencing to lay the foundation for studies to understand the full range of antigens that may be involved in B10 cell selection. In both the spleen and peritoneal cavity B10 cells studied, BCR gene utilization was diverse, and the expressed BCR transcripts were largely unmutated. Thus, B10 cells are likely capable of responding to a wide range of foreign and self-antigens in vivo. </p><p>Studies in Chapter 4 determined the predominant antigens that drive B cell IL-10 secretion during homeostasis. A novel in vitro B cell expansion system was used to isolate B cells actively expressing IL-10 in vivo and probe the reactivities of their secreted monoclonal antibodies. B10 cells were found to produce polyreactive antibodies that bound multiple self-antigens. Therefore, in the absence of overarching active immune responses, B cell IL-10 is secreted following interactions with self-antigens.</p><p>Chapter 5 of this dissertation investigated whether foreign antigens are capable of driving B10 cell expansion and effector activity during an active immune response. In a model of contact-induced hypersensitivity, in vitro B cell expansion was again used to isolate antigen-specific B10 clones, which were required for optimal immunosuppression. </p><p>The studies described in this dissertation shed light on the relative contributions of BCR-derived signals during B10 cell development and effector function. Furthermore, these investigations demonstrate that B10 cells respond to both foreign and self-antigens, which has important implications for the potential manipulation of B10 cells for human therapy. Therefore, B10 cells represent a polyreactive B cell population that provides antigen-specific regulation of immune responses via the production of IL-10.</p> / Dissertation
7

Investigation of a role for Ikaros in repressing the type-I interferon response gene program in T-cells

Derosia, Nicole 12 June 2019 (has links)
Ikaros is a transcription factor expressed in blood cells. Germline Ikaros mutations yield abnormal T cells due to defects in T cell maturation. Therefore, to study the role of Ikaros in mature CD4+ T cells, a conditional knockout mouse was developed such that Ikaros is expressed until CD4+ T cells have matured. Ikaros-deficient CD4+ T cells from these mice have a phenotype which is associated with inflammatory diseases and autoimmunity. In experiments described in this thesis, I show that lack of Ikaros in CD4+ T cells results in the upregulation of type I interferon (IFN)-induced gene programs. Upregulation in interferon sensitive genes (ISGs) is not due to environmental cues since α/β receptor (IFNAR1) signaling pathways are not activated. In addition, the phenotype is localized to CD4+ T cells containing the Ikaros mutation, as increased ISG expression is not observed in macrophages. Enhanced ISG expression also impairs the ability of Ikaros-deficient CD4+ T cells to be infected with virus. In addition, the Ikaros conditional knockout mice showed an increased population of CD11b+ T cells in the spleen, which may be related to the increase in ISG expression, as cells with this phenotype arise during viral infection when type I IFN expression would be high. Furthermore, we were able to obtain human Jurkat cell lines with CRISPR engineered Ikaros knockouts. However, I was unable to confirm that Ikaros was successfully knocked out in these cell lines. Taken together, these data demonstrate a role for Ikaros in the repression of type I IFN gene programs, which are critical for preventing and fighting viral infections, and also play a role in autoimmunity. Ikaros may also play a role in the regulation of CD11b+ T cell populations, which remains to be explored.
8

Expression and function of co-inhibitory receptors PD-1, TIGIT, TIM-3, and LAG-3 in systemic sclerosis

Fleury, Michelle 12 June 2018 (has links)
Systemic sclerosis is an autoimmune connective tissue disorder associated with fibrosis of the skin and internal organs. Co-inhibitory receptors (Co-IRs) regulate immune responses and have been shown to control autoimmune phenotypes. We explored the role of these receptors in systemic sclerosis through their expression in circulating lymphocytes and their control of lymphocyte function in vitro and in vivo. We found that individual co-IRs were increased on specific lymphocyte populations in patients. PD-1 was increased on CD4+ memory T cells, while TIGIT was increased on both CD4+ and CD8+ memory T cells. Changes in TIM-3 expression were limited to cytotoxic NK cell populations while LAG-3 remained low and unchanged on all lymphocyte populations identified. The blockade of PD-1 in vitro, in particular, had a greater effect on modulating cytokine production in systemic sclerosis PBMCs compared to the blockade of TIGIT and TIM-3 versus a similar modulation of cytokine production by PD-1, TIGIT, and TIM-3 in healthy controls. This indicates an increased level of exhaustion in PBMCs from systemic sclerosis patients that can be overcome by the blockade of PD-1, but not TIGIT or TIM-3. However, the blockade of TIM-3 in vitro had the greatest effect on modulating the production of soluble factors that regulate pro-fibrotic changes in gene expression in systemic sclerosis fibroblasts. In vivo, TIGIT and TIM-3 were unable to consistently regulate the autoimmune phenotype of sclerodermatous GvHD mice. These data indicate a potential function for lymphocyte exhaustion in regulating the autoimmune and inflammatory response in systemic sclerosis, with specific co-IRs playing defined roles in disease pathogenesis.
9

Exposure of 3D organotypic vaginal tissues to semen induces expression of the chemokine MCP-1, but does not alter tissue integrity

Singh, Subha 24 July 2018 (has links)
Studies using cell lines indicate that human semen induces inflammatory changes in vaginal epithelial cell cultures, which may promote HIV transmission. Since the normal human vagina is differentiated into multiple cell layers, we conducted a study to determine the effect of semen on EpiVaginal™, a 3-D organotypic differentiated vaginal tissue model. We measured the upregulation of inflammatory cytokines by Luminex assay and microarray technology, and tissue integrity by histology and transepithelial electrical resistance (TEER) assessments. We used three multilayered differentiated EpiVaginal™ models: VEC-FT, which contained both epithelium and fibroblast layers; VEC-PT, which is comprised of differentiated epithelium only, and VLC, which has a normal epithelium in addition of fibroblasts and Langerhans cells. We hypothesized that semen is not toxic to the EpiVaginalTM tissue, which is morphologically similar to native vaginal mucosa, and does not induce a proinflammatory response. We found that semen and/or seminal plasma did not induce the expression of proinflammatory cytokines, but did significantly upregulate the expression of MCP-1, a chemokine that can attract HIV target cells such as CD4+ T cells and macrophages. We believe this research closes an important gap in understanding the impact of semen on vaginal epithelium cells by showing that semen does not have a broad proinflammatory effect on intact fully differentiated human vaginal tissues, but may induce the expression of MCP-1.
10

CD4+ TH1 helper cells: the unifying link between periodontitis and type II diabetes mellitus inflammation

Habib, Chloe 12 July 2018 (has links)
Periodontitis (PD) and type II diabetes mellitus (T2D) are chronic inflammatory diseases that affect populations worldwide. While it has been well established clinically that T2D is a risk factor for PD, previous studies have failed to determine the molecular mechanism linking T2D and PD. As a result, the objectives of this study were as follows: to characterize the inflammation present in gingival tissue immune cells in subjects with periodontitis (PD) and subjects with type II diabetes mellitus and periodontitis (T2D/PD) compared with healthy subjects (H); to identify the effect of T2D on inflammation in PD; and to determine the predominant cell type responsible for the production of pro-inflammatory cytokines. Using flow cytometry to sort and purify cells based on CD45+ cell surface expression into CD4+, CD8+, CD11b+, CD19+, and CD56+ cell subgroups, we used the Enzyme Linked ImmunoSpot (ELISPOT) assay to quantify cytokine production in gingival cells from the three groups (H, PD, and T2D/PD). We identified CD4+ T helper cells as the predominant cell type in gingival tissues from T2D/PD subjects and found that these cells produced higher concentrations of Th1 cytokines IL-2, IL-10, IFN-y, and TNF-a in T2D/PD subjects than in H and PD subjects. As a result, we concluded that T2D increases inflammation in PD by an increase Th1 cell persistence.

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