Browsing by Subject "immune system"
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Item Diverse Immune Responses Mediated by Beta-Adrenergic and Corticotropin-Releasing Hormone Receptors in a Model of Pneumococcal sepsis(2010-08-01) Kim, Byung-Jin; Harlan JonesNeuroendocrine stimulation can impact disease states by regulating immune function. The purpose of our studies was to define the functional role of stress-induced neuroendocrine factors, catecholamines and corticotropin-releasing hormone (CRH) on immune responses involved in the pathogenesis of Streptococcus pneumoniae (S. pneumoniae) infection implementing both in vitro and in vivo methodology. Dendritic cells play a pivotal role in antigen presentation and cytokine production, influencing both innate and adaptive immunity. Initial studies examined the potential immunomodulatory effect of epinephrine and CRH on DC cytokine production in response to the bacterial pathogenic ligand, lipopolysaccharide (LPS). In addition, the ability of DC to dictate CD4+ T cell activation as a consequence of CRH or epinephrine pre-treatment was examined using an in vitro co-culture system. Epinephrine and CRH pre-treatment resulted in a preferential increase in IL-23 and IL-10 cytokine production. In contrast, IL-12p70 was significantly attenuated in response to epinephrine and CRH pre-treatment. Preferences in IL-23 and IL-10 cytokine production by DC pre-treated with epinephrine and CRH corresponded with an increase in IL-4 and IL-17A, but not IFN-y cytokine production by CD4+ T cells. These results suggest that exposure to stress-derived epinephrine/CRH dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogen. Our second study examined the functional properties of IL-23 during pulmonary S. pneumoniae infection. IL-23 plays a crucial role in establishing host defenses against extracellular pathogens. Further investigation is still required to define the impact of IL-23 on acute pulmonary S. pneumoniae infection. Utilizing IL-23p19 genetic deficient mice, we determined bacterial load, cytokine production and the contribution of neutrophils against S. pneumoniae infection using monoclonal antibody-mediated systemic neutrophil depletion. The absence of IL-23 induced a higher bacterial load in lung and blood as compared to IL-23 competent counterparts. In the absence of IL-23, production of proinflammatory cytokines such as IL-6, IL-12p70 as well as IL-17A and IFN- were dampened as compared to wild type mice. In addition, neutrophil distribution was also altered in IL-23-deficient mice, suggesting impaired neutrophil recruitment into lung. Interestingly, neutrophil depletion did not impact bacterial load in lung and blood in both IL-23 competent and deficient mice. These findings, suggest a novel role of IL-23 in pulmonary S. pneumoniae infection, potentially independent of neutrophil function. We next examined the possible impact of CRH and catecholamines as regulators of immune function against acute bacterial infection in response to stress. Utilizing a murine model of acute pulmonary S. pneumoniae infection and restraint stress, we selectively blocked CRH receptors (CRHR1 and CRHR2) as well as the 2 adrenergic receptor prior to restraint stress followed by intranasal pulmonary S. pneumoniae infection. Antagonist administration did not impact restraint stress-induced physiological responses as compared to restraint stressed mice, which did not receive receptor antagonists. However, following S. pneumoniae infection, physiological changes including weight and temperature were altered in response to administration of selective CRH receptor and β2 adrenergic receptor antagonists. Survival rate, bacterial load and cytokine production corresponded with physiological differences observed in response to selective CRH receptor and 2 adrenergic receptor antagonists. Importantly, preferential differences in bacterial colonization and survival corresponded with distinct differences in inflammatory cytokine production and immune cell distribution along pulmonary airways. In particular, opposing effects in IL-17A and neutrophil accumulation was found among mice administered the CRHR1 versus the CRHR2 antagonists. Together, these findings indicate that activation of each receptor can influence immune responses against S. pneumoniae infection. Thus, our findings provide further understanding of how stress-derived neuroendocrine factors directly impact immune responses related to immunopathology and immunoprotection.Item Signaling in Natural Killer Cells: NK Cell Activation by LLT1 Receptor(2008-05-01) Bambard, Nowland D.; Jerry Simecka; Richard Easom; Harlan JonesBambard, Nowland D., Signaling in Natural Killer Cells: NK Cell Activation by LLT1 Receptor. Doctor of Philosophy (Microbiology and Immunology), May 2008, 162 pp., 1 table, 30 illustrations, bibliography, 179 titles. Natural Killer (NK) cells are large granular lymphocytes of the innate immune system that constitute the first line of defense against viral pathogens and cancer. Unlink cells of the adaptive immune response, NK cells do not recognize specific antigens expressed on MHC receptors, rather they recognize tumorgenic and virally infected cells through a complex balance of activating and inhibiting receptors expressed on the surface of human NK cells. LLT1 is expressed on numerous immune cells and subsequent functional analysis indicates that LLT1 plays an activating role on NK cells by way of stimulating interferon-gamma (IFN-G) secretion. LLT1 has also been shown to have a role on non-immune cells, inhibiting the formation and function of osteoclasts. Additionally, the natural ligand of LLT1 has been identified as NKR-P1A (CD161), an NK cell inhibitory receptor known to play an important role in immune regulation. We hypothesize that LLT1 employs multiple signaling pathways to accomplish its activating functions on human NK cells, and may be associated with one of four known transmembrane accessory proteins associated with NK cell activating receptors. We activated LLT1 on NK92 cells with target cells expressing its natural ligand CD161 and analyzing IFN-G production in the presence of pharmacological inhibitors specific for various signaling mechanisms. These results indicate that LLT1 employs Src-PTK, p38 and ERK signaling pathways, but not PKC, P13K or calcineurin. These results were followed up with phosphorylation analysis, which confirmed that the ERK signaling pathway is associated with LLT1 IFN-G production. Finally, by analyzing IFN-G mRNA we found that LLT1 activation is not associated with any detectable change in IFN-G mRNA levels, suggesting that LLT1 stimulates NK IFN-G production by modulating post transcriptional or translational events. Identification of the signaling pathways associated with LLT1 is of great medical significance as this may provide us with novel insights into activating NK cells to counter infection and cancer.Item The Characterization of T Cell Responses Along the Respiratory Tract(2004-05-01) Ivey Jr., James A.; Brown, Mary B.; Fling, John; Wu, Ming-ChiIvey, James A., The Characterization of T Cell Responses Along the Respiratory Tract. Masters (Immunology). May, 2004. 63 pages. 2 tables, 10 figures. 55 titles. This research converged on T cell responses to respiratory agents, tobacco smoke and allergens in humans, and T cell responses to an extracellular bacterium, M. bovis, in calves. In the first chapter, we will discuss the basic functions of the immune system. In the second chapter, we will discuss the basic functions of the immune system. In the second chapter, we characterized the impact of tobacco smoke on T cell responses in atopic smokers and atopic nonsmokers. The results were inconclusive and the study was postponed until the proper allergens were found. We also characterized the T cell responses of calves infected with Mycoplasma bovis in the third chapter. The results showed an increase in T lymphocytes in the upper respiratory tract of infected calves, which correlated with sites of infection.