Rozprawy doktorskie: „Immune response – Regulation”

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Dahal, Lekh Nath. "Soluble CTLA-4 and immune regulation". Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202565.

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Madera, Laurence. "Mechanisms of immune response regulation by innate defense regulator peptides". Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43066.

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The growing threat of antibiotic-resistant bacteria necessitates the development of new anti-infective therapeutics. Innate defense regulator (IDR) peptides are a novel class of immunomodulatory agents shown to combat bacterial pathogens in murine models of infection via the augmentation of host immune functions, including the stimulation of chemokine production and enhancement of leukocyte recruitment, while suppressing bacterial-induced inflammation. Although IDR-peptides present the potential for future broad-range anti-infective agents, our limited understanding of how they modulate host immunity remains an obstacle in their development as clinical therapeutics. I hypothesized that IDR-peptides impact host immunity by modulating the immune responses of monocytes, a cell population necessary for IDR-mediated protection against infection. In this study, IDR-1002 was found to be a multi-faceted regulator of monocyte migration. IDR-1002 induced the production of monocyte-specific chemokines MCP-1 and MCP-3, as well as neutrophil-specific chemokines, IL-8 and GRO-α in human peripheral blood mononuclear cells (PBMCs), correlating with the activation of the mitogen-activated protein kinases (MAPK), p38 and extracellular-regulated kinase (ERK)-1/2, in monocytes. IDR-1002 was also found to enhance human monocyte migration towards chemokines through the enhancement of β1-integrin-mediated adhesion to fibronectin via regulation of the phosphatidylinositol-3-kinase (PI3K)-Akt signalling pathway. In addition, IDR-1002 increased monocyte responsiveness to the chemokines MIP-1α and RANTES via modulation of CCR5 expression. These results demonstrate an overall promotion of monocyte motility by IDR-1002. In contrast to the immune-strengthening effects of IDR-1002, the production of pro-inflammatory cytokines in human PBMCs stimulated with bacterial lipopolysaccharide (LPS) was suppressed by the peptide, and correlated with a suppression of LPS-induced NFκB and p38 MAPK signalling and activation of PI3K-Akt signalling in monocytes. These results demonstrate that IDR-peptides are potent modulators of human monocyte function via their extensive regulation of monocyte signalling networks, potentially accounting for their multifunctional effects on host immunity in murine models of bacterial infection.

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Cheung, Ka-wa Benny. "Immune regulation in response to mycobacterial infection". Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634206.

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Cheung, Ka-wa Benny, i 張嘉華. "Immune regulation in response to mycobacterial infection". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634206.

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Alasoo, Kaur. "Regulation of gene expression in macrophage immune response". Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/263855.

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Gene expression quantitative trait loci (eQTL) mapping studies can provide mechanistic insights into the functions of disease-associated variants. However, many eQTLs are cell type and context specific. This is particularly relevant for immune cells, whose cellular function and behaviour can be substantially altered by external cues. Furthermore, understanding mechanisms behind eQTLs is hindered by the difficulty of identifying causal variants. We differentiated macrophages from induced pluripotent stem cells from 86 unrelated, healthy individuals derived as part of the Human Induced Pluripotent Stem Cells Initiative. We generated RNA-seq data from these cells in four experimental conditions: naïve, interferon- gamma (IFNɣ) treatment (18h), Salmonella infection (5h), and IFNγ treatment followed by Salmonella infection. We also measured chromatin accessibility with ATAC-seq in 31-42 individuals in the same four conditions. We detected gene expression QTLs (eQTLs) for 4326 genes, over 900 of which were condition-specific. We also detected a similar number of transcript ratio QTLs (trQTLs) that influenced mRNA processing and alternative splicing. Macrophage eQTLs and trQTLs were enriched for variants associated with Alzheimer’s disease, multiple autoimmune disorders and lipid traits. We also detected chromatin accessibility QTLs (caQTLs) for 14,602 accessible regions, including hundreds of long-range interactions. Joint analysis of eQTLs with caQTLs allowed us to greatly reduce the set of credible causal variants, often pinpointing to a single most likely variant. We found that caQTLs were less condition- specific than eQTLs and ~50% of the stimulation-specific eQTLs manifested on the chromatin level already in the naive cells. These observations might help to explain the discrepancy between strong enrichment of diseases associations in regulatory elements but only modest overlap with current eQTL studies, suggesting that many regulatory elements are in a ‘primed’ state waiting for an appropriate environmental signal before regulating gene expression.

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6

Lim, Andrew Yih-Fan. "Mechanisms of immune regulation in HIV disease". University of Western Australia. School of Surgery and Pathology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0081.

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[Truncated abstract] HIV infection compromises the ability of the host to mount effective immune responses. In untreated HIV disease, immune activation drives high rates of cell turnover and apoptosis, ultimately leading to abnormal and dysregulated cellular function. Immune activation may also induce the expansion of CD4+ regulatory T (Treg) cell populations capable of suppressing anti-HIV responses. Treatment with antiretroviral therapy (ART) allows the recovery of CD4+ T cell numbers in most patients. Persistent deficiencies in the number and function of CD4+ T cells seen in a proportion of individuals may reflect elevated numbers of Treg cells or an imbalanced regulatory-to-effector cytokine milieu. Furthermore, some patients develop paradoxical illnesses associated with the recovery of cellular function, known as immune restoration disease (IRD). The first part of this thesis addresses the role of CD4+ Treg cells in untreated and treated HIV disease. The second part addresses the phenotype of immune cells that express IL-10 and its receptor in untreated and treated patients, and the role of IL-10 in mycobacterial IRD. Firstly, several cell surface markers were evaluated to find a flow cytometry assay that could be used routinely to identify CD4+ Treg cells in HIV-infected patients. I tested CD25, GITR, CTLA-4, NRP-1 and LAG-3, but their expression did not mirror the expression of FoxP3, an intracellular transcription factor specific to CD4+ Treg cells (Chapter 2). Two published studies then described the use of CD127 to identify CD4+FoxP3+ Treg cells in humans. Using CD127, I determined the proportions and numbers of CD4+ Treg cells in untreated HIV-infected patients and in patients in their first year of ART. Proportions of CD4+ Treg cells correlated with the proportions of activated (HLA-DRHI) CD4+ T cells and with plasma HIV RNA levels in untreated patients, but showed an inverse correlation with CD4+ T cell count. In both untreated and treated patients, the proportions and numbers of FoxP3+ cells that expressed CD8 were significantly higher than in uninfected donors. This was clearest in patients with CD4+ T cell counts below 300/'L (Chapter 3). This body of work suggests that the frequencies of CD4+ Treg cells are directly related to the level of HIV-associated immune activation. Phenotyping of FoxP3+CD4+ Treg cells in untreated and treated patients and in uninfected donors revealed that co-expression of CD45RO, CD28, CTLA-4 and markers of activation were similar in all HIV-infected patients and controls. ii FoxP3+CD8+ T cells exhibit lower levels of CD45RO, CD28 and CTLA-4, but higher expression of PD-1 and CD57 (Chapter 4). This suggests that FoxP3+CD8+ T cells may have a reduced functional capacity. It is unclear whether they have regulatory activity by virtue of FoxP3 expression. ... Both patients produced higher levels of IFN? compared with IL-10 in response to mycobacterial antigens. In contrast, patients who experienced uneventful immune reconstitution produced higher levels of IL-10 (Chapter 6). Part 1 of this thesis highlights the importance of using specific cellular markers to identify CD4+ Treg cells, and confirms CD127 as a valuable marker for routine monitoring of blood Treg cells. Part 2 of this thesis demonstrates the important regulatory role of IL-10 in patients receiving ART.

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Källberg, Eva. "Regulation of the immune response; focusing on somatic hyper-mutation". Lund : Lund University, Dept. of Cell and Molecular Biology, 1995. http://catalog.hathitrust.org/api/volumes/oclc/39071819.html.

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Mehta, Ninad T. "Early Epigenetic Regulation of the Adaptive Immune Response Gene CIITA". Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/biology_theses/24.

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The precise regulation of Major Histocompatibility class II (MHC-II) genes plays an important role in the control of the adaptive immune response. MHC-II genes are expressed constitutively in only a few cell types, but their expression can be induced by the inflammatory response cytokine interferon gamma (INF-γ). The regulation of MHC-II is controlled by a Master Regulator, the class II transactivator (CIITA). Multiple studies have shown that CIITA regulated expression of MHC-II is controlled and induced by INF-γ. It has been also shown that a functional CIITA gene is necessary for the expression of MHC-II genes. CIITA is thus a general regulator of both constitutive and inducible MHC-II expression. Although much is known about the transcription factors necessary for CIITA expression, there is little information as to the epigenetic modifications and the requisite enzymes needed to provide these transcription factors access to DNA. Previous studies in the Greer lab have shown that increased levels of acetylation of histones H3 upon INF-γ stimulation, as does tri-methylation of H3K4 upon prolonged cytokine stimulation. Similar observations were made at early time points post IFN-γ stimulation, where there is an instantaneous increase in the levels of H3K18ac and H3K4me3. In contrast to this, the levels of silencing modifications begin to drop with in the first 20 minutes of IFN-γ stimulation. The binding of STAT1 reaches its peak at about 60 minutes and the first transcripts for the protein start to appear as early as 40 minutes post the cytokines stimulation. Our study is the first to link the rapidly occurring epigenetic changes at the CIITA promoter pIV to EZH2

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Wheway, Julie Elizabeth School of Medicine UNSW. "The Y1 receptor for NPY: a novel regulator of immune cell function". Awarded by:University of New South Wales. School of Medicine, 2006. http://handle.unsw.edu.au/1959.4/25194.

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Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY), regulates anxiety and is a part of the stress response. The NPY system also modulates immune functions such as cytokine release, cell migration, and innate immune cell activity. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five receptors (Y1, Y2, Y4, Y5, and y6). Additionally, immune cells themselves release NPY following activation. Previous studies have shown that Y1 mediates NPY-immune effects and data presented here shows expression of Y1 on a wide range of immune cells. Results presented in this thesis, using Y1-deficient mice (Y1-/-), have uncovered a novel role for Y1 on immune cells. NPY acts endogenously to inhibit T cell activation whereas Y1-/- T cells are hyper-responsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signalling through the Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, in Y1-/- mice, T cell differentiation to Th1 T cells appears to be defective as these mice were resistant to T helper type 1 (Th1) cell???mediated inflammatory responses and showed reduced levels of the Th1 cell???promoting cytokine interleukin 12 and reduced interferon ?? production. This defect was due to functionally impaired antigen presenting cells (APCs). Y1-deficient APCs are defective in their ability to produce Th1-promoting cytokines and present antigens to T cells and consequently, Y1-/- mice had reduced numbers of effector T cells. Key reciprocal bone marrow chimera experiments indicated that this effect is intrinsic to immune cells and not driven by other Y1-expressing cell types. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. The findings presented in this thesis uncover a sophisticated molecular mechanism regulating immune cell functions and thus adds to a growing number of signalling pathways shared by the immune and nervous system.

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Cheung, Ka-wa Benny, i 張嘉華. "Mechanism of Bacillus Calmette Guerin-induced immune response". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29488989.

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Utješanović, Nataša. "Neuropilin-1 in immune regulation and formation of immunological memory". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610593.

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Daniels, Brodie Belinda. "Molecular and cellular analysis of the interaction between soluble CD23 and CD11/CD18 integrins". Thesis, Nelson Mandela Metropolitan University, 2010. http://hdl.handle.net/10948/1217.

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The low affinity IgE receptor, CD23, is expressed by a wide variety of cells and cleaved from its original 45 kDa size to several smaller soluble CD23 proteins. Soluble CD23 function depends on the form of the protein and its interaction with various ligands. CD23 is believed to play an important role in regulating allergic responses and in inflammation, amongst others. β2 integrins are important in a variety of cell-adhesion reactions during immune-inflammatory mechanisms and the binding of their natural ligands generates outside-in cellular signalling, leading to cell activation. Although the binding of CD23 to β2 integrins contributes to this signalling in monocytes, the interaction site for CD23 is unknown. This study focused on the interaction of three soluble CD23 proteins with the β2 integrins CD11b/CD18 and CD11c/CD18. Differentiated HL60, THP1 and U937 monocytic cells were used to demonstrate the binding of three recombinant CD23 constructs (corresponding to 16, 25 and 33 kDa human soluble CD23) to upregulated CD11b/CD18 and CD11c/CD18. This binding was partially blocked by an antibody specific for the CD11b/CD18 αI domain, demonstrating that αI domains are involved in binding to CD23. Recombinant αI domain proteins of CD11b and CD11c were demonstrated to bind CD23 using ELISA and in surface plasmon resonance spectroscopy. The dissociation constants for CD23-CD11b/CD18 and CD23-CD11c/CD18 are comparable to other integrin ligands. This study has shown that CD23 interacts directly with the αI domains of β2 integrins and that the interaction surface likely spans the lectin domain as well as either the stalk and/or C-terminal tail of CD23. This study also looked at the effect that soluble CD23 proteins had on monocyte biology. It appears that iv sCD23 proteins have little effect on the phagocytic or chemotactic ability of monocytes, while an increase in oxidative burst was shown with the 16 kDa and 25 kDa CD23 proteins. Signalling pathways for the production of reactive oxygen species were investigated and it appears that the CD23 proteins signal mainly through the phosphoinositide-3 kinase pathway, although the mitogen activated protein kinase and Src kinase pathways may also play a role. These data suggest that sCD23 proteins induce outside-in signalling of β2 integrins and are able to change the activation state of CD11b/CD11c by stimulating oxidative burst. This needs to be further investigated by determining how the three sCD23 proteins are binding the CD11 proteins and investigating further leukocyte function and inflammatory responses by the cells.

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Pereira, Melanie Claire. "The molecular analysis of the interation surface between sCD23 and the B2-integrins, CD11b & CD11c". Thesis, Nelson Mandela Metropolitan University, 2012. http://hdl.handle.net/10948/d1014734.

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Both CD23 and the β2 integrins (also known as CD11/CD18) have very important immunological functions, especially during the allergic response where the binding of CD23 to β2 integrins contributes to various types of signalling in monocytes which can result in drastic sensitivities experienced by some allergic individuals. CD23, also known as the low affinity receptor for immunoglobulin E or (FcεRII), is a type II transmembrane glycoprotein which is synthesized by haematopoietic cells and has biological activity in both membrane-bound and freely soluble forms. It acts via a number of receptors, including the β2 integrins. β2 integrins are specifically found on leukocytes and they play important roles in cell–cell or cell–matrix adhesion via their ability to bind multiple ligands. These molecules occur as heterodimers consisting of an alpha (α) and beta (β) subunit. The α-subunits of β2 integrins contain an approximately 200-amino-acid inserted domain or I-domain which is implicated in ligand binding function. There are four different types of β2 integrins, namely CD11a, CD11b, CD11c and CD11d, all dimers with the common beta subunit, CD18. CD23 and CD11/18 are natural ligands of each other; however the interaction site for CD23 is unknown. It is postulated that the integrin recognizes a tripeptide motif in a small disulfide-bonded loop at the N-terminus of the lectin head region of CD23, which is focussed around Arg172, Lys173 and Cys174 (RKC). This study thus focused on the interaction between the I-domain of CD11 (b and c) and a recombinant 25kDa construct of sCD23. In order to understand the characteristics of ligand binding between the relevant proteins of interest, alanine substitutions on the RKC motif of CD23 were made via site-directed mutagenesis. Consequently, a recombinant form of the I-domain of CD11 (b and c) as well as a wild type (containing the RKC motif) and mutant form (containing an AAC motif) of sCD23 were expressed and purified. The CD11 recombinant proteins were purified via affinity chromatography and the CD23 recombinant proteins via gel filtration chromatography. In addition, synthetic (CD23 derived) peptides, one containing the RKC sequence and the other the AAC sequence, were designed and custom synthesized. The synthetic peptides as well as the recombinant CD23 proteins were then analyzed for their interaction with the CD11 I-domain via ELISA. Subsequent ELISA analyses showed that the native sCD23 and the RKC peptide were able to bind to the integrin α I-domain whereas the mutant sCD23 and the corresponding synthetic AAC peptide failed to bind. This interaction was also analysed via flow cytometry using differentiated U937 cells, yielding similar results. ELISA analyses for the sCD23-CD11b I-domain interaction showed a Kd of 0.36 ± 0.14 μM whereas the RKC-CD11b I-domain interaction yielded a Kd of 1.75 ± 0.58 μM. Similarly, the sCD23-CD11c I-domain interaction yielded a Kd of 0.39 ± 0.09 μM and 1.53 ± 0.72 μM for the RKC-CD11c I-domain interaction. Peptide inhibitory analysis, analysed via ELISA and flow cytometry, reinforced the fact that the RKC motif on sCD23 is a prerequisite for ligand binding of the CD11b/c I-domain.

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Kay, R. A. "The mucosal regulation of the systemic immune response to cholera toxin". Thesis, University of Edinburgh, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380413.

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Leggat, Jamie Alexander. "Innate immunity & CD8+ T lymphocyte regulation of the immune response". Thesis, King's College London (University of London), 2005. http://kclpure.kcl.ac.uk/portal/en/theses/innate-immunity--cd8-t-lymphocyte-regulation-of-the-immune-response(7795ae39-e852-4841-9d6d-18abc9ca849c).html.

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Díaz, de Ståhl Teresita. "Fcγ Receptors in the Immune Response". Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1545.

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Circulating immune complexes play an important role in the modulation of antibody responses and in the pathogenesis of immune diseases. This thesis deals with the in vivo regulatory properties of antibodies and their specific Fc receptors.

The immunosuppressive function of IgG is used clinically, to prevent rhesus-negative women from becoming sensitized to rhesus-positive erythrocytes from the fetus. The mechanism behind this regulation is poorly understood but involvement of a receptor for IgG, FcγRII, has been suggested. It is shown in this thesis that IgG and also IgE induce immunosuppression against sheep erythrocytes to a similar extent both in mice lacking all the known Fc receptors as in wild-type animals. These findings imply that antibody-mediated suppression of humoral responses against particulate antigens is Fc-independent and that the major operating mechanism is masking of epitopes.

Immunization with soluble antigens in complex with specific IgG leads to an augmentation of antibody production. The cellular mechanism behind this control is examined here and it is found that the capture of IgG2a immune complexes by a bone marrow-derived cell expressing FcγRI (and FcγRIII) is essential. An analysis of the ability of IgG3 to mediate this regulation indicated that, in contrast, this subclass of IgG augments antibody responses independently of FcγRI (and FcγRIII). These findings suggest that distinct mechanisms mediate the enhancing effect of different subclasses of antibodies.

Finally, the contribution of FcγRIII was studied in the development of collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis in humans. It was discovered that while DBA/1 wild-type control mice frequently developed severe CIA, with high incidence, FcγRIII-deficient mice were almost completely protected, indicating a crucial role for FcγRIII in CIA.

The results presented here help to understand how immune complexes regulate immune responses in vivo and show that Fc receptors for IgG, if involved, could be new targets for the treatment of immune complex-related disorders.

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Knight, Derek Andrew. "Preparation of a site-specific lymphotoxin- mutant to be used in protein characterization and receptor binding studies". CSUSB ScholarWorks, 1995. https://scholarworks.lib.csusb.edu/etd-project/987.

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Sprong, Kaitlin. "Analysis of the interaction between recombinant human Beta2 integrin I-domains and CD23". Thesis, Nelson Mandela Metropolitan University, 2014. http://hdl.handle.net/10948/d1021078.

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In order to further elucidate the interaction between CD23 and β2 integrins (CD11b/CD18) the following objectives were established: Expression and purification of CD11b I-domain as a GST-fusion protein using Escherichia coli; Cloning, synthesis and expression of CD18 I-Like domain.CD11b I-domain has previously been expressed as a GST-fusion protein (Daniels, 2010) and consequently led to comparable expression of CD18 I-like domain as a GST-fusion protein; Preparation of two site-directed mutants of CD18 I-Like domain in order to study the function of the serine residue involved in the S116P mutation. The serine was mutated to proline, as in LAD patients, as well as alanine, a non-polar alternative, in order to contrast and compare binding characteristics.  Expression, refolding and purification of sCD23, and a double mutatedsCD23 (RKΔAA) from E. coli; This was performed according to the method described by Daniels et al. (2005); Investigation of the CD23-CD11b I-like domain interaction through surface plasmon resonance spectroscopy.

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Southern, Kristina L. "Phenotypic and functional characteristics of T-lymphocytes during the course of infection with leishmania major". Virtual Press, 1995. http://liblink.bsu.edu/uhtbin/catkey/941372.

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If used early in infection, prophylactic treatment with the immunomodulatory drug cyclosporin A of Leishmania ma'or infected Balb/c mice has been shown to enhance resistance of these mice to serious disease. It is thought that CsA treatment affects disease progression by altering the balance of specific T lymphocyte populations as well as the secretion of various cytokines. We have followed the levels of L3T4+ T cells, Ly-2+ T cells, and total T and B lymphocytes, as well as IL-4 in susceptible Balb/c mice, CsA-treated Balb/c mice, and naturally resistant C57B1/6 mice during the course of L. ma'or infection. The CsA-treated mice displayed a disease pattern similar to that of the C57B1/6 group throughout infection. Most importantly, CsA treatment appeared to inhibit IL-4 production early post infection in both spleen and lymph node, and also appeared to inhibit the dramatic early increase of L3T4+ (CD4+) T cells which is characteristic of the susceptible Balb/c mice.
Department of Biology

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Hall, Samuel Wittenoom. "Immunomodulation by Schistosoma mansoni larval products in the non-obese diabetic mouse". Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648708.

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Clutton, Genevieve Tyndale. "HIV-specific interleukin-10 responses and immune modulation". Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589623.

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Interleukin-l0 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of mv -specific IL-l0-producing cells in chronic HIV-I infection, and the effect of IL-10 blockade on responses to candidate HIV -I vaccines. A cytokine capture assay was used to determine the HIV -specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV -I Gag-specific IL-10-producing population; these cells were restricted to ART-naive individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-y. A proportion of the population (median 48% and 9% respectively) expressed the P7 chain of the gut-homing integrin a4p7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-y during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CDI4+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag- specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two mV-I candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-y production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIV A, and a significant increase in IFN-y ELISPOT responses to the subdominant Gl (Gag) epitope of HIV consv in vitro. Collectively, these data suggest that IL-10 producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-IO blockade to be explored as a therapeutic strategy in humans

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Clarke, Jodie Louise, i n/a. "Regulation of Cytokines and Chemokines during Lung Infection with Nontypeable Haemophilus influenzae". University of Canberra. n/a, 2008. http://erl.canberra.edu.au./public/adt-AUC20081210.084252.

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An animal model of respiratory infection was used to determine the effect of various factors, thought to influence the ability of the host to clear bacteria, on the host?s innate response to an NTHi lung infection. Mucosal immunisation with NTHi has previously been shown to enhance the clearance of NTHi from the lung in an animal model of infection through the increased recruitment of phagocytes. Comparisons of cytokine and chemokine kinetic profiles were made in order to determine differences between innate and acquired immune response and the way in which mucosal immunisation controls the innate immune response to NTHi. Increased production of proinflammatory cytokines and chemokines in the early stages of NTHi lung infection enhanced the ability to clear bacteria from the rat lung in the immune animals through the increased recruitment of phagocytes to the site. Mucosal immunisation was found to alter the cytokine and chemokine mRNA profiles of CD4+ and CD8+ cells, with increased levels of MCP-1 protein being detected in both types of immune cells. An antecedent viral infection has been shown to increase the chance of developing a respiratory bacterial infection. The NTHi model of respiratory infection was used to characterise the effect that a viral infection had on the host response to the host?s innate response to a bacterial infection and the ability to clear the bacteria. The host?s ability to clear NTHi from the rat lung was enhanced by an antecedent viral infection through alterations to the innate immune response and the cytokine and chemokine kinetic profiles. The use of a mutant strain of NTHi deficient in a component of Lipooligosaccharide (LOS), Phosphorylcholine (ChoP), was utilised as a tool to characterise the innate immune response to LOS. Animals challenged with the LOS mutant strain had a reduced inflammatory response to NTHi through the decreased production of pro-inflammatory cytokines and chemokines and the reduced recruitment of phagocytes to the site of infection. This thesis has contributed valuable information to enable a better understanding of the host?s innate immune response to respiratory infection. This study has identified the role of cytokines and chemokines in the innate response to a respiratory bacterial infection and the enhanced ability of the host to clear NTHi from the lung.

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Gomes, Andreia Ferreira de Castro. "Regulation of lymphocyte activation and apoptosis in the immune response in multiple sclerosis /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-910-2/.

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Cook, Peter Charles. "Regulation of the immune response in mice following multiple infections with schistosoma mansoni". Thesis, University of York, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516633.

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De, Glanville Benjamin. "Activation and regulation of the innate immune system in response to Ureaplasma infection". Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/73702/.

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The bacteria Ureaplasma has long been associated with a wide range of adverse health implications, including preterm birth, preterm premature rupture of the membrane and lung disorders, such as bronchopulmonary dysplasia in neonatal infants, but still, little is known about the pathogenic properties of Ureaplasma and possible direct association with adverse health complications. Estimated prevalence of Ureaplasma colonisation in sexually active adults is between 40 – 80%, therefore further understanding of its pathogenic properties and its ability to initiate an immune response is crucial. Specifically selected human cell-lines were examined in vitro to determine whether an innate immune response could be activated by Ureaplasma infection. If inflammatory immune responses were detected in human cell-lines, pathogenic properties of Ureaplasma would be confirmed, and its role in pregnancy and neonatal complications could be supported. Using a range of techniques, activation of immune response pathways were examined, as too were the production of detrimental pro-inflammatory cytokines that would strengthen the suggested associations of Ureaplasma infection with the above-mentioned complications. Myeloid-derived leukocytic monocytes, human bronchial epithelial cells and human amniotic epithelial cells were examined, as these would be the most relevant cell lines to determine if Ureaplasma could induce preterm birth, preterm premature rupture of the membrane and bronchopulmonary dysplasia. All cell lines studied showed immune response and inflammatory cytokine production after stimulation with Ureaplasma. This supports that Ureaplasma is capable of causing tissue damage in neonatal respiratory tracts that may lead to bronchopulmonary dysplasia and damage to the amniotic and chorion membranes that may lead to preterm premature rupture of the membrane. Ureaplasma was detected at the cell surface of human amniotic epithelial cells (HAECs) by TLR2 and TLR2/6 heterodimers. Results suggest that Ureaplamsma multiple banded antigen (MBA) is the strong ligand for TLR2 and TLR6 and stimulation of HAECs with MBA alone caused an immune response. TLR9 was responsible for the detection of internalised Ureaplasma, which is also able to initiate an immune response and inflammatory cytokine production. v Ureaplasma stimulation results in the production of the inflammatory cytokines TNF-α, IL-8 IL-6 via the NF-κB signaling pathway. Production of the potent inflammatory cytokine IL-1β was also observed, which would suggest the formation of inflammasome complexes. NLRs were investigated to find which NLR inflammasome were activated. It was shown that genetically knocking down NLRP7 significantly reduced the amount of IL-1β that was produced after Ureaplasma stimulation, suggesting that NLRP7 inflammsones are activated by Ureaplasma. Reduction in IL-1β was also observed, but to a lesser extent, when NLRP3 was knocked down. We decided to investigate the role of NLRP7 further and found a novel immune pathway, where NH3 causes activation and formation of the NRLP7 inflammasone. NH3 is produced as a bi-product of urease activity, which an essential process for Ureaplasma. The addition of a potent urease inhibitor to HAECs being stimulated with Ureaplasma significantly reduced the production of IL-1β, strongly supporting that NH3 plays a significant role in the detection of Ureaplasma infection and is responsible for causing the tissue damage that contributes to preterm premature rupture of the membrane leading to preterm birth. This investigation strongly supports that Ureaplasma is responsible for causing preterm birth and health complications in neonates, and that more robust treatment and monitoring of Ureaplasma is required, especially in pregnant women. These undertakings will hopefully reduce the rates of preterm birth and the associated health implications, in addition to reducing rates of bronchopulmonary dysplasia in neonates.

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26

Mee, Edward. "Manipulation of the immune response to malaria antigens using bacterial-derived lipoproteins". Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:c98c8f59-092d-482c-b159-6033b9844908.

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Huang, Zhi Hua. "Regulation of macrophage functions by polyunsaturated fatty acids /". Adelaide, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phh8743.pdf.

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Al, souhail Qasim Mohammed. "Characterization, regulation and biophysical studies of immune-related peptides from Manduca sexta". Diss., Kansas State University, 2016. http://hdl.handle.net/2097/32618.

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Doctor of Philosophy
Biochemistry and Molecular Biophysics Interdepartmental Program
Michael Kanost
Insects secrete antimicrobial peptides as part of the innate immune response. Most antimicrobial peptides from insects have antibacterial but not antifungal activity. We have characterized an antifungal peptide, diapausin-1 from hemolymph of a lepidopteran insect, Manduca sexta (tobacco hornworm). Diapausin-1 was isolated by size exclusion chromatography from hemolymph plasma of larvae that were previously injected with a yeast, Saccharomyces cerevisiae. Fractions containing activity against S. cerevisiae were analyzed by SDS-PAGE and MALDI-TOF MS/MS and found to contain a 45-residue peptide that was encoded by sequences identified in M. sexta transcriptome and genome databases. A cDNA for diapausin-1 was cloned from cDNA prepared from fat body RNA. Diapausin-1 is a member of the diapausin family of peptides, which includes members known to have antifungal activity. The M. sexta genome contains 14 genes with high similarity to diapausin-1, each with 6 conserved Cys residues. Diapausin-1 was produced as a recombinant protein in Escherichia coli. Purified recombinant diapausin-1 was active against S. cerevisiae, with IC₅₀ of 12 μM, but had no detectable activity against bacteria. Spores of some plant fungal pathogens treated with diapausin-1 had curled germination tubes or reduced and branched hyphal growth. Diapausin-1 mRNA level in fat body strongly increased after larvae were injected with yeast or with Micrococcus luteus. In addition, diapausin-1 mRNA levels increased in midgut and fat body at the wandering larval stage prior to pupation, suggesting developmental regulation of the gene. Our results indicate that synthesis of diapausin-1 is part of an antifungal innate immune response to infection in M. sexta. Biophysical analysis showed that diapausin-1 binds to the β-1,3 glucan component of the S. cerevisiae cell wall. A second insect peptide investigated in this project was M.sexta stress-response peptide 1(SRP1), an immune-related peptide upregulated under different stress conditions including immune-challenge. Preliminary results for NMR structure determination are presented. Most of the amino acid residue spin systems were assigned, and we determined the connectivities of many amino residues as a first step to solve the NMR structure. The circular dichroism spectrum of SRP1 indicates that the peptide lacks alpha-helical structure and may contain beta strands and turns.

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29

Caesar, Joseph J. "Investigations into mechanisms of complement regulation and bacterial invasion of the innate immune response". Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711641.

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Green, Lisa J. "The production of IL-2, IL-4, and TNF-gas in murine leishmaniasis". Virtual Press, 1991. http://liblink.bsu.edu/uhtbin/catkey/774758.

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Prophylactic administration of the immunosuppressive drug cyclosporine A protects Balb/c mice from fatal Leishmania major infections. It is believed that distinct subpopulations of CD4+ T lymphocytes and their distinctive cytokines may determine susceptibility and resistance to leishmaniasis among inbred strains of mice. CsA may enhance disease resistance in Balb/c mice by modulating these T cell subsets and/or their cytokines. We have measured lymphoid cell production of IL-2, IL-4, and TNF-a in naturally resistant C57/Bl/6, CsA-treated Balb/c, and nontreated Balb/c mice during the course of L. major infection. CsA treatment inhibited IL-2 and IL-4 production for the first week of infection. Thereafter the cytokine production of all three groups of mice did not differ greatly except in week two when the treated mice produced significantly enhanced levels of IL-4. C57B1/6 mice did produce slightly more TNF-a than either group of Balb/c mice, but as the CsAprotected and diseased Balb/c mice produced similar amounts of this cytokine, the elevation in C57B1/6 animals probably reflects a strain-related difference rather than disease resistance.
Department of Biology

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31

Clary, Sara Reed. "The effects of nitrosoureas on Thymocyte differentiation and T cell activation". Thesis, Virginia Tech, 1990. http://hdl.handle.net/10919/41939.

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Coombes, Janine. "Interactions between regulatory T cells and dendritic cells in intestinal immune regulation". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670085.

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Groom, Joanna Ruth School of Medicine UNSW. "Loss of immune regulatory checkpoints in BAFF transgenic mice". Awarded by:University of New South Wales. School of Medicine, 2006. http://handle.unsw.edu.au/1959.4/27281.

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Multiple checkpoints control the survival and activation of auto-reactive B cells. The discovery of the TNF family cytokine BAFF has been crucial to understanding peripheral B cell tolerance mechanisms. Homeostatic levels of BAFF are tightly regulated to maintain tolerance in the periphery. Chronically increased levels of BAFF lead to the survival of autoreactive B cells. Autoimmune patients display elevated serum BAFF levels. BAFF Tg mice model this situation with systemically high levels of BAFF and the subsequent development of two separate but related autoimmune syndromes; systemic lupus erythematosus (SLE) and Sj??gren???s syndrome (SS). The work conducted in this thesis further investigates the defects in tolerance down-stream of self-reactive B cell survival, which may contribute to autoimmune disease development in BAFF Tg mice. Expansion of the Marginal zone (MZ) B cell population correlates with the pathogenesis of several models of autoimmune disease. BAFF Tg mice are unique in that they not only display an increased splenic MZ B cell population, but also MZ B cells are found in the salivary glands of mice developing SS. The examination of genes differentially regulated between MZ and Follicular (Fo) B cells led to the investigation of sphingosine-1-phosphate receptor biology. The expression of S1P receptors was shown to be required for the positioning of MZ B cells in the spleen. Chronic BAFF stimulation alters the retention of MZ B cells through the alteration of S1P receptors and decreased integrin activation. The alteration of S1P receptors and increased ligand sensitivity leads to the accumulation of MZ B cells in the inflamed salivary glands of BAFF Tg mice. This works provides a potential mechanism for the tissue specificity seen in systemic autoimmune disease. The provision of T cell help to auto-reactive B cells is thought to underlie the development of SLE. BAFF Tg mice deficient in T cells surprisingly developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did however require signals through the toll-like receptor (TLR)-associated signalling adaptor, MyD88, which controlled the production of pathogenic autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, which requires TLR signalling and is independent of T cell help. It is likely that autoimmune patients with elevated levels of BAFF show a similar basis for disease.

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34

Ng, Wan Fai. "The role of anergic T cells in the regulation of immune response in man". Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406268.

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Roberts, Tara Laurine. "Cellular responses to immunostimulatory DNA /". [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18175.pdf.

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Chen, Ting, i 陳楟. "Dendritic cell biology regulated by Epstein-Barr virus (EBV) and its associated tumors". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B3138285X.

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Freitag, Lori Linn 1959. "EFFECT OF RECOMBINANT INTERLEUKIN 2 ON DAUDI CELL KILLING IN NEWBORNS". Thesis, The University of Arizona, 1987. http://hdl.handle.net/10150/276458.

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Experiments were done to determine the effect of recombinant interleukin 2 (rIL-2) on mononuclear cells (MC) of newborns and adults. MC were tested for (1) ability to lyse Daudi cells in a 51Cr release assay, (2) cell surface markers using monoclonal antibodies and flow cytometer analysis, and (3) cell types as determined by differential cell counts. Without rIL-2 adults show greater cytotoxicity than newborns in vitro. Incubation with rIL-2 dramatically increased the cytotoxicity expressed with cord blood and adult MC showing equivalent responses. Differences in cell surface markers between newborns and adults prior to rIL-2 exposure were in agreement with those previously published. This study did not demonstrate changes in phenotypes after exposure to rIL-2. Slight changes in differential cell counts occurred after increased incubation periods and rIL-2 exposure.

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38

Mautsa, Nicodemus. "Structural and functional characterisation of the protein inhibitor of activated STAT3 (PIAS3)". Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1004050.

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The signal transducer and activator of transcription (STAT) and protein inhibitor of STAT(PIAS) system represent an elegant regulatory mechanism of transcriptional control IN mammalian cytokine signalling. Abnormal activation of the system is associated with immune disorders and a large group of diverse tumours. PIAS3 is a multiple domain protein with distinct functions involved in regulation of cytokine-mediated gene activation pathways.Its over-expression significantly inhibits cell growth and renders cancer cells more sensitive to drugs. The objective of this study was to structurally and biochemically characterise the function of the PIAS3 protein using in silico, in vivo and in vitro analysis approaches.The conservation pattern of the PIAS protein family and critical conserved residues in the PINIT (Proline, Isoleucine, Asparagine, Isoleucine, Tyrosine) domain were identified. The PINIT domain model was generated based on the PINIT domain structure of yeast PIAS3 homologue Siz1 and structural determinants in the PIAS3-STAT3 interaction were evaluated.Guided by the in silico findings, in vivo analysis of the localisation of the PIAS3, mutantderivatives of PIAS3 (PIAS3-L97A, PIAS3-R99N, PIAS3-R99Q), PINIT and acidic domain was conducted. PIAS3 was completely localised in the nucleus while PIAS3 mutants appeared to exhibit diffuse cytoplasmic distribution. The PINIT domain was predominantly localised in the nucleus with some apparent perinuclear staining while the acidic domain exhibited a predominantly perinuclear staining pattern. Further analysis of the PINIT domain and the effect of the mutants on PIAS3-STAT3 interaction were assessed by in vitro analysis. Guided by in silico analysis, the PINIT domain and mutant derivatives of PINIT domain (PINIT-L97A, PINIT-R99N, and PINIT-R99Q) were heterologously expressed in Escherichia coli and subsequently purified using a combination of immobilized metal affinity and size exclusion based chromatography. The size and structural elements of the PINIT domain and its mutants were characterised. The 23 kDa PINIT domain was found to exist as a monomer in solution and its secondary structure was shown to consist of 66 % β-sheets by fourier transformed infrared spectroscopy consistent with the generated homology model.Using surface plasmonresonance spectroscopy (SPR) the PINIT domain was shown to bind to STAT3 in a specific concentration dependent manner. Recombinant PINIT-L97A,PINITR99N and PINIT-R99Q mutants, which exhibited similar structural integrity to the wildtype, were found to abrogate binding to STAT3. These findings suggest that these residues form part of a potential binding surface for stat3. In conclusion, this study has provided evidence that the PINIT domain is an important determinant of PIAS3 interaction with STAT3 and that the interaction is mediated by defined conserved residues directly involved in the PINITSTAT3 interaction.

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39

Rajsbaum, Ricardo. "Expression of TRIM genes in different immune cells and mechanism of regulation of their expression : implications for the immune response to pathogens". Thesis, Open University, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494626.

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The tripartite motif (TRIM) proteins are important in a variety of cellular functions including antiviral activity. We systematically analyzed mRNA expression of representative TRIMs in primary mouse macrophages, myeloid and plasmacytoid dendritic cells, and a selection of CD4+ T cell subsets. These cells have different effector functions in innate and adaptive immune responses, to a large extent due to the different patterns of cytokines that they produce. Here, we defined four clusters of TRIM genes based on their selective expression in these cell subsets. The first group of TRIMs was preferentially expressed in CD4+T cells and contained the C0S-FN3 motif.

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40

Jankord, Ryan D. "The influence of physical activity on cytokine production in healthy older males". Virtual Press, 2002. http://liblink.bsu.edu/uhtbin/catkey/1236370.

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The purpose of this study was to examine the influence of physical activity on cytokine production in healthy older males. Twelve males (six very active, six less active) ages 65 to 74 were recruited for this study. Blood was obtained at rest and serum concentrations for MIP-I a, IL-1 ra, IL-6 and IL-10 were measured. No difference was found in MIP-la and IL-Ira concentrations between the two groups. The serum concentration of IL-6 was significantly lower (p = 0.016) in the very active group compared to the less active group. The very active group had a significantly higher (p = 0.016) concentration of IL-10 compared to the less active group. The beneficial influence of physical activity on cytokine production is clinically important because of the role of IL-6 and IL-10 in disease development in older adults. Through influencing cytokine concentrations, our results provide further insights into the role of physical activity in attenuating the effects of aging.
School of Physical Education

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41

Ford, Megan. "The role and mechanism of B6/1pr TCRÃß§+CD4§-CD8§- T cells in immune response regulation". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ63098.pdf.

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42

Ke, Qi. "Negative Regulation of Host Innate Immune Signaling and Response Pathways by Viral and Host Regulatory Factors". University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470185159.

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Gay, Gabrielle. "Subversion de la réponse immune de l'hôte par Toxoplasma gondii". Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV029/document.

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Une caractéristique majeure de l’infection par Toxoplasma gondii est le contrôle rapide de la population parasitaire par une réponse immunitaire engageant des cellules résidentes et recrutées ainsi que des cytokines pro- et anti-inflammatoire. Dans ce contexte, l’IFNγ active une multitude d’activité anti- T. gondii des cellules immunes et non-immunes, mais peut aussi contribuer à l’immunopathologie. T. gondii a élaboré des mécanismes pour contrer les défenses de l’hôte en interférant avec la transcription des gènes stimulés par l’IFNγ. Nous avons identifié TgIST (T. gondii inhibitor of STAT1 transcriptional activity) comme un interrupteur moléculaire exporté par les parasites intracellulaires et qui est localisé dans le noyau des cellules hôtes, où il inhibe l’expression des gènes pro-inflammatoires dépendants de STAT1. Nous avons montré que TgIST séquestre STAT1 à des sites spécifiques, et promeut la formation de chromatine non permissive grâce à sa capacité à recruter le remodeleur chromatinien NuRD. Nous avons montré que durant l’infection aiguë en souris, les parasites déficients pour TgIST sont rapidement éliminés par les monocytes pro-inflammatoires GR1+, ce qui montre le rôle protecteur de TgIST contre les défenses médiées par l’IFNγ. En révélant les fonctions de TgIST, cette étude montre de nouvelles évidences sur la façon dont T.gondii a élaboré une arme moléculaire de choix pour prendre le contrôle sur la réponse immune, de façon à promouvoir le parasitisme à long terme
An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii–targeting activities in immune and nonimmune cells but can also con- tribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ–stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ–mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism

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44

MacKenzie, Jason Roderick. "The role of eosinophils in the regulation of CD4+ T helper 2 regulated inflammation /". View thesis entry in Australian Digital Theses Program, 2004. http://thesis.anu.edu.au/public/adt-ANU20051007.121844/index.html.

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45

Meng, Hui. "Regulation of Interferon-Inducible 2’-5’-Oligoadenylate Synthetases by Adenovirus VAI RNA". elsevier, 2012. http://hdl.handle.net/1993/11460.

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Viral double-stranded RNA is a key pathogen invasion signal recognized by the human innate immune system. All adenoviruses synthesize at least one highly structured RNA (VAI) to suppress this antiviral response by attenuating the activity of antiviral proteins. Surprisingly, VAI RNA was previously shown to positively regulate the activity of one interferon-inducible antiviral protein, 2’-5’-oligoadenylate synthetases (OAS). The present thesis focuses on investigating the regulation of a human OAS1 isoform by VAI RNA and its derivatives. An Escherichia coli protein expression and purification system has been developed for OAS1 protein production. A combination of biochemical and biophysical approaches was employed to examine VAI RNA binding affinity, activation potential for OAS1 and OAS1:VAI RNA complex formation. Taken together, I have found that while full-length VAI does indeed activate OAS1 in vitro, a truncated version lacking the terminal stem has the opposite effect, and this is the physiologically important response.

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46

Kaufman, Robin L. "Immunoregulation in myasthenia gravis". Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/30683.

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Myasthenia Gravis (MG) is an autoimmune disorder of neuromuscular transmission. Clinically, the disease is manifested by abnormal muscle fatigue with recovery on resting. Circulating nicotinic acetylcholine receptor antibodies (nAchR Ab) are highly characteristic of myasthenia gravis. These antibodies have been shown to be directly pathogenic at the muscle endplate and are responsible for impaired neuromuscular transmission through several mechanisms. While it is clear that the immune system does not function normally in MG, the mechanisms by which the response to nAchR is initiated and perpetuated remain unknown. Moreover, it is not clear whether immunoregulatory defects actually precede development of MG or are secondary features of the disease. The overall goal of the present investigation has been to more clearly define the nature of the immune regulatory defects existing in MG, both at the cellular level and in terms of possible relationship to disease progression. To begin these studies it was necessary to develop an assay that could be used to measure nAchR Ab secreted by lymphocytes in culture. Thus, we modified the original nAchR Ab immunoassay described by Lindstrom (1976) for this purpose. Additionally, in order to gain access to an appropriate patient base for our study, we established a further modification with improved sensitivity for detection of serum nAchR Ab. This important diagnostic test had not been available in this country. Therefore, our assay was made available in Canada for clinical purposes. Through the study of in vitro nAchR Ab and polyclonal IgG secretion by peripheral blood mononuclear cells (PBMNC), we were able to identify two previously unrecognized subgroups of seropositive, generalized MG patients. PBMNC from patients with long disease duration had low capacity for in vitro Ab production (Nonsecretors). Among patients of short disease duration, PBMNC produced nAchR Ab and also secreted higher than normal levels of polyclonal IgG (Secretors). The data suggested that there were nonspecific abnormalities affecting the immune response in myasthenia gravis. Moreover, regulation of B lymphocyte mediated immune function appeared to be related to disease progression. It was hypothesized that circulating auto-antibody may contribute to deregulation of the immune response at certain stages of disease through direct interactions with leukocyte determinants. Separation/reconstitution experiments with CD4+ enriched, T-helper/inducer lymphocytes and B enriched (E- cells) lymphocytes suggested that the control of antibody production in myasthenia gravis was operative at the T-helper/inducer level. Preliminary studies with serum pretreated, CD4+ enriched, T-helper/inducer lymphocytes suggested that serum of Secretor MG patients indeed contained a factor(s) which interfered with the function of a CD4+ lymphocyte subset. We further hypothesized that nAchR Ab would have the potential to behave as anti-lymphocyte Ab if nAchR were expressed on lymphocytes. Accordingly, direct binding studies, using the nicotinic antagonist, alpha-bungarotoxin, were carried out to look for such receptors on PBMNC. Specific, saturable binding of alpha-bungarotoxin to the rhabdomyosarcoma cell line, TE671, was confirmed and characterized. However, in parallel studies, alpha-bungarotoxin binding to PBMNC of healthy individuals or MG patients was not detected. These results suggested that nicotinic acetylcholine receptors, of the type expressed by muscle endplate, do not occur on human peripheral blood mononuclear cells.
Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate

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47

Szymczak, Wendy A. "The Role Of Chemokines and Dendritic Cells In Regulation of IL-4 and Fungal Immunity". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266607502.

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48

Welsby, Iain. "PARP12, a novel interferon stimulated gene potentially involved in the control of protein translation and innate immunity". Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209714.

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Poly(ADP-ribose) polymerases belong to a family of proteins with 17 members in human beings. PARP1, the founding member of the family is a protein that synthesizes linear or branched polymers of ADP-ribose on itself or on target proteins. Different members of this family, that do not all possess ADP-ribosyl polymerase activity, are involved in the regulation of various cellular mechanisms. Some members of the family are particularly involved in the positive or negative control of the immune response. PARP1 is a key player in the regulation of inflammation, through its positive control of cell death and of proinflammatory cytokine production. On the other hand, the tankyrases (PARP5a and PARP5b) and PARP14 seem to regulate inflammatory responses in a negative fashion. PARP12 is a poorly characterized member of the family, whose expression is greatly increase following stimulation with type-I interferons, cytokines mainly involved in antiviral defences.

PARP12 is a protein that possesses three main domains: A putative RNA binding N-terminal domain composed of tandem CCCH zinc-fingers, a central WWE domain and a C-terminal PARP catalytic domain. In this work, we have shown that the expression of PARP12 is strictly-dependent on type-I interferons, that it possesses ADP-ribosyl transferase activity and that in can regulate the translation of messenger RNA into proteins. PARP12 can be found in stress granules, sites of storage of untranslated mRNAs, and is capable of directly inhibiting the translation of a reporter mRNA when tethered to it, in a manner dependent on its catalytic activity. Furthermore overexpression of wild-type PARP12, in contrast to overexpression of a mutant with no detectable catalytic activity (PARP12-G575W), leads to a general arrest of most cellular translation.

On the other hand, we have shown that PARP12 can activate the transcription of genes under the control of an NFκB-dependent promoter, especially when its zinc-fingers are deleted or mutated (PARP12ΔZnF). PARP12ΔZnF is located in structures that can enclose TRIF, RIP1, NEMO, p62/SQSTM1 and ubiquitin. These proteins have all possess an important role in the activation of NFκB signalling cascades. Moreover, we have shown that endogenous PARP12 is situated in ALIS (Aggresome-Like Induced Structures) in LPS-stimulated macrophages. These structures have a possible role in the presentation of antigens on class I major histocompatibility complexes, implying that PARP12 may be involved in the regulation of antigen presentation.

Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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49

Debock, Isabelle. "Study of the development of Th17-type immune response in early life". Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209700.

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Par rapport à l’adulte, le nouveau-né présente une susceptibilité accrue aux agents infectieux et au développement d’allergies. Une polarisation de l’immunité acquise vers des réponses de type Th2, productrices d’IL-4, d’IL-5 et d’IL-13, et un défaut de réponses immunes de type Th1, sécrétant de l’IFN-γ, peuvent rendre compte de ce statut immunitaire particulier. De plus, un retard de production et de maturation des anticorps, caractéristiques de l’immunité humorale, s’observe en début de vie.

Récemment, de nouveaux lymphocytes T auxiliaires ont été décrits, les lymphocytes Th17, producteurs d’IL-17A, d’IL-17F et d’IL-22, d’une part, et les lymphocytes Tfh, sécrétant de l’IL-21 et exprimant CXCR5, ICOS et PD-1, d’autre part. La différenciation des lymphocytes Th17 dépend de la présence d’IL-6 ou d’IL-21 et de TGF-β, et est inhibée par l’IL-4 ;tandis que les lymphocytes Tfh sont induits en présence d’IL-21, d’IL-6 et du répresseur transcriptionnel Bcl6. Alors que les lymphocytes Th17 sont associés à des réponses inflammatoires par le recrutement de neutrophiles, les lymphocytes Tfh aident les lymphocytes B à produire des anticorps de haute affinité.

L’objectif principal de notre travail est l’étude du développement potentiel de réponses de type Th17 chez le nouveau-né de souris soumis à une stimulation allogénique et au manque d’IL-4. De plus, l’existence potentielle de lymphocytes Tfh induits chez le nouveau-né immunisé avec un vaccin constitué d’ovalbumine de poulet et d’Alum, sera investiguée.

Dans notre modèle de tolérance néonatale, l’immunisation de nouveau-nés BALB/c à l’aide de cellules spléniques semi-allogéniques F1 (AJAX x BALB/c) induit une polarisation de type Th2, associée à l’établissement d’un chimérisme lymphoïde et à l’acceptation d’une greffe de peau présentant les alloantigènes rencontrés à la naissance. Des nouveau-nés soumis à cette immunisation allogénique et à la privation d’IL-4, réalisée par l’utilisation d’anticorps monoclonaux ou de souris IL-4-/-, rejettent de façon aiguë les greffons de peau et présentent une proportion réduite de cellules chimériques. Cette rupture de la tolérance néonatale est associée à l’inhibition de la réponse allospécifique de type Th2 et au développement de lymphocytes Th17 alloréactifs, produisant de l’IL-17A. L’inhibition de la voie Th17 ne conduit toutefois pas à l’acceptation des allogreffes de peau. Par contre, la neutralisation de l’IL-6 ou de l’IL-17A et la réduction du nombre de neutrophiles restaurent la proportion de cellules chimériques présentes dans la rate, démontrant que la réponse de type Th17 allospécifique néonatale contrôle le chimérisme lymphoïde.

En réponse au vaccin OVA-Alum, les nouveau-nés présentent une proportion accrue de lymphocytes Tfh CXCR5+ PD-1+, bien que cette proportion lymphocytaire soit significativement diminuée par rapport aux adultes. Les lymphocytes Tfh néonataux expriment en outre des taux moindres des ARNm d’IL-21, d’IL-4 et de Bcl6, suggérant que la génération de lymphocytes Tfh est altérée en début de vie. En parallèle, les titres et la maturation des anticorps produits suite à la vaccination sont réduits chez les nouveau-nés, en comparaison avec les adultes. Cependant, qu’ils soient déficients en IL-4 ou non, des lymphocytes T CD4+ néonataux activés in vitro en présence d’IL-6 induisent une production d’anticorps par des lymphocytes B compétents, suggérant qu’il n’y a pas de défaut intrinsèque des lymphocytes T du nouveau-né à développer une capacité d’aide aux lymphocytes B.

En conclusion, nous avons montré que la polarisation de type Th2 néonatale inhibe la différenciation de lymphocytes Th17 alloréactifs contrôlant le rejet de cellules allogéniques, un mécanisme pouvant intervenir dans la relation immunitaire entre la mère et l’enfant. Nos résultats indiquent également que le nouveau-né est capable de différencier des lymphocytes Tfh, bien que le développement de ces derniers semble réduit. \
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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Busse, Matthew Schmidt. "Transcriptional regulation of antimicrobial peptide induction by NF-[kappa]B family members during the Drosophila melanogaster immune response". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3243870.

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Thesis (Ph. D.)--University of California, San Diego, 2007.
Title from first page of PDF file (viewed February 12, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 85-93).

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