Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item THE FUNCTIONAL REGULATION OF FCRN EXPRESSION AND FCRN-MEDIATED ANTIGEN PRESENTATION(2009) Liu, Xindong; Zhu, Xiaoping; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The neonatal Fc receptor for IgG (FcRn), a major histocompatibility complex (MHC) class I-related molecule, plays an important role in IgG transport and protection. The transport of IgG across epithelial and endothelial barriers and the IgG homeostasis maintained by FcRn contributes to the effective humoral immunity. Thus, the level of FcRn itself will affect the IgG-associated immune responses. Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown.I showed here that FcRn was up-regulated by the stimulation of inflammatory cytokines or Toll-like receptor ligands in human peripheral blood mononuclear cell (PBMC) and THP-1 cell line. By chromatin immunoprecipitation, I identified three NF-κB binding sites within introns 2 and 4 of the human FcRn gene. These intronic binding sites boost FcRn transcription activities through looping with the promoter region. In contrast, FcRn expression was down-regulated by Th1 cytokine IFN-γ, and the down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. It has been demonstrated that IFN-γ activated STAT1 bound with GAS sequence in human FcRn promoter, and which blocked the transcriptional machinery. Fc gamma receptors (FcγRs) expressed in macrophages (MФ) and dendritic cells (DCs) can mediate antigen presentation in both MHC class II and MHC class I pathways. We tested here the role for FcRn in antigen presentation of IgG-restricted Immune complexes (ICs). It was observed that the expression of FcRn in MФ, but not in DC enhanced the phagosomal ICs antigen presentation to CD4 T cells. A low pH value in phgosome of MФ facilitated FcRn binding to ICs, stabilizing the antigens and promoting the efficient MHC II-peptide assembly. However, the alkalized phagosomes in DC failed FcRn to enhance the antigen presentation of ICs.Item Characterization of the Type II Activated Macrophage and the Regulation of Heparin Binding EGF-like Growth Factor(2008-03-28) Edwards, Justin Philip; Mosser, David M; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Three populations of activated macrophages were generated in vitro and characterized each. These include the classically (Ca-MΦ), alternatively (AA-MΦ), and type II activated (MΦ-II) macrophages. Here, a side-by-side comparison of the three cell types is presented, focusing primarily on differences between MΦ-II and AA-MΦ, because both have previously been classified as M2 macrophages, distinct from Ca-MΦ. I show that MΦ-II are similar to Ca-MΦ in that MΦ-II and Ca-MΦ, but not AA-MΦ, produce high levels of NO and have low arginase activity. MΦ-II and Ca-MΦ express relatively high levels of CD86, whereas AA-MΦ are virtually devoid of this co-stimulatory molecule. Ca-MΦ and MΦ-II are efficient antigen presenting cells (APCs), whereas AA-MΦ fail to stimulate efficient T-cell proliferation. The differences between Ca-MΦ and MΦ-II are more subtle. Ca-MΦ produce IL-12/23 and give rise to Th1 cells when used as APCs. MΦ-II produce high levels of IL-10 and low IL-12 and thus give rise to Th2 cells secreting IL-4 and IL-10. I identify two new markers for the MΦ-II, sphingosine kinase and LIGHT. Thus, classically, type II, and alternatively activated macrophages represent three distinct populations of cells with different biological functions. The expression of Heparin-Binding Epidermal Growth Factor-like Growth Factor (HB-EGF) by MΦ-II is then characterized. HB-EGF has previously been associated with a number of physiological and pathological conditions, including tumor growth and angiogenesis. MΦ-II exhibit increased HB-EGF mRNA levels and protein secretion relative to resting and Ca-MΦ. HB-EGF induction is dependent upon the activation of the MAPKs ERK1/2 and p38. The transcription factor, Sp1, was recruited to 3 sites within the first 2kb of the HB-EGF promoter following stimulation, and the site located at -83/-54 was required for HB-EGF promoter activity. These regions of the promoter became more accessible to endonuclease activity following activation, and this accessibility was contingent upon activation of ERK. We show that several conditions which enhanced macrophage IL-10 production also resulted in HB-EGF induction, suggesting that these two genes may be coordinately regulated. These observations indicate that in addition to the secretion of the anti-inflammatory IL-10, another characteristic of MΦ-II is their production of angiogenic HB-EGF.