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1
Moon, Alice E. "Immune signalling in insect cells." Thesis, Kingston University, 2009. http://eprints.kingston.ac.uk/20407/.
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Immune responses in insects include components and mechanisms that are highly evolutionarily conserved. In addition to providing insight into the insects themselves, knowledge of the conserved mechanisms involved in insect immunity can offer valuable insight that is broadly relevant to a wide variety of other species. Three aspects of insect immune cell signalling have been studied here. Cell signalling responses have been investigated in two insect cell lines following treatment with double stranded (ds) RNA, a common intermediate of viral replication. It has been established that both cell lines investigated, from the fruitfly Drosophila melanogaster and vector mosquito Aedes albopictus, do not exhibit activation of mitogen activated protein kinases (MAPKs) or NF-KB proteins as a direct response to dsRNA. Secondly, a detailed analysis of the mechanisms of transcriptional regulation has been carried out on the Drosophila drosomycin gene, a key factor both in terms of its function during the immune response and in terms of its role during previous characterisation of Drosophila immune signalling. The drosomycin promoter was found to be regulated independently by the Toll and IMD signalling pathways via distinct sequence elements. Finally, investigation of the responses of an A. albopictus cell line to treatment with bacterial cell wall components has revealed key differences in the mechanisms involved in immune-induced regulation of transcription compared with the model established in Drosophila. A role for p38 MAPK has been identified in the negative regulation of transcription of A. albopictus cecropin Ai, an inducible antimicrobial peptide gene.
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Ng, Siaw Wei. "Calcium signalling in immune cells." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:b3843e43-9503-4855-a280-35c0d28f65e6.
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Inappropriate stimulation of mast cells can trigger allergies including asthma, allergic rhinitis and eczema which, combined, affect almost 30% of the population in western societies. Mast cell activation begins with aggregation of IgE receptors in response to antigen. This then triggers a series of reactions resulting in the tyrosine phosphorylation of Syk kinase, PKC activation and ultimately both degranulation and secretion of leukotrienes and cytokines. CRAC channels are expressed on mast cells, and are essential for IgE-mediated mast cell activation. Previous work in our laboratory has shown that local Ca<sup>2+</sup> influx through CRAC channels activates Ca2+-dependent phopholipase A₂, ERK and 5-lipoxygenase, resulting in LTC₄ secretion from mast cells. Therefore, I have investigated how Ca2+ microdomains through CRAC channels are detected and how they trigger cellular responses. I find that phosphorylation of Syk following antigen stimulation is enhanced by Ca<sup>2+</sup> influx through CRAC channels. I also show synergy between CRAC channels and antigen in activating Syk. These findings reveal a novel positive feedback step in mast cell activation, where local Ca<sup>2+</sup> entry through CRAC channels activates Syk which, in turn, supports CRAC channels. Earlier work from our group has demonstrated that in RBL cells, Ca2+ influx through CRAC channels induces expression of the gene c-fos, an important regulator of pro-inflammatory gene expression. I have discovered that local Ca<sup>2+</sup> entry is sensed by the non-receptor tyrosine kinase Syk, which accumulates at the cell periphery. Syk then signals to the nucleus through recruitment of the transcription factor STAT5. The results therefore identify Syk as a new link in excitation-transcription coupling, converting local Ca<sup>2+</sup> influx into expression of genes that are essential for immune cell activation. Activation of G protein-coupled cysteinyl leukotriene type I receptors by the pro-inflammatory molecule LTC₄ is tightly linked to immune cell function and the receptor is an established therapeutic target for allergies including asthma. Desensitization of cysteinyl leukotriene type I receptors arises following protein kinase C-dependent phosphorylation of three serine residues in the receptor C-terminus. Here I show that abolishing leukotriene receptor desensitization suppresses agonist-driven gene expression. Physiological concentrations of LTC₄ led to repetitive cytoplasmic Ca<sup>2+</sup> oscillations, which were accompanied by the opening of store-operated CRAC channels in the plasma membrane. Ca<sup>2+</sup> microdomains near the open channels were relayed to the nucleus to increase expression of the transcription factor c-fos. In the absence of receptor desensitization, agonist-driven gene expression was suppressed. Mechanistically, stimulation of non-desensitizing receptors evoked prolonged Ca<sup>2+</sup> release, which led to accelerated Ca<sup>2+</sup>-dependent inactivation of CRAC channels and a subsequent loss of excitation-transcription coupling. Rather than serving to turn off a biological response, the experiments show that reversible receptor desensitization is an ‘on’switch’, sustaining long-term signalling in the immune system.
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Hamer, Rebecca K. "The structural basis of immune receptor signalling." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:32312040-2e22-4fe3-b05e-6f868233e27e.
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This work investigates the mechanisms of binding of T cell receptors (TCRs) to Class I MHC-peptide complexes (pMHC). The structure of a TCR specific for the Melan-A tumour antigen bound to its cognate pMHC was solved to a resolution of 2.5 Å which gives insight into how this TCR could be mutated to optimize binding and subsequently used as a cancer vaccine. Detailed sequence and geometric analyses of all currently available structures of Class I TCR-pMHC complexes revealed that TCRs can bind to pMHC with a range of orientations, yet always focus on the central portion of the peptide and use a specific subset of six residues on the MHC helices for binding. The most striking finding was the use of aromatic residues in the TCR CDR loops to bind to residue Q155 on the MHC α2 helix. Attempts were also made to express and purify Toll-like receptors (TLRs) with the aim of solving one or more of these structures. However, despite testing of over 50 different constructs from 12 different TLRs or associated proteins, insufficient soluble protein expression was obtained for crystallization trials. Finally, a protein disorder prediction tool was developed to aid construct design for structural biology studies and improve the chances of obtaining protein crystals. This tool is based on a novel type of neural network and blind tests comparing it to 8 other disorder prediction tools showed it is one of the best in the field. It is freely available at www.strubi.ox.ac.uk/RONN. Analysis of large datasets revealed that the position of order/disorder transitions is quite precisely defined in amino-acid sequences and that transition regions have an amino acid composition distinct from that of bulk ordered and disordered sequences. There is a steady decrease in order-promoting residues on the ordered side of boundaries as well as a weak sequence signal, both of which signify the approaching disorder and may prove useful for improving existing disorder prediction tools.
4
Akha, Amir Akbar Sadighi. "Signalling through the B lymphocyte antigen receptor." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318620.
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5
Morris-Davies, A. C. "Functional analysis of poly-ubiquitin chains in immune signalling." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1383788/.
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NF-κB transcription factors play essential roles in regulating the expression of a large array of genes involved in immune and inflammatory responses, cell proliferation, apoptosis and oncogenesis. In recent years, ubiquitination of key components has emerged as a crucial regulatory mechanism in NF-κB signalling pathways. This can either directly modulate the activity of the target substrate or provide a scaffold for the recognition and recruitment of other signalling molecules via their respective ubiquitin binding domains. NEMO, the regulatory subunit of the IKK complex, is a prime example of a signalling component which interacts with ubiquitin chains of different topologies as well as being modified by ubiquitination. These events are thought to regulate the activation of the kinase subunits of the complex, IKKα and IKKβ, which ultimately results in liberation of NF-κB and translocation to the nucleus. NEMO itself possesses two ubiquitin-binding domains: the CoZi/UBAN domain and a C-terminal zinc finger (ZF). The work presented in this thesis shows that the synergistic action of these two domains confers specificity for K63-linked ubiquitin chains. Importantly, chain length plays a crucial role in these binding events. The discovery that NEMO becomes modified by the E3 ligase LUBAC with a novel type of ubiquitin chain, termed linear, opened up a whole new exciting area of research. So far, LUBAC is the only E3 ligase known to synthesize this type of chain. This thesis provides a first glimpse into the mechanistic determinants which allow LUBAC to enforce the formation of linear ubiquitin chains and demonstrates, for the first time, that one of its subunits, HOIL-1L, transfers ubiquitin to a substrate via a thioester intermediate.
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Dawson, Charlotte Helen. "STAT 6 and IL-4 signalling." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245716.
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7
Silva, Couto Daniel. "Regulation of receptor kinase-mediated immune signalling by dynamic phosphorylation." Thesis, University of East Anglia, 2015. https://ueaeprints.uea.ac.uk/59391/.
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Plants recognize pathogen-associated molecular patterns (PAMPs) via cell surface-localized pattern recognition receptors (PRRs), initiating a broad-spectrum defense response against pathogens, known as PRR-triggered immunity (PTI). However, immunity comes at a cost; and immune responses need to be tightly regulated. How PTI signalling is negatively regulated in plants is not fully understood. PRRs are present at the plasma membrane in dynamic kinase complexes that heavily rely on trans-phosphorylation to initiate signaling. The Arabidopsis cytoplasmic kinase BIK1 associates with different PRRs and plays a central role in the activation of downstream immune signaling. In this study, we identify the protein phosphatase PP2C38 as a negative regulator of BIK1 activity and BIK1-mediated immunity. PP2C38 dynamically associates with BIK1, as well as with the PRRs FLS2 and EFR, but not with the regulatory receptor kinase (RK) BAK1. PP2C38 regulates PAMP-induced BIK1 phosphorylation and impairs the phosphorylation of the NADPH oxidase RBOHD by BIK1, leading to reduced oxidative burst and stomatal immunity. Notably, upon PAMP perception, PP2C38 is phosphorylated on serine 77, most likely by BIK1, and dissociates from the PRR-BIK1 complex. We suggest that this mechanism relieves the negative regulation imposed by PP2C38 to enable efficient BIK1 activation. This study uncovers an important regulatory mechanism of this central immune component, and extends our knowledge on how plant immunity is appropriately controlled.
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Wahl, Karen. "Role of Notch signalling in the induction of immune responses." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/23239.
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The expression and the role of Notch receptors and ligands during the induction of an immune response were investigated. I have shown that components of the Notch pathway were present in peripheral CD4 and CD8 T cells. Upon culturing and activation <i>in vitro</i>, in many Notch components were differentially expressed, in particular targets of Notch activation. In contrast, bone marrow-derived dendritic cells (DCs) expressed only low levels of Notch targets. However, the Notch ligand Jagged1 was strongly upregulated upon maturation of DCs with TNFα or LPS. By regulating the expression of the ligands, a role for antigen presenting cells (APCs) as the “signalling cells” is likely, whereas T cells expressing Notch receptors and Notch target genes may be the “receiving cells”. To investigate this hypothesis <i>in vivo</i>, transgenic mice with inducible overexpression of Jagged1 or Delta1 in DCs were generated. An <i>in vitro</i> approach to study the role of Notch ligands on APCs was carried out using an I-A<sup>b</sup> transfected murine fibroblast cell line (I-A<sup>b+</sup> L cells) with endogenous B7.1 expression. I-A<sup>b+</sup> L cells co-transfected with Jagged1 or Delta (Jagged1<sup>+</sup> or Delta1<sup>+</sup>L cells, respectively) were used as APCs in a mixed lymphocyte reaction (MLR) <i>in vitro.</i> Jagged1<sup>+</sup> and I-A<sup>b+</sup> L cells induced similar levels of allogeneic T cell proliferation, whereas Delta1<sup>+</sup> L cells had a slightly increased capacity to activate T cell proliferation. There were no phenotypical differences or changes in the level of apoptosis observed between T cells activated by Jagged1<sup>+</sup>, Delta1<sup>+</sup> or I-A<sup>b+</sup> L cells. However, IFNγ secretion by T cells in response to Jagged1<sup>+</sup> L cells was strongly reduced, whereas Delta1<sup>+</sup> and I-A<sup>b+</sup> L cells induced normal levels of IFNγ secretion. There were no significant differences neither in the level of intracellular IFNγ nor of IFNγ transcripts between T cells in response to Jagged1<sup>+</sup>, Delta1<sup>+</sup> or I-A<sup>b+</sup> L cells. Therefore I hypothesise that Jagged1-induced Notch signalling may be involved at the level of IFNγ secretion.
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Beyers, Albertus Daniel. "Transmembrane signalling by the CD2 and CD4 molecules of T lymphocytes." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291324.
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Watkinson, Ruth Elizabeth. "Intracellular antibody receptor TRIM21 in viral neutralisation and innate immune signalling." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708305.
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11
Rieser, Eva. "The role of HOIL-1, HOIP and SHARPIN in immune signalling." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/17941.
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Members of the tumour necrosis factor receptor (TNFR) superfamily, the interleukin-1 Receptor (IL-1R), the Toll-like Receptor (TLR) and the NOD-like receptor (NLRs) families play crucial roles in the initiation of innate immune responses. Even though the stimulation of these different receptors is triggered by upstream signalling components which are largely receptor-specific, their signalling cascades generally converge in the activation of both mitogen-activated protein kinases (MAPKs) and the inhibitor of nuclear factor– B (I B) kinases (IKKs). The activation of MAPKs and IKKs are crucial events in the signalling cascades of TNFR-, IL-1R-, TLR- and NLR family members and result in the activation of distinct transcription factors such as AP-1 and NF- B, respectively. In order to gain a more comprehensive picture of the signalling components associated with TNFR1 our group developed a modified tandem affinity purification (moTAP) strategy. This led to the identification of three novel components of the native TNFR1 signalling complex (TNFRSC): HOIL-1, HOIP and SHARPIN. Together, they form the “linear ubiquitin chain assembly complex” (LUBAC), a tripartite E3 ligase complex which generates linear ubiquitin chains. LUBAC activity is required for efficient TNF-mediated activation of NF- B and JNK by linearly ubiquitinating NEMO and RIP1 in the TNF-RSC. Mutation of the SHARPIN-encoding gene in mice results in chronic proliferative dermatitis (cpdm). The cpdm phenotype is characterised by inflammatory skin lesions and defective lymphoid organogenesis. In this thesis it is shown that mouse embryonic fibroblasts (MEFs) and primary keratinocytes generated from cpdm mice showed impaired activation of the MAPK- and NF- B signalling pathways following stimulation by various TNF and IL-1 family members as well as by different TLR ligands. These alterations were also apparent in bone marrow-derived macrophages isolated from cpdm mice. Thereby, lack of SHARPIN exerted an inhibitory effect on gene-activatory signal transduction by these immune stimuli. Similar defects in NF- B and MAPK signalling were also observed with a ligand for the NLR family member NOD2. Cells generated from mice conditionally deficient for the other LUBAC components exhibited similar alterations in diverse innate immune signalling pathways. These results imply that SHARPIN and HOIL-1 cannot substitute each other but instead cooperate with HOIP to generate linear ubiquitin chains in the signalling pathways that are activated by diverse immune receptors. In summary, the results of this thesis identify LUBAC and the linear ubiquitin chains it generates as previously unrecognised components of various signalling pathways which are central to the induction of immunity and regulation of inflammation.
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Wyszynski, Rafal Wlodzimierz. "Differential control of immune cell function by HIF-1 signalling pathway." Thesis, University of Kent, 2014. https://kar.kent.ac.uk/47691/.
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Human inflammatory/innate immune responses lie at the core of resistance to infectious disease and determine the nature of pathophysiological reactions of hematopoietic cells like leukaemia and allergy. The crucial step in these events is the ability of immune cells to function properly, which depends on their adaptation to stress caused by pro-inflammatory stimulation. The mechanisms underlying this crucial biochemical dogma, and its role in normal and pathological cross-links between immune cells, are not well understood. This PhD programme was devoted to investigation of these important problems. We found that the inflammatory mediator interleukin 1 beta (IL-1β), derived from human innate immune cells, triggers production of the major hematopoietic growth factor, the stem cell factor (SCF) in MCF-7 human epithelial cells. This process is controlled by the hypoxia-inducible factor 1 (HIF-1) transcription complex, which regulates cellular adaptation to inflammatory/hypoxic stress by promoting angiogenesis and glycolytic degradation of the glucose. Translational mechanism, which is majorly dependent on the mammalian target of rapamycin (mTOR) kinase pathway underlies IL-1β-induced HIF-1 accumulation and also contributes to SCF biosynthesis. The effect is applicable in both in vitro and in vivo systems. Further experiments demonstrated the involvement of this biosynthetic mechanism in the differential control of normal and pathological functions of inflammatory cells including monocytes, basophils and mast cells. Our results also demonstrated possible biochemical mechanisms regarding the cross-talk between inflammation and SCF-dependent blood cancer (leukaemia), which remains a serious medical burden worldwide. Finally, the pathways investigated could be further considered as potential therapeutic targets for pharmacological correction of human inflammatory reactions and treating cancer/leukaemia by classic and principally novel approaches, such as utilisation of gold nanoparticles.
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Murray, James. "PI 3-kinase : a key effector in C-FMS signalling." Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264478.
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14
Schreuder, Lisa Jane. "Effects of Mycrobacteria on the Signalling Machinenary of Bovine Innate Immune Cells." Thesis, Royal Veterinary College (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499275.
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15
Banham-Hall, Edward James. "The role of p110[delta] signalling in immune defence against Streptococcus pneumoniae." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708138.
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16
Smith, Emma Marie. "Studies on the role of notch signalling in the adult peripheral immune system." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497290.
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17
Roberts, Luke Bryan. "The influence of non-neuronal cholinergic signalling on the type 2 immune response." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/56913.
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Acetylcholine (ACh) is synthesised from choline and acetyl-CoA, primarily by the enzyme choline acetyltransferase (ChAT). Traditionally known as a crucial neurotransmitter synthesised and released by neurons of the central and peripheral nervous systems, in recent years there has been an increased interest in the role of ACh synthesised by alternative cells types - particularly those of the haematopoietic immune system. Non-neuronal ACh plays many important roles in the regulation of various immune responses in addition to being associated with the development of a number of disease pathologies. A significant number of animal parasitic nematode species have evolved to secrete active acetylcholinesterase enzymes (AChEs) which hydrolyse ACh and inhibit it from transducing cholinergic signals, suggestive perhaps of an attempt to immunomodulate their hosts in this way. Utilising the ChATBAC-eGFP reporter mouse (Tallini et al., 1996) immune cell populations capable of ACh production were identified, and the dynamics of their capacity to produce ACh were followed throughout type 2 immune responses generated during nematode infection (modelled using Nippostrongylus brasiliensis) or during allergic airway inflammation (modelled using an allergenic extract of the fungus Alternaria alternata). In carrying out these studies, type 2 innate lymphoid cells (ILC2) were newly identified as cholinergic cells capable of ACh synthesis and release during type 2 immune settings. The cholinergic phenotype of these cells was found to be closely associated with their activation state. Importantly, the cholinergic phenotype of pulmonary ILC2 could be induced by treatment of the cells with the alarmin cytokines IL-33 and IL-25, - IL-25 demonstrated a more potent capacity for this both in vitro and in vivo. Additionally, treatment of the cells with IL-2 greatly augmented the actions of IL-25 and IL-33 alone with regards to expression of the ILC2 cholinergic phenotype. Finally, in an attempt to understand the roles ACh may play during type 2 immunity in the lung, recombinant active and mutant-inactive forms of an AChE expressed by N. brasiliensis were generated using a yeast expression system. These were administered intranasally to female BALB/c mice during N. brasiliensis infection and during Alternaria allergen extract (ALT)-induced airway inflammation. Among the results observed, administration of active AChE significantly increased gut worm burden as well as influencing effector mechanisms such as neutrophilia, eosinophilia, type 2 cytokine production by ILC2 and alternative activation of macrophages, dependent on the model in question. The data presented in this thesis contribute to the understanding of how immune cell derived ACh may influence type 2 immunity and supports the argument that parasite AChEs may have evolved as immunomodulators of host immunity.
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Jan, Afnan. "A role for connexin signalling in the innate immune response in the skin." Thesis, Glasgow Caledonian University, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.726766.
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19
Bhandage, Amol K. "Glutamate and GABA signalling components in the human brain and in immune cells." Doctoral thesis, Uppsala universitet, Fysiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282422.
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Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions. Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.
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Lo, Yu-Lan (Sandra). "Alternatively Spliced Forms of Tollip Regulate Inflammatory Signalling in Macrophages." Thesis, Griffith University, 2012. http://hdl.handle.net/10072/366923.
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Alternative splicing is one of the mechanisms which drives diversification of innate immune responses. Spliced isoforms of Toll-interacting protein (Tollip), a negative regulator of TLR2-, TLR4- and IL-1R-induced signalling, have been identified to express at endogenous level in human and mouse macrophages. In the current study, we focused on two Tollip isoforms, the full-length Tollip.a and a mouse-specific isoform Tollip.b that lacks the ubiquitin-binding CUE domain. We asked for the effects and consequences of alternative splicing of Tollip in innate immune responses. We wanted to know if alternative splicing of this negative regulator has causative effect in the diversification of immune signalling and if each isoform plays a role in resolving inflammatory responses.
We have developed a mouse cell model to study the function of these Tollip isoforms by over-expressing or knocking-down the variants in a macrophage-like cell line, RAW264.7. Our studies showed that endogenous Tollip.b was expressed at a very low level, whereas Tollip.a was expressed abundantly in macrophages. Over-expressing either of the Tollip isoforms caused dramatic changes in cell morphology and cell proliferation. Further investigation into LPS-responsive signalling in these recombinant cell lines revealed an altered capacity to signal through MAPK pathways, resulting in altered cytokine production.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Biomolecular and Physical Sciences<br>Science, Environment, Engineering and Technology<br>Full Text
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Shweash, Muhannad Abdulmajeed Muhammad. "The pathological effects of Leishmania mexicana infection on macrophage cell signalling and immune responses." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14478.
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22
Fuseya, Yasuhiro. "The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC." Kyoto University, 2020. http://hdl.handle.net/2433/259006.
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Kouroumalis, Andreas. "Characterization of immune receptor-cognate ligands expression and signalling pathways in human intestinal myofibroblasts." Thesis, University of Bath, 2004. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405156.
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Bilkei-Gorzo, Orsolya. "Ubiquitylation regulates vesicle trafficking and innate immune responses on the phagosome of inflammatory macrophages." Thesis, University of Dundee, 2018. https://discovery.dundee.ac.uk/en/studentTheses/8661922d-9d5e-4a4a-bfd4-b0f5e5717c61.
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Macrophages are sentinels present in most tissues of the body, where they recognise and respond to biological dangers. Recognition and uptake of particles is mediated through phagocytic receptors which upon activation induce appropriate responses. These responses need to be tightly regulated in order to destroy pathogens but prevent uncontrolled inflammation. Phagocytosis is an evolutionarily conserved process required for host defence and homeostasis. During phagocytosis, particles are recognised by cell surface receptors that trigger rearrangement of the actin cytoskeleton and internalization of the bound particle into a de novo, membranous organelle known as the phagosome. Regulation of phagocytosis and phagosome maturation can be achieved through changes in transcription/translation and differential recruitment of proteins but also through their non-translational modifications. Here I explored the role of ubiquitylation in the phagosome biogenesis of Interferon-gamma (IFN-ɣ) activated macrophages. Ubiquitylation is a diverse, reversible post-translational modification which is not only involved in protein degradation but also in vesicle trafficking and immune signalling. My data shows that phagosomes are enriched in polyubiquitylation, which is further enhanced by IFN-ɣ. I applied a targeted AQUA peptide approach by which we quantified ubiquitin chain linkage peptides from phagosome samples by PRM. This data shows that all chain linkages apart from M1/linear chains are present on phagosomes. Furthermore, IFN-ɣ activation enhanced K11, K48 and K63 chains significantly. In order to identify the molecular function of this polyubiquitylation, I characterized the ubiquitinome of phagosomes of IFN-γ activated macrophages and can demonstrate that ubiquitylation is preferentially attached to proteins involved in vesicle trafficking, thereby delaying fusion with late endosomes and lysosomes. I demonstrated that most ubiquitin chains are on the cytoplasmic site of the phagosome enabling an interaction of ubiquitin chains with cytosolic proteins such as Rab7. Rab7 a major regulator of vesicle trafficking could be shown to be ubiquitylated on phagosomes. I further showed that phagosomal recruitment of the E3 ligase RNF115 is enhanced upon IFN-γ stimulation and RNF115 is responsible for most of the increase of K63 polyubiquitylation of phagosomal proteins. Knock-down of RNF115 promotes phagosome maturation and induces an increased pro-inflammatory response to Toll-like receptor (TLR) agonists, indicating that RNF115 is a negative regulator of vesicular trafficking to the lysosome and disruption of this pathway induces pro-inflammatory responses in macrophages. In conclusion, this is the first study showing unbiasedly that ubiquitylation plays an important role in vesicle trafficking to the lysosome.
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Ayyar, Priya Vijay. "Uncovering the role of S-nitrosylation in jasmonic acid signalling during the plant immune response." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25783.
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Plants have evolved a plethora of effective mechanisms to protect themselves from biotic stresses. Jasmonates (JAs) are employed as vital defence signals against both insect and pathogen attack. Jasmonic acid (JA) signalling plays a central role in plant defence and development. S-nitrosylation, a redox-based post-translational modification plays an important role in plant disease resistance. S-nitrosoglutathione (GSNO) is formed by the reaction of antioxidant glutathione (GSH) and nitric oxide (NO) and acts as a mobile reservoir of NO bioactivity. The Arabidopsis thaliana S-NITROSOGLUTATHIONE REDUCTASE (AtGSNOR1) controls multiple modes of disease resistance via S-nitrosylation. In this context, the Arabidopsis lossof- function mutant atgsnor1-3 exhibits higher susceptibility to Botrytis cinerea a necrotrophic pathogens and Pieris rapae insect attack. Accumulation of JA was reduced in atgsnor1-3 after mechanical wounding. JA marker genes were also downregulated in atgsnor1-3 compared to Col-0 after Methyl Jasmonate (Me-JA) treatment. The relative gene expression of Vegetative Storage Protein (VSP) was reduced in atgsnor1-3 compared to wild type. Further, protein-protein interaction experiments in yeast two hybrid assays revealed an inhibition of Coronatine-insensitive 1 (COI1) and Jasmonate ZIM domain (JAZ1) interactions upon NO donor application. Interestingly it was also shown that Nitric oxide donor may inhibited the degradation of JAZ1-β-glucoronidase (GUS) fusion protein driven by a CaMV35s:: JAZ1-GUS transgene in GUS histochemical analysis but not in flurometric assay. A biotin switch assay of recombinant JAZ1-Maltose-binding protein (MBP) has shown that JAZ1-MBP was S-nitrosylated and mass spectrometry suggested Cysteine229 (Cys229) was the site of this modification. Further, CaMV35S::JAZ1-Flag transgene expressed in either a wild-type or atgsnor1-3 genetic background, suggested that JAZ1 was S-nitrosylated in vivo. Collectively, our data imply that JA-signalling engaged in response to either insect predation or attempted B. cinerea infection is under redox control as high SNO in atgsnor1-3 has disrupted the JA signalling pathway. Furthermore, our data suggest that S-nitrosylation of Cys-229 of JAZ1 may control JA-mediated signalling by blocking the interaction of this protein with COI1, thus reducing the turnover of JAZ1 by the 26S proteasome and consequently enabling continued JAZ1-mediated repression of JA-dependent gene expression in the presence of Me-JA. Thus our findings highlight the importance of NO and associated S-nitrosylation in JA signalling during plant immune response.
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Bolukbasi, Ekin. "Characterization of Poly : a novel mediator of insulin receptor signalling in Drosophila." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5700.
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Poly is a novel, essential protein in Drosophila melanogaster, loss of function of which results in late larval lethality. Importantly, Poly is evolutionarily conserved with a human homologue. poly mutation was isolated in a P-element mutagenesis screen that aimed to generate a larger collection of single P-element induced mutants. Mutant poly larvae are characterized by extreme larval longevity without pupation, formation of melanotic masses, smaller imaginal discs and brains, and abnormal nuclear morphology in neuroblasts. During the course of my project, I attempted to identify cellular processes and pathways that Poly might be involved in. Interestingly, my data suggest that Poly is a novel interactor and regulator of Insulin receptor/target of rapamycin (InR/TOR) signalling in Drosophila. Linking environmental cues to cell growth and metabolism is an essential process that multicellular organisms need to accomplish successfully for normal development. InR/TOR signalling is a highly conserved pathway that mediates the link between the environment and cellular processes such as growth, metabolism and ageing. My analysis in Drosophila suggests that Poly interacts physically with the InR and mutation of Poly leads to an overall down-regulation of InR/TOR signalling in Drosophila as revealed by decreases in the phosphorylation levels of Akt, S6K and 4E-BP - all downstream effectors of this pathway. In addition, loss of poly results in constitutive activation of autophagy in Drosophila fat body and a decrease in stored triglyceride levels. Furthermore, I show that localisation and levels of Poly protein are dependent on insulin action in both Drosophila and human cells. Together, these data suggest that Poly is a novel mediator of InR signalling that promotes an increase in cell growth and metabolism. Taking into consideration the observed poly mutant phenotype, I also investigated the potential involvement of Poly during cell cycle progression and the Drosophila innate immune response. While my analysis suggests that poly loss of function does not have a direct effect on cell cycle progression, alteration of Poly has consequences on various aspects of the Drosophila innate immune response. Therefore, I conclude that the Drosophila innate immune response is a cellular process in which Poly plays a crucial role.
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Ghaffari, Emma Louise Marie. "Early growth response genes -2 and -3 are essential for optimal immune responses." Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/8134.
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Early Growth Response Genes (EGR) is a family of four transcription factors containing a unique zinc finger domain. EGR-2 and EGR-3 are important for hindbrain development and myelination. These transcription factors are also necessary for lymphocyte function however, the mechanisms are still unclear. Previous findings have shown that EGR-2cKO mice develop lupus-like autoimmune disease with high levels of pro-inflammatory cytokines despite showing normal T and B cell proliferation after mitogenic stimulation. Therefore we established the CD2-EGR-2-/-EGR-3-/- mouse model to explore the phenotype, susceptibility to autoimmune disease and relevant lymphocyte function. We discovered that CD2-EGR-2-/-EGR-3-/- mice developed severe systemic autoimmune disease and expressed high levels of inflammatory cytokines. More importantly we discovered a novel finding that CD2-EGR-2-/-EGR-3-/- T and B cells had impaired cell proliferation after mitogenic stimulation. Further investigations revealed that the molecular mechanism defected in the T cell receptor signalling pathway is due to a dysfunction in Activator Protein-1 (AP-1). AP-1 is a heterodimeric protein composed of AP-1 family members including Jun, Atf and Fos. Our data shows that EGR-2 and EGR-3 directly bind with the Atf family member Batf, which prevents Batf’s inhibitory function on AP-1 activation. This research demonstrates that EGR-2 and EGR-3 intrinsically regulate chronic inflammation and also positively regulate antigen receptor activation. In conclusion EGR-2 and EGR-3 are essential for providing optimal immune responses, whilst limiting inflammatory immunopathology. We propose that this new model could be used for studying autoimmune disease.
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Sotsios, Yannis. "Chemokines and T cells : activation requirements for RANTES secretion and CXCR4 signalling in mature T cells." Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323606.
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Ehrenberg, Stefanie [Verfasser], and Josef [Akademischer Betreuer] Mautner. "Notch2 signalling in B cell activation, immune response and lymphomagenesis / Stefanie Ehrenberg. Betreuer: Josef Mautner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1096162849/34.
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Cheng, Xiaoxiao. "The nature of protein interactions mediating co-stimulatory signalling in the immune system, involving PD-1." Thesis, University of Oxford, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.600227.
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PD-l , a costimulatory receptor expressed by T -cells, B-cells, NKT cells and monocytes, has emerged as one of the most potent inhibitory molecules in the immune system, and a very promising therapeutic target. The biophysical properties of the interactions of PD-i with its two ligands PD-Lt and PD-L2, however, are incompletely characterized. The question of why there are two ligands for PD-l is also unanswered. An unexpected interaction between PD-Lt and B7- 1, which also binds to other costimulatory receptors, has further complicated the interpretation of the functions of these molecules. In this thesis , experiments were undertaken to more fully characterize the interactions of PD-l within the wider context of costimulatory interactions involving T cells. Monomeric forms of PD-l, PD-Lt, PD-L2 and B7-1 were produced in order to re-analyze their interactions using surface plasmon resonance-based assays. The three- to four-fold greater affinity of PD-L2 versus PD-Ll for PO-l in humans (PD-IIPO-Ll- 7.8 μM, PO-IIPO-L2 -2.2μM) was principally due to the three-fold smaller dissociation rate for PO-L2 binding. The affinity of PO-Ll with B7-1 was much weaker than previously reported, and the interactions of PO-l with its ligands in the murine system had similar affinities, albeit ones considerably weaker than the respective human interactions. The thermodynamic properties of the PD-l system were characterized using two different approaches, van't Hoff analysis and isothermal calorimetry, and this showed that the PO-IIPO-Ll interaction is driven entropically, whereas for PD-I and PD-L2 binding enthalpy is dominant. The ΔCp values for both interactions were similar, with a slightly more negative value obtained for PO-IIPO-Ll than for PO-IIPD-L2, and consistent with binding involving the burial of relatively large hydrophobic surfaces. Comparison of the binding surface residues perturbed during ligand binding using nuclear magnetic resonance (NMR)-based analyses showed that the binding foot-print of PD-Ll is larger than that of PD-L2, even though PD-L2 binds PD-l more strongly. Comparison of the NMR data with the published crystal structures of murine PD- I complexed with human PD-Ll and mouse PD-L2 suggested that the human and mouse interactions differ in detail. Mathematical simulations based on the affinity and kinetic data, and on rigorous expression data revealed an unexpectedly limited contribution of PD-L2 to PD-I ligation during interactions of activated T-cells with mature dendritic cells (mDCs): PD-I engaged more than four-fold fewer PD-L2 than PD-Ll molecules due to the low expression of PD-L2 on mDCs. These observations suggest that the function of PD-L2 is not to enhance human PD-l engagement but to provide qualitatively different signals. The simulations also implied that the B7-IIPD-Ll interaction might have limited impact in the presence of CTLA-4, CD28 and PD-I. Finally, a novel method for identifying new receptor ligands suggested that there are unlikely to be high affinity ligands for several B7-, PD-Ll- and PD-L2-related proteins, raising the possibility that these proteins have ligand-independent functions. These findings provide a new, more rigorous structural and biophysical framework for interpreting the functions of PD-I.
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Gaughan, Daniel. "The role of DNA damage response proteins in innate immune signalling : a new role for BRCA1." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:252f589f-40c0-4f7f-be3d-124e588e92a8.
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Pattern Recognition Receptors (PRRs), which have evolved to detect a diverse array of pathogenic features known as Pathogen Associated Molecular Patterns (PAMPs), are localised optimally for interaction with their cognate ligands. Upon Receptor activation, signal transduction pathways are induced which converge at different points to direct a specific inflammatory response. TBK1 is activated and recruited to multiple PRRs, where it in turn recruits and phosphorylates IRF3 which then translocates to the nucleus and induces the expression of type I IFN. In this study, the major breast cancer susceptibility protein BRCA1, known for its functional role in maintaining genomic stability, is found to be phosphorylated following PRR triggering. This event is demonstrated to be DNA Damage, DNA Damage Response (DDR) signalling, and oxidative stress-independent. Further to this, phosphorylated BRCA1 localises to Golgi-related microsomes in perinuclear zones where TBK1 and the adaptor STING can be found. Here, BRCA1 interacts biochemically with and facilitates full activation of TBK1. BRCA1-deficient cells show abrogated IRF3 phosphorylation, type I IFN production and ISG induction in response to a diverse array of PRR agonists as well as both HSV1 and Sendaï virus (SeV). Subsequently, BRCA1 deficiency impairs antiviral responses to pathogens such as HSV1.
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Thoma, Martine. "Role of IkappaB/NF-kappaB signalling pathways in the immune response of the mosquito Anopheles gambiae." Strasbourg, 2009. https://publication-theses.unistra.fr/restreint/theses_doctorat/2009/THOMA_Martine_2009.pdf.
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Elsheikh, Ayman A. "Drug immunogenicity and co-stimulatory signalling : evidence for formation of a functional antigen through immune cell metabolism." Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548759.
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Bielig, Harald Frank Verfasser], Jonathan [Akademischer Betreuer] Howard, and Mats [Akademischer Betreuer] [Paulsson. "Screening for components involved in NLR-mediated immune signalling / Harald Frank Bielig. Gutachter: Jonathan Howard ; Mats Paulsson." Köln : Universitäts- und Stadtbibliothek Köln, 2012. http://d-nb.info/1038226805/34.
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Bielig, Harald Frank [Verfasser], Jonathan Akademischer Betreuer] Howard, and Mats [Akademischer Betreuer] [Paulsson. "Screening for components involved in NLR-mediated immune signalling / Harald Frank Bielig. Gutachter: Jonathan Howard ; Mats Paulsson." Köln : Universitäts- und Stadtbibliothek Köln, 2012. http://d-nb.info/1038226805/34.
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Karsten, Elisabeth. "Red blood cells: the immune system’s hidden regulator, investigation into the role of red blood cells in inflammatory cytokine signalling." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16929.
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Red blood cells are the most abundant cell type in mammals, although, they are mostly described as inert carriers of haemoglobin that function only in gas exchange and transport. Evidence is now mounting that these enucleate cells are more complex than previously understood. Studies have reported that red blood cells from healthy individuals regulate immune cell activity and maturation, but red blood cells from inflammatory disease cohorts are dysfunctional. Red blood cells are known to bind a small number of chemokines and have been described as a sink for these molecules, and the loss of this activity is correlated with disease progression. This results of this thesis support a broader role for red blood cells in regulating inflammation by acting as a cytokine buffer and modulating cell activity. The aims and hypotheses of this thesis were founded on the discovery that red blood cells are a major reservoir for the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF); in fact, they contribute 1000-fold more per millilitre than plasma. Red blood cells were also identified to be a major reservoir of 30 additional cytokines, chemokines, and growth factors. Further investigation showed that red blood cells bind and release significant quantities of these proteins, a function that can be modulated by other cells and by enzyme inhibitors. Incubating red blood cells with a cancer cell line (A549 cells) resulted in the significant increase of eight pro-tumorigenic cytokines in the red blood cell lysates. These primed red blood cells altered the activity of lymphocytes by stimulating the proliferation of T cells compared to controls, and promoted the expression of cell activation markers. This study supports the hypothesis that red blood cells act as a buffer for cytokines through binding and release, and that alterations in red blood cells from cell-to-cell interactions affects the activity of T cells. This thesis proposes that red blood cells have multiple functions and the results have implications for the study of inflammation, the role of red blood cells in diagnostics, and on the development of red blood cell derived therapeutics.
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Florey, Oliver John. "Effects of anti-endothlial cell antibodies, immune-complexes and sphingosine-1-phosphate on leukocyte adhesion and cell signalling." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498233.
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Weber, Sabine [Verfasser], and Daniela [Akademischer Betreuer] Männel. "Effects of TNF Receptor Signalling on the the Function of Suppressive Immune Cells / Sabine Weber. Betreuer: Daniela Männel." Regensburg : Universitätsbibliothek Regensburg, 2016. http://d-nb.info/1096751755/34.
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Homem, Rafael Augusto. "Redox signalling and innate immunity : a role for protein S-nitrosylation in the immune response of Drosophila melanogaster." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/15971.
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Over the past three decades, nitric oxide (NO) has been recognised as one of the most versatile and important players in many aspects of physiology, including immune responses. More recently, S-nitrosylation, the incorporation of a NO moiety into a protein thiol group, has emerged as a major post-translational modification (PTM) during pathophysiological responses in plants and animals. The main goal of this work was to investigate the role of S-nitrosylation in physiology and innate immunity of animals using the genetic reference system, Drosophila melanogaster. The S-nitrosylated derivative of glutathione (GSH), S-nitrosoglutathione (GSNO), is the main non-protein S-nitrosothiol (SNO) in the cell and extracellular fluids. GSNO can trans-S-nitrosylate other thiols and is considered a reservoir of NO bioactivity. The levels of GSNO and total S-nitrosylation have been shown to be controlled by S-nitrosoglutathione reductase (GSNOR) in yeast, plants and mammals. By employing an overlapping deletion technique to knock-out gsnor, a role for S-nitrosylation in the immune response of D. melanogaster is proposed. Compared to wild type flies, gsnor overlapping deletion flies presented lower expression of antimicrobial peptides in response to infections, and succumbed more rapidly to both Gram-positive bacterial and fungal pathogens. As the Toll pathway mediates responses against these pathogens, key components of this network were tested for their propensity to being S-nitrosylated. Two CLIP-domain serine proteases of the Toll signalling pathway, Persephone (PSH) and Spätzle-Processing Enzyme (SPE), were shown to be S-nitrosylated both in vitro and in vivo and this process seemed to control the quaternary structure of these proteins and interfere with the immune response of D. melanogaster. At least for PSH, S-nitrosylation at C254 has an immune significance as the expression of non-Snitrosylable PSHC254S in gsnor knock-out flies partially recovered the resistance of these animals to infections with the entomopathogenic fungus Beauveria bassiana. These findings might represent a novel mechanism by which NO and S-nitrosylation regulate immunity. Further results presented in this thesis reveal an interplay between reactive oxygen species (ROS) and reactive nitrogen species (RNS) in D. melanogaster physiology and immunity. Similarly to what has been reported in Arabidopsis thaliana, gsnor knock-out flies presented higher tolerance to the herbicide paraquat, an inducer of superoxide (O2 -) production. Moreover, additional mutations in Catalase (Cat), a hydrogen peroxide (H2O2) scavenger enzyme, partially restored the immunodeficiency phenotypes of gsnor knock-out flies. These findings suggest an inter-relation between the levels of ROS and RNS during stress responses of plants and animals. In addition, CRISPR/Cas9 technology was employed to generate gsnor knock-outs in the genome of D. melanogaster. These flies were shown to have no GSNOR activity, presented lower tolerance to pharmacological-induced nitrosative stress and succumbed faster to infections with B. bassiana compared to wild type flies. These results support the role played by GSNOR in regulating NO homeostasis and immunity in D. melanogaster.
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Reder, Gabor. "Development of a phosphoproteomic screen of innate immune signalling : identification and characterisation of a novel phosphorylation of NFkB1/p105." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6150.
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Toll-like receptors (TLRs) expressed by antigen-presenting cells of the innate immune system, such as macrophages, detect microbial products and activate signalling cascades that initiate specific gene expression programmes that define the subsequent adaptive immune response. However, it is poorly understood how TLR-specific responses arise, as many of the signalling components are common to multiple TLRs, and it is likely that as yet undiscovered phosphorylations of signalling proteins contribute to specificity of TLR pathways. TLR4, the receptor for lipopolysaccharide (LPS), is used as a model system for TLR signalling, as it activates many of the signalling mechanisms utilised by other TLRs, and I attempted to discover novel regulatory phosphorylations in LPS-activated RAW 264.7 macrophages. Because it is not yet possible to accurately predict post-translational modifications from genomic data, the exact sites of phosphorylation have to be identified experimentally, and the method of choice for this is mass spectrometry-based phosphoproteomics. Using an optimised phosphoproteomics workflow and stringent filtering criteria, I identified 445 phosphorylation sites in unstimulated and LPS-treated RAW macrophages, several of which were potential LPS-induced regulatory phosphorylations, including a previously uncharacterised phosphorylation of the NF-κB protein p105, a key regulator of TLR and other inflammatory signalling pathways. Following validation of a phospho-specific p105 antibody, I demonstrated that the novel phosphorylation of p105 was induced by LPS, other TLR ligands, tumour necrosis factor (TNF)-α, and prostaglandin E2 in RAW macrophages and primary human macrophages, and by interleukin (IL)-1β in 4 primary human skin fibroblasts. Moreover, the LPS-induced phosphorylation of p105 was blocked by the protein kinase A (PKA) inhibitor H89. These results indicate that the novel phosphorylation of p105 may be important for the regulation of TLR and other inflammatory signalling pathways in both hemopoietic and non-hemopoietic cells.
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ARTUSA, VALENTINA. "Modulation of the Innate Immune Response by Targeting Toll-like Receptor 4 Signalling: Exploring the Role of Natural Products." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/375443.
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Per secoli, i prodotti naturali e i loro derivati hanno fornito una ricca fonte di composti per lo sviluppo di nuovi immunomodulatori. Gli immunomodulatori naturali possono fornire la chiave per controllare e, infine, sconfiggere i disturbi che colpiscono il sistema immunitario, stimolando o inibendo la risposta immunitaria con pochi effetti collaterali negativi. Molti di questi composti sono attualmente in fase di sperimentazione clinica, in particolare come agenti antiossidanti, antimicrobici e antitumorali. Tuttavia, la funzione e il meccanismo di azione dei prodotti naturali, e il modo in cui interagiscono con il sistema immunitario, devono ancora essere ampiamente esplorati.
Negli ultimi anni, la conoscenza del ruolo dei macrofagi nel contesto dell'infiammazione ha aperto numerose nuove strade, tra cui la possibilità di intervento terapeutico mirato sfruttando la plasticità intrinseca dei macrofagi per il trattamento di patologie infiammatorie acute e croniche. I recettori Toll-simili (TLR), incluso TLR4, svolgono un ruolo cruciale nelle malattie a base infiammatoria; pertanto, la via di segnalazione di TLR4 è stata identificata come bersaglio terapeutico per l'intervento farmacologico.
Questo lavoro mira a valutare il potenziale dei fitoestratti e delle sostanze fitochimiche di influenzare la via di segnalazione di TLR4 in un modello cellulare di macrofago. Nello specifico, sono stati testati estratti ottenuti da chicchi di caffè verde (GCE) e tostato (RCE), nonché acido clorogenico puro (5-CQA). Inoltre, è stato valutato l'effetto antinfiammatorio della palmitoiletanolamide (PEA) e del suo analogo sintetico RePEA.
Come modello in vitro sono stati impiegati macrofagi originati da monociti umani, derivanti dalla differenziazione di una linea cellulare (THP-1) e/o da monociti umani primari. Il saggio MTT è stato utilizzato per determinare gli effetti citotossici dei trattamenti. L'attivazione di TLR4 è stata stimolata mediante esposizione delle cellule all'endotossina batterica LPS (E. coli) in presenza o assenza di trattamento. Sono stati valutati diversi parametri: produzione di citochine pro-infiammatorie, ma anche attivazione e traslocazione nucleare dei mediatori di segnalazione intracellulare. Questi parametri sono stati misurati applicando differenti tecniche di biologia cellulare e molecolare, principalmente test di immunoassorbimento enzimatico (ELISA), immunofluorescenza e immunofissazione (Western blot). Inoltre, abbiamo impiegato diverse cellule transfettate stabilmente disponibili in commercio come strumenti per studiare il meccanismo d'azione del nostro estratto o della nostra molecola, rispettivamente le cellule THP1-XBlue™, RAW-Blue™ e HEK-Blue™.
I risultati chiave includono un marcato effetto inibitorio, dose-dipendente, degli estratti di caffè verde e tostato verso il rilascio di interferone-β (IFN-β) dopo la stimolazione con LPS. Coerentemente, l'acido clorogenico, un importante componente polifenolico degli estratti di caffè, ha mostrato un'attività biologica comparabile. Complessivamente, i risultati ottenuti forniscono nuove prove sugli effetti immunomodulatori e sul meccanismo d'azione degli estratti di caffè e dell'acido clorogenico, in particolare come modulatori della via di segnalazione pro-infiammatoria mediata da TLR4. Inoltre, la capacità della PEA di ridurre il rilascio di TNF-α da parte delle cellule microgliali stimolate con LPS è stata corroborata anche nel nostro modello di macrofagi, confermando il suo potenziale antinfiammatorio. Inoltre, RePEA, un analogo sintetico della PEA progettato per essere degradato più lentamente, si è rivelato più attivo del suo composto originario.
Questi risultati aiutano a convalidare le suddette molecole naturali, 5-CQA e PEA, ma anche RePEA, come potenziali nuovi candidati per ulteriori indagini precliniche per il trattamento delle malattie autoimmuni e infiammatorie.<br>For centuries, natural products and their derivatives have provided a rich source of compounds for the development of new immunomodulators in the treatment of human diseases. Natural immune modulators may provide the key to control and ultimately defeat disorders affecting the immune system, by either up- or down-regulating the immune response with few adverse side effects. Many of these compounds are currently undergoing clinical trials, particularly as anti-oxidative, anti-microbial, and anti-cancer agents. However, the functions and mechanisms of action of natural products, and how they interact with the immune system, has yet to be extensively explored.
In recent years, the increasing body of knowledge regarding the role of macrophages in the steady-state and in the context of inflammation has opened diverse new avenues of investigation and possibilities for therapeutic intervention targeting the inherent plasticity of macrophages for the treatment of acute and chronic inflammatory disease. Toll-Like Receptors (TLRs), including TLR4, play a crucial role in inflammatory-based diseases, therefore TLR4 signalling has been identified as a therapeutic target for pharmacological intervention.
This work aims to screen and investigate the potential of phytoextracts and phytochemicals to affect TLR4 signalling in a macrophage-like cell model. Specifically, extracts from green (GCE) and roasted (RCE) coffee beans as well as pure chlorogenic acid (5-CQA) were tested. Also, the anti-inflammatory effect of palmitoylethanolamide (PEA), and its synthetic analogue RePEA, was assessed.
Human monocyte-derived macrophages, deriving from the differentiation of a monocytic cell line (THP-1) and/or from human primary CD14+ monocytes, were employed as an in vitro model. MTT was used to determine cytotoxic effects of the treatments. TLR4 activation was stimulated by exposure of cells to bacterial endotoxin LPS (E. coli), in presence or absence of treatments. Different readouts were evaluated: endpoint pro-inflammatory cytokines production, as well as phosphorylation and nuclear translocation of intracellular signalling mediators. These parameters were measured applying different cellular and molecular techniques, mainly enzyme-linked immunosorbent assay (ELISA), High Content Analysis (immunofluorescence microscopy), and Western blot. Alongside, we employed different commercially available stable transfected cells as tools to investigate the mechanism of action of our tested extract or molecule, THP1-XBlue™, RAW-Blue™ and HEK-Blue™ cells, respectively.
Key findings include a dramatic, dose-dependent, inhibitory effect of both green and roasted coffee extracts towards interferon-β (IFN-β) release, upon LPS stimulation. Consistently, chlorogenic acid, a major polyphenolic component of coffee extracts, showed a comparable biological activity. Additionally, novel evidence towards the immunomodulatory effects and mechanism of action of coffee extracts and chlorogenic acid as modulators of TLR4-related pro-inflammatory signalling have been provided. Alongside, PEA capability of reducing TNF-α release from LPS-stimulated microglial cells, was corroborated in our macrophage model also, confirming its anti-inflammatory potential. Moreover, RePEA, a synthetic PEA analogue designed to be degraded slower, was revealed to be more active than its parent compound.
These experimental data demonstrate that natural products may act as lead molecules for the development of safe and effective immunomodulators.
Taken together, these findings help to validate the above-mentioned natural molecules, 5-CQA and PEA, but also RePEA, as potential novel candidates for further preclinical investigations for the treatment of inflammatory-based disorders.
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Ekholm, Dag. "Cyclic nucleotide signalling systems in vascular smooth muscle cells and immune cells with special reference to phosphodiesterases PDE3 and PDE4." Lund : Lund University, 1998. http://books.google.com/books?id=KPFqAAAAMAAJ.
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Korir, Patricia Jebett [Verfasser]. "Immune regulation in Plasmodium berghei ANKA infected mice either lacking type I interferon signalling or mimicking malaria tolerance / Patricia Jebett Korir." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1155825454/34.
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Sidwaba, Unathi. "Electrochemical poly(ProDOT) dendritic DNA aptamer biosensor for signalling interferon gamma (IFN-ɣ) TB biomarker". University of the Western Cape, 2017. http://hdl.handle.net/11394/5507.
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Philosophiae Doctor - PhD<br>Tuberculosis (TB) is an infectious disease that, despite all efforts devoted towards its
eradication, remains a threat to many countries including South Africa. Current diagnostic
assays do offer better performance than the conventional sputum smear microscopy and
tuberculin skin tests. However, these assays have been proven to be affected by various factors
including the condition of an individual's immune system and vaccination history. By far,
electrochemical biosensors are amongst the currently investigated techniques to address the
shortcomings associated with these diagnostics.<br>2020-08-31
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Anselm, Bettina [Verfasser], and Bianca [Akademischer Betreuer] Schaub. "Early priming of the immune system: Identifying predictive markers of innate immunity and calcium signalling for the development of asthma / Bettina Anselm ; Betreuer: Bianca Schaub." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1204827915/34.
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Westphal, Andreas [Verfasser], Kyeong-Hee [Akademischer Betreuer] Lee, Norbert [Akademischer Betreuer] Reiling, and Georgios [Akademischer Betreuer] Tsiavaliaris. "Lysosomal trafficking regulator Lyst controls innate immune cell signalling and function : regulation of TLR-mediated TRIF signalling and control of mast cell-mediated allergic reactions / Andreas Westphal ; Akademische Betreuer: Kyeong-Hee Lee, Norbert Reiling, Georgios Tsiavaliaris ; Institut für Klinische Chemie." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2017. http://d-nb.info/1143981758/34.
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Käbisch, Romy Astrid [Verfasser], Markus [Akademischer Betreuer] Gerhard, and Dirk [Akademischer Betreuer] Haller. "Effect of Helicobacter pylori infection on dendritic cell maturation, signalling and subsequent adaptive immune response / Romy Astrid Käbisch. Gutachter: Dirk Haller ; Markus Gerhard. Betreuer: Markus Gerhard." München : Universitätsbibliothek der TU München, 2013. http://d-nb.info/1060482630/34.
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Sistigu, Antonella. "Inflammatory and immune reactions in response to chemotherapy-induced cell death. Viral mimicry chemotherapy : ds RNA sensors and IFNAR signalling indispensable for immunogenic tumor cell death." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T052.
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Certains motifs moléculaires associés à la mort cellulaire semblent identifier les cancers prompts à répondre à une thérapie cytotoxique. Ceci en élaborant une réponse anti-tumorale basées sur une réponse T protectrice. Mon travail de thèse montre que le traitement par chimiothérapie immunogène active des voies moléculaires mimant une infection virale. Ceci conduit au niveau des cellules tumorales à une signalisation autocrine via l’IFNαβ / IFNAR1/2, initiée par la reconnaissance d’ARN double brin (dsRNA) endogène par les Récepteurs endosomaux de Reconnaissance des Motifs (PRRs). De façon plus détaillée, nous montrons que les axes TLR3/TRIF (senseurs endosomaux de dsRNA) et IFNAR1/2 (Récepteurs de l’IFN de Type I) doivent signaliser au niveau de la cellule tumorale pour que la chimiothérapie puisse aboutir à l’induction de l’axe CXCL10/CXCR3 et éliciter une réponse efficace in vivo. L’analyse du profil ARN de cellules tumorales Tlr3+/+ (mais pas Tlr3-/-) exposées aux anthracyclines a révélé une forte empreinte virale/IFN, indispensable à l’efficacité/activité anti-tumorale. Le fait d’affecter les axes TLR3 ou IFNAR1/2 au niveau tumorale soit à l’aide d’anticorps neutralisants, soit à l’aide de modèles KO abroge le relarguage de CXCL10 induit par la chimiothérapie, et ainsi la capacité à contrôler la pousse tumorale à moins que de l’IFNαβ ou du CXCL10 exogène soit co-administré aux anthracyclines. De plus la chimiorésistance des tumeurs traitées par des molécules n’induisant pas de signature virale peux être réversée par de l’IFN de Type I exogène. Enfin, la détection d’une signature IFN au niveau de biospies de cancers du sein humains permet de prédire la bonne réponse au traitement adjuvant par anthracyclines. D’un point de vue de l’évolution, alors que les tumeurs (comme les virus) ont élaboré des mécanismes pour échapper aux réponses IFN, la signature virale induite par la chimiothérapie devrait contribuer à contrecarrer cette immunoédition<br>Distinct cell death-associated molecular patterns might define cancers proned to respond to a cytotoxic therapy by mounting a protective T cell-based anticancer immunity. My PhD Thesis work shows that immunogenic chemotherapy phenocopies viral infection leading to autocrine IFNαβ/IFNAR1/2 signalling in tumor cells initiated by recognition of self dsRNA by endosomal pattern recognition receptors (PRRs). In detail, TLR3/TRIF (endosomal dsRNA sensors) and IFNAR1/2 (Type I IFN receptors) must signal within the tumor cells so that chemotherapy can induce downstream CXCL10/CXCR3 axis and elicit therapeutic responsiveness in vivo. RNA profiling of Tlr3+/+ (but not Tlr3-/-) tumor cells exposed to anthracyclines revealed a strong IFN/viral fingerprint, indispensable for the tumoricidal activity. Neutralization by antibodies or genetic defects affecting tumor –associated TLR3 or IFNAR1/2 compromised chemotherapy-induced CXCL10 release and tumor control unless exogenous IFNαβ or CXCL10 are concomitantly supplied to anthracyclines. Moreover, chemoresistance of tumors treated by drugs failing to induce a viral signature can be reversed by exogenous Type I IFN. Finally, the IFN fingerprint of human breast cancers allowed to predict tumors proned to benefit from adjuvant anthracyclines. From an evolutionary viewpoint, while tumors (like viruses) have evolved mechanisms to evade an IFN response, chemotherapy-induced viral mimicry might contribute to bypass such as immunoediting
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Lambourne, Jonathan Richard. "An investigation of human immune signalling pathways during Staphylococcus aureus colonisation and bacteraemia leading to an investigation of mannose-binding lectin in S. aureus bacteraemia, chronic hepatitis and acute aspergillosis." Thesis, St George's, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546773.
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Zmarlak, Natalia Marta. "Regulation of immune signalling in the malaria mosquito vector, Anopheles : the secreted mosquito leucine-rich repeat protein APL1C is a pathogen binding factor essential for immunity to Plasmodium ookinetes and sporozoites." Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS053.
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L’anophèle est le moustique vecteur du parasite Plasmodium, responsable du paludisme. Chez ce moustique, des protéines de type LRR (à motifs riches en leucine) ont été décrites comme antagonistes cruciaux du développement de Plasmodium. L’une d’entre elles, APL1C (Anopheles Plasmodium-responsive factor) protège spécifiquement le moustique contre les parasites Plasmodium de rongeurs en collaboration avec la protéine TEP1 du complément. En combinant des approches de biologie cellulaire et de génomique fonctionnelle, mon travail de thèse montre que le repas sanguin des moustiques induit le recrutement d’APL1C au niveau du pôle basal de l’épithélium digestif. Ce positionnement d’APL1C lui permet de se lier aux stades ookinètes du parasite émergeant du côté basal de l’épithélium, et ce, indépendamment de la fonction de TEP1. Néanmoins, cette action d’APL1C requiert la contribution des phagocytes et de la Nitration. Par ailleurs, mon travail montre que l’action d’APL1C ne se restreint pas à l'ookinète car elle agit aussi contre le dernier stade de développement de Plasmodium, les sporozoïtes. Avec la capacité de se lier aux sporozoites, APL1C contrôle la prévalence d’infection des glandes salivaires du moustique, mais avec des partenaires différents de ceux agissant sur les ookinètes. Finalement, une étude transcriptomique m’a permis d’identifier des facteurs agissant en aval d’APL1C. L’ensemble de ces résultats génère de nouvelles connaissances relatives à la fonction de cette famille de protéines LRR en tant que récepteurs de reconnaissance d'agents pathogènes capable de déclencher une réponse immunitaire dans différents compartiments tissulaires du moustique<br>Anopheles mosquito is a vector of Plasmodium parasite, the causative agent of malaria. The Anopheles leucine-rich repeat (LRR) proteins were described as key antagonists of Plasmodium parasites in Anopheles mosquito midgut. APL1C (Anopheles Plasmodium-responsive factor) is a representative of LRR members which specifically protects against rodent malaria parasites by stabilizing the complement-like protein TEP1. By combining cell biology with functional genomic approaches, this study shows that mosquito bloodmeal induce the presence of an extracellular layer of APL1C protein surrounding the midgut beneath of the basal lamina. Consistently with the formation of this layer, APL1C binds to the ookinetes that emerged on the basal side of the midgut. This presence occurs independently from TEP1 function, requires the contribution of the phagocytic cells and nitration pathway. In addition, APL1C defence function is not restricted to the ookinete in the midgut but it also acts against the latest Plasmodium stage, the sporozoites. APL1C inhibits salivary glands infection prevalence, and consistently, it also binds to the surface of the sporozoites in the hemocoel. However, unlike to the midgut stages, anti-sporozoites APL1C-dependent mechanism involves different partners. Moreover, RNAseq study revealed APL1C gene targets, including genes with immune-like function. These results generate novel biological insight for the function of APL1C, and probably other LRR family members, as a pathogen recognition receptor inducing immune response against pathogens that come in contact with mosquito hemolymph compartment