Browsing by Subject "immunology"
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Item Evaluation of NK Cell – Astrocyte Interactions: Potential Role in HIV-Associated Neurocognitive Disorders and HIV- Associated Dementia(2015-05-01) Bowen, Kelly E.; Mathew, Porunelloor A.; Mathew, Stephen O.; Hodge, Lisa M.NK cells play important roles in immunity against pathogens and cancer. NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells. During pathological conditions, NK cells were shown to be recruited to the CNS and could impact CNS physiology by killing glial cells and by secreting IFN-g. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS and reactive astrogliosis is a key feature in HIV-associated neurocognitive disorders (HAND). There is little data on NK cell-astrocyte interactions and ligands expressed on astrocytes that could impact NK cell function. This study aimed to identify NK-associated ligands expressed by human astrocytes that confer this NK-directed cytotoxicity of astrocytes and assay the cytotoxicity differences in presence and absence of HIV 3S peptide. Using a fusion protein consisting of the extracellular domain of NKp44 fused to Fc portion of human IgG, we determined the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with 3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study demonstrated that NKp44 has a protective effect on astrocytes from NK cell mediated killing during HIV infection. Astrocytes could also secrete cytokines that affect the expression of NK receptors on NK cells. We evaluated the expression of receptors on NK cells after co-culture with astrocytes. CD38 expression was increased on primary NK cells after incubation with astrocytes. CD38 is expressed on both NK cells and astrocytes and has an important implication in HIV-1 infection. Blocking CD38 signaling in our studies decreased astrocyte lysis, suggesting CD38 signaling has important implications in NK-astrocyte interactions. Future studies providing novel insights into the role of NK cells in the pathogenesis of HAND and other brain disorders might result in the development of NK cell based therapies for brain pathologies.Item Extracellular Superoxide Dismutase Indirectly Enhances the Release of Immature Neutrophils from the Murine Bone Marrow(2016-08-01) Witter, Alexandra R.; Berg, Rance E.; Hodge, Lisa M.; Mummert, Mark E.Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species (ROS) to protect tissues during infection and inflammation. Using ecSOD HI, ecSOD WT, and ecSOD KO mice, we have previously shown that ecSOD activity enhances neutrophil recruitment to the liver, yet inhibits the innate immune response against Listeria monocytogenes leading to increased host susceptibility. Using adoptive transfer experiments, we observed that ecSOD activity does not affect neutrophil recruitment or function in a cell-intrinsic manner. Additionally, we noted that ecSOD activity results in decreased retention of immature neutrophils in the bone marrow without altering granulopoiesis. Furthermore, we determined that ecSOD activity protects the extracellular matrix (ECM) and increases concentrations of neutrophil-attracting chemokines leading to an increase in immature neutrophils in the liver. Since ecSOD can be produced by cells from the hematopoietic lineage as well as non-hematopoietic cells, we used bone marrow chimeric mice to investigate the relative contribution of ecSOD produced by cells from each lineage. Ultimately, it was determined that ecSOD from both hematopoietic and non-hematopoietic cells contributes to the overall phenotype observed in ecSOD congenic mice. Collectively, our data suggest that ecSOD activity inhibits degradation of the ECM and promotes egress of immature neutrophils out of the bone marrow and into the liver where they provide inadequate protection against L. monocytogenes. These studies highlight the potential therapeutic value of ecSOD inhibitors to enhance immune responses during bacterial infections.Item Harris, Elizabeth, Ph.D.(1980-01-01) Harris, Elizabeth; Stokes, C. RayThe first faculty member to be employed by TCOM, Dr. Harris was associate professor and for many years chairman of the microbiology and immunology department. She shares her teaching experiences at the college from its beginnings on the fifth floor of the Fort Worth Osteopathic Hospital on October 1, 1970, to the present state-of-the-art facilities provided in Medical Education Building 2. Interviewed by C. Ray Stokes, November 19 and December 17, 1980Item Molecular Basis for 2B4-CD48 Interactions(2001-08-01) Huynh, Van T.; Mathew, Porunelloor A.; Goldfarb, Ronald; Das, HridayHuynh, Van T., Molecular Basis for 2B4-CD48 Interactions. Master of Science, Molecular Biology and Immunology, August 2001, 93 pp., 3 tables, 19 illustrations, bibliography, 51 titles. Natural killer cells are lymphocytes that play a role against cancer and viral infections. 2B4 is a membrane glycoprotein expressed on natural killer cells. In the present study we characterized 2B4 from mice strains BALB/c, 129/svj and A.CA. Nucleotide and peptide analysis revealed that polymorphyic residues in 2B4 are located in the variable domain. My second project was to determine the amino acids involved in the binding between 2B4 and CD48. Twelve mutations were made in human 2B4 to disrupt their interaction. In the last part of the study, an attempt has been made to elucidate the role of tyrosine and threonine amino acids found in the novel tyrosine motifs (TxYxxI/V) that reside in the cytoplasmic domain.Item THE AGE-RELATED LOSS OF FOXN1 AND SUBSEQUENT THYMIC INVOLUTION CONTRIBUTES TO AGE-RELATED AUTOIMMUNITY BY ALTERING IMMUNOTOLERANCE(2014-03) Coder, Brandon; Wang, Hongjun; Su, Dong-MingThe thymus is the organ responsible for developing a type of white blood cell called T cells. However, with age comes an increased susceptibility to T cell derived autoimmune disease. Additionally, the thymus progressively shrinks with increased age due to the progressive loss of the gene FoxN1. We want to determine if the loss of FoxN1leads to the thymus being unable to either delete or suppress autoimmune T cells. We utilize a mouse model that has a progressive loss of the FoxN1 gene. Our findings are significant because knowledge gained about the role of the FoxN1 gene with age-related autoimmune disease may lead to novel evidence-based gene therapy that targets the FoxN1 gene to help treat a wide range of autoimmune diseases associated with aging. Purpose (a): The thymus protects against autoimmune disease by generating immunotolernace to self-tissues. This is accomplished through the process of negative selection where self-reactive T cell clones are deleted and also by the generation of natural regulatory T cells (nTregs), which help suppress autoimmunity in the periphery. However, natural aging is associated with thymic atrophy driven by the progressive loss of the gene FoxN1. We wanted to determine if thymic aging impairs immunotolerance, either by disrupting negative selection or altering the generation of suppressive nTreg cells. Methods (b): We answered this question by utilizing a FoxN1 conditional knockout (FoxN1 cKO) mouse model that mimics natural thymic aging through the progressive loss of FoxN1. Results (c): We found that the loss of FoxN1 is associated with the impairment of negative selection characterized by increased single positive T cells and a decrease in Aire+ medullary thymic epithelial cells. Recent thymic emigrants from the FoxN1 cKO thymus have increased proliferation and are more often CD44+, indicating that they are antigen experienced and may be self-reactive T cells. Furthermore, we found that the frequency of nTregs was increased in the FoxN1 cKO thymus, but was normal in the spleen. Additionally, nTregs from the FoxN1 cKO thymus retained normal suppressive function. We adoptively transferred aged wild-type splenocytes, in which there are a higher proportion of Treg cells, into young Rag2-/- mice. We found that the young periphery was able to reverse the accumulation of Tregs. Additionally, the adoptive transfer led to an increase in infiltrating lymphocytes to the salivary gland, which was independent of peripheral age. Conclusions (d): We conclude that the loss of FoxN1 impairs negative selection, which may lead to an escape of self-reactive T cells. However, rather than being cell-intrinsic, the age-related accumulation of Tregs depends on the age of the peripheral microenvironment. These results indicate that the increased susceptibility to autoimmune disease observed with aging is likely due to defects in negative selection rather than changes in nTregs.Item Thymic involution perturbs negative selection and leads to chronic inflammation(2015-08-01) Coder, Brandon D.; Dong-Ming Su; Rance E. Berg; Hriday K. DasThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).