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Christou, Charita. "C-type lectin-like receptors and their interactions." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509908.
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Kerscher, Berhard Gerhard Richard. "Characterisation of the C-type lectin receptor Clecsf8." Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230779.
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C-type lectin-like receptors (CTLRs) play critical roles in immunity and homeostasis by recognising a variety of microbial or endogenous ligands. Clecsf8 is a member of the Dectin-2 family of CTLRs. Clecsf8 shares important similarities with its relatives Mincle and Dectin-2, such as the lack of an integral signalling motif and a single, calcium dependent ligand binding domain. They were shown to associate with the FcRγ adaptor, which is essential for receptor surface expression and downstream signalling. Recent publications revealed an important role for Clecsf8 in anti-mycobacterial immunity. It was reported to recognise the mycobacterial cord factor (TDM), similar to the related CTLR Mincle, as well as a possible role in candidiasis. In this study, we characterised the underlying mechanism of Clecsf8 expression in a context of mycobacterial disease. The generation of novel anti-Clecsf8 monoclonal antibodies allowed us to characterise the expression of Clecsf8 in detail in homeostasis and inflammation in murine models in vivo and culture systems in vitro. We found Clecsf8 to be predominantly expressed on monocytes/macrophages and neutrophils within e. g. the peritoneal cavity, blood and bone marrow. Notably, Clecsf8 was expressed only weakly in the lung, but strongly upregulated in a pulmonary mycobacterial infection model. In vitro, Clecsf8 expression on elicited macrophages was strongly induced upon treatment with microbial stimuli in a Myd88- and Mincle dependent manner. Interestingly, surface expression of Clecsf8 in a murine fibroblast cell line was greatly enhanced by co-transfection of Mincle, but not another related CTLR, Dectin-2. Notably, we confirmed mycobacteria as a ligand of CLECSF8, but found no role for the receptor in Candida immunity. In conclusion, Clecsf8 is a myeloid expressed, mycobacterial receptor, showing significant interdependence with Mincle and is regulated through the Myd88 pathway.
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Clark, Alexandra Elsie. "Characterisation of the C-type lectin-like receptor 1 (CLEC-1)." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=210080.
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Mayer-Lambertz, Sabine [Verfasser]. "Role of C-type lectin receptors in bacterial recognition / Sabine Mayer-Lambertz." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2019. http://d-nb.info/1192752465/34.
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Drummond, Rebcca Anne. "The role of C-type lectin receptors in Candida albicans specific immunity." Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=211412.
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Candida albicans is a human fungal pathogen responsible for superficial mucosal infections and life-threatening systemic disease. Despite the availability of potent antifungal drugs, mortality rates of systemic candidiasis remain high. Alternative therapies and vaccines are therefore desirable; however their generation depends on a comprehensive understanding of antifungal immunity. Innate recognition of fungi by the immune system is primarily mediated by a class of myeloid-expressed molecules termed the C-type lectin receptors (CLRs). CLRs mediate a variety of functions including phagocytosis, fungal killing, initiation of inflammation, and the generation of adaptive immunity. Adaptive responses are required for long-term memory and are shaped by the initial innate immune response controlled by CLR-expressing myeloid cells, yet the influence of CLRs on fungal-specific adaptive immunity is not well understood. In this thesis, the generation of C. albicans-specific T-cell immunity, particularly the CD4+ T-cell response, was investigated using OT.II transgenic T-cells and an ovalbumin-expressing strain of C. albicans. Using this model system, a novel role for the CLR, Dectin-1, was found in controlling CD4+ T-cell viability and recruitment to the GI tract. No roles for Dectin-1, or the related CLR Dectin-2, were found in controlling T-cell responses in the C. albicans infected kidney. However, it was found that, surprisingly, antigen-specific CD4+ T-cells did not migrate into the kidney during infection. Artificial restoration of this defect using immunoliposomes could significantly protect against infection, thus highlighting the importance of these lymphocytes to antifungal immunity. Furthermore, this thesis also explores the generation of better tools to study C. albicans-specific T-cell responses, and the roles of uncharacterised CLRs in the generation of adaptive immunity. Collectively, this research provides new insights into the generation and regulation of antigen-specific CD4+ T-cell immunity during C. albicans infections.
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Fuchsberger, Felix Franz Robert [Verfasser]. "Quantification of C-type lectin receptors signal transduction / Felix Franz Robert Fuchsberger." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1235400352/34.
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Maglinao, Maha Fay Binudin [Verfasser]. "C-type lectin receptors in cell-specific targeting and malaria infection / Maha Maglinao." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1042940037/34.
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Alshahrani, Mohammad. "The role of C-type lectin receptors in the recognition of Pseudiminas aeruginosa." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/53553/.
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Cystic fibrosis patients endure serious lung infection caused by colonisation and persistent infection by a wide range of pathogens, most commonly Pseudomonas aeruginosa (PA). One of the factors that facilitates establishment of chronic lung infection is formation of biofilms which are structures resistant to antimicrobial drugs and immune attack. Biofilms are embedded within extracellular polymeric substance (EPS) that maintains the structure of biofilms. PA produces two important polysaccharides Pel and Psl, which have been implicated in promoting biofilm development and biofilm maintenance, respectively, as well as cell aggregation . To the best of our knowledge, there has not been any study showing the presence of specific immune receptors for the recognition of PA biofilms. C-type lectin receptors (CLRs) are pathogen-recognition receptors that contribute to the recognition of infectious agents through the detection of carbohydrates moieties representing a subset of pathogen-associated molecular patterns (PAMPs). We hypothesized that CLRs such as DC-SIGN (CD209) and mannose receptor (MR) (CD206) could play a crucial role in the immune recognition of PA biofilms through the binding to different carbohydrate-containing components. Investigating the CLR-PA cross-talk and the response of immune cells expressing CLRs to different PA components could lead to a novel strategy to eradicate infections. The main aim of this thesis is to determine the capability of CLRs, particularly MR and DC-SIGN, to interact with PA biofilms. We have shown that CTLD4-7, a region of MR, and DC-SIGN bind to PA biofilms with DC-SIGN binding significantly better than MR. Both lectins also recognised several independent preparations of EPS lacking Pel. Surprisingly, we found that DC-SIGN also binds to planktonic PA in the absence of Psl and Pel which indicates that DC-SIGN could recognize non-EPS carbohydrate-containing ligands in the bacteria. Further investigation unveiled that DC-SIGN requires the presence of the common polysaccharide antigen (CPA) which is shared among all PA serotypes to bind planktonic cells. These results indicate that CPA is a candidate ligand for DC-SIGN in PA. To determine the significance of these findings, assays incubating human dendritic cells with purified EPS and planktonic PA were performed but no definitive conclusion could be drawn. These findings shed light on the potential impact of PA Psl and CPA-LPS on the recognition of PA by immune cells expressing CLRs and might open new avenues for therapeutic approaches.
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Salvage-Jones, Judith. "The Macrophage Inducible C-type Lectin (Mincle) is a Receptor for the Yeast, Candida Albicans." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/367510.
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The Macrophage-Inducible C-type Lectin (Mincle) belongs to the family of C-type lectin receptors some of which have been well characterised. We investigated a role for Mincle in response to systemic candidiasis both in vivo and ex vivo.
Our results show that while Mincle recognises C. albicans it is not phagocytic or candicidal. It does however, recognise this yeast as measured by reduced TNF-α production in Mincle deficient bone marrow-derived macrophages. Furthermore, there was a significant reduction in the cytokines KC, IL-1β, IL-10, IL-13, GCS-F, MIP-1β and RANTES in these cells.
By using a mouse model of systemic infection, we were able to investigate levels of yeast fungal burden and tissue damage inMincle-/- and isogenic control mice. Mincle deficient mice were more susceptible to C. albicans infection, demonstrated by increased fungal burden and increased tissue damage in the kidney and brain of our knock-out mice, confirming a role for Mincle in control of C. albicans infection.
Mincle shares some features in common with the β-glucan receptor (Dectin-1) and its close relative Dectin-2. Dectin-1 and Dectin-2 have both been shown to recognise the yeast Candida albicans. We therefore, went on to look at the RNA and protein expression profiles of these three C-type lectins and found Mincle was consistently upregulated in response to Candida in the brain, kidney, lung and spleen. Dectin-1 showed delayed induction and Dectin-2 was significantly up-regulated in all tissues in the absence of Mincle.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Tomlinson, Neil David. "Regulation of C-type lectin-like receptors dectin-1 and CLEC-2 by tetraspanins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/826/.
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Tetraspanins are a superfamily of glycoproteins that function as ‘organisers’ of membranes by clustering with each other to form tetraspanin-enriched microdomains, into which certain other receptors and signalling proteins are recruited and regulated. Tetraspanin microdomains have been implicated in a range of biological processes including cell signalling, adhesion, intracellular trafficking, cell-cell fusion and viral entry. The tetraspanin CD37 was recently shown to negatively regulate the C-type lectin-like receptor dectin-1, which is essential for innate immune responses to fungal pathogens. The aim of this thesis was to firstly develop a cell line model system to investigate the mechanism by which tetraspanins inhibit dectin-1, and to secondly extend this work to the dectin-1-related CLEC-2, which is essential for platelet thrombus formation and stability. Using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay in the Jurkat T-cell line, transient over-expression of CD37 was found to powerfully inhibit dectin-1 signalling following stimulation with its ligand, β-glucan. Over-expression of other tetraspanins also inhibited dectin-1 signalling, but did not globally inhibit receptor signalling because the platelet collagen receptor, GPVI, was unaffected. Similar to dectin-1, CLEC-2 signalling in response to its ligand, the snake venom toxin rhodocytin, was also abrogated following tetraspanin over-expression. However, stable tetraspanin over-expression only partially reduced signalling. Moreover, knockdown of the major Jurkat cell tetraspanin, CD81, and deletion of the major platelet tetraspanin, CD9, did not affect dectin-1 and CLEC-2 signalling, respectively. In summary, the importance of transient tetraspanin over-expression for dectin-1 and CLEC-2 inhibition, and the fact that any tetraspanin can inhibit, suggests that tetraspanin microdomains are disrupted by the presence of one over-expressed tetraspanin. This leads to a failure of dectin-1 and CLEC-2 signalling by a mechanism that is not clear, but suggests that tetraspanin microdomains are important for signalling by these C-type lectin-like receptors.
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Asamaphan, Patawee. "Exploring the structure and function of MelLec, a C-type lectin-like receptor that recognises DHN melanin." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=239859.
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Osorio, Olivares F. B. "Role of Syk-coupled C-type lectin receptors in T cell immunity to fungal stimuli." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/793714/.
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Innate signals are fundamental to determine the class of adaptive response against infection. The translation of microbial signatures into adaptive immunity is mediated by pattern recognition receptors (PRRs), which are expressed in specialized leukocytes called dendritic cells (DCs) and results in responses matched to the nature of the offending microbe. Here, I provide evidence that two Syk-coupled C-type lectin receptors (CLRs), Dectin-1 and Dectin-2, act in the coordination of adaptive immune responses to fungal stimuli and fungal pathogens. DC activated via Dectin-1 are strong elicitors of IL-17 production by CD4+ T cells. Results presented in this thesis demonstrate that Dectin-1 signalling in DCs results in the generation and Foxp3+-IL-17+ T cells, a cell type that defies either regulatory or Th17 classification. This process is dependent on IL-23, which is produced by DCs upon Dectin-1 ligation. In addition, this work identified an additional CLR responsible for the induction of Th17 responses during the course of fungal infections. This thesis demonstrates that Dectin-2 is a second Syk-coupled PRR involved in DC activation by fungi. In a model of Candida albicans systemic infection, Dectin-2 is essential for the induction of Th17 responses to the organism. Finally, I have generated tools to study responses of T cells specific for a fungal-associated antigen. Furthermore, I provide preliminary evidence regarding the activation, proliferation and trafficking of antigen-specific CD4+ and CD8+ T cells during systemic fungal infections.
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Sáez, Borderias Andrea. "Regulation of natural killer and cd4+T cell function by NKG2 C-type lectin-like receptors." Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7133.
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This work is centered on the study of the NKG2 C-type lectin-like receptors on NK and CD4+T cells. We provide evidence supporting that CD4+T cells specific for Human Cytomegalovirus (HCMV) may express different NK cell receptors, and demonstrate that the C-type lectin-like receptor NKG2D is expressed on cytotoxic CD4+T cells with an effector/memory phenotype, enhancing their TCR-dependent proliferation and cytokine production. A second part of the work is centered on the study of the CD94/NKG2 receptors on NK cells. We show that NKG2A can be induced on NKG2C+ NK cells upon activation with rIL-12 or when cocultured with HCMV-infected dendritic cells, and that NKG2A expression inhibits the response of NKG2C+NK clones against HLA-E-expressing targets, providing a potential regulatory feedback mechanism to control cell activation. Altogether, our results support that expression of NKG2 C-type lectin like receptors may be shaped during the course of viral infections, providing mechanisms to finely regulate both NK and CD4+T cell functions.Aquesta tesi es centra en l'estudi dels receptors lectina de tipus C NKG2 en cèl·lules Natural Killer i T CD4+. Demostrem que les cèl·lules T CD4+ específiques pel Cytomegalovirus Humà poden expressar diferents receptors NK, i que el receptor lectina tipus C NKG2D s'expressa en cèl·lules citotòxiques i de memòria, potenciant la proliferació i secreció de citocines depenent del TCR. La segona part d'aquesta tesi es centra en l'estudi de l'expressió dels receptors CD94/NKG2 en cèl·lules NK. Mostrem com l'expressió de CD94/NKG2A s'indueix en cèl·lules CD94/NKG2C+ estimulades amb IL-12 o cultivades amb cèl·lules dendrítiques infectades pel Cytomegalovirus Humà, i que l'expressió de CD94/NKG2A inhibeix la resposta de clons NK CD94/NKG2C+ envers dianes HLA-E+, constituint un possible mecanisme de feedback negatiu per controlar l'activació cel·lular. En resum, els nostres resultats demostren que l'expressió dels receptors lectina tipus C NKG2 pot ser modificada durant les infeccions víriques consitutint un possible mecanisme per regular la resposta tant de cèl·lules NK com T CD4+.
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Juneja, Puneet [Verfasser]. "Structural and functional analysis of Cysteine loop receptors, Chorismatases and a C-type like Lectin protein / Puneet Juneja." Konstanz : Bibliothek der Universität Konstanz, 2014. http://d-nb.info/1081016442/34.
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Eriksson, Magdalena Karin Matilda [Verfasser]. "C-type Lectin Receptors: from Immunomodulatory Carbohydrate Ligands to a Role in Murine Colitis / Magdalena Karin Matilda Eriksson." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1044576324/34.
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Dunstan, Kerrie Women's & Children's Health Faculty of Medicine UNSW. "Understanding the early interactions between vaccinia virus and dendritic cells - towards an enhanced vaccine vector." Awarded by:University of New South Wales. Women's and Children's Health, 2007. http://handle.unsw.edu.au/1959.4/32456.
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In the post smallpox era, vaccinia virus (VACV) has emerged as an important candidate vaccine vector. As yet, the binding receptors and entry mechanisms utilised by the two infectious forms, IMV and EEV, in dendritic cells (DCs) are unknown. We have investigated the interactions between VACV and C-type lectin receptors (CLRs) that are known to be utilised by many other viruses for binding and entry in DCs. Using a variety of CLR ligands and inhibitors we were unable to inhibit IMV or EEV binding to MDDCs and we conclude that they do not bind to CLRs. We have also investigated VACV entry in MDDCs and show that both IMV and EEV enter MDDCs via an endocytic pathway. Using a variety of drugs that inhibit cellular processes we found IMV and EEV entry to be actin- and calcium-dependent. EEV entry was also cholesterol- and energy-dependent, whereas IMV entry was only partially dependent on these factors. Both IMV and EEV colocalised with endolysosomal markers. This data suggests that EEV may enter DCs via caveolin-mediated endocytosis whereas IMV entry can occur via multiple complementary mechanisms, including endocytosis and fusion. Macropinocytosis may also constitute a minor route of entry for IMV as entry was partially inhibited by dimethyl amiloride and the virus colocalised with dextran. Finally we have provided a comprehensive flow cytometric analysis of Toll-like receptor (TLR) expression at the protein level in MDDCs and monocyte-derived Langerhans cells (MDLCs) as models for different myeloid DC subsets. We found TLR expression to be cell type-specific and MDDCs expressed the full repertoire of TLRs 1-9, including small amounts of TLR8 and TLR9 on the cell surface. The expression of these TLRs that recognise nucleic acids on the surface of cells may constitute an early warning system for signalling the presence of viral invaders that would normally subvert the function of DCs. We also found TLR expression in mature cells to be dependent on the nature of the maturation stimulus (lipopolysaccharide versus cytokine/prostaglandin cocktail) and VACV infection induced profound down-regulation of all TLRs. These findings will have important implications for the rational design of VACV-vectored vaccines.
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Porkolab, Vanessa. "Développement de ligands multivalents de nature glycomimétiques dirigés contre les récepteurs lectines de type-C." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV013/document.
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Les composantes innée et acquise de l'immunité travaillent ensemble pour assurer une protection efficace de l'organisme. Les cellules dendritiques, cellules sentinelles de l’immunité capturent via des récepteurs de surface les agents pathogènes et les présentent aux lymphocytes T pour stimuler les réponses immunitaires adaptatives spécifiques. Une famille de ces récepteurs, nommée Récepteurs Lectines de type C (CLRs) ont un rôle important dans la reconnaissance de motifs oligosaccharides des pathogènes. Leurs fonctions sont parfois détournées par certains pathogènes à leur avantage et notamment le VIH. La reconnaissance du virus par DC-SIGN, une des CLRs, favorise la dissémination du virus. A l’inverse, la langerine, autre CLR, est considérée comme une barrière naturelle au VIH. Ainsi, DC-SIGN est devenue une cible thérapeutique prometteuse mais sa reconnaissance des ligands osidiques est largement partagée par la langerine.Ce travail vise à développer des antagonistes de DC-SIGN spécifiques et de hautes affinités permettant de rivaliser avec la présentation multivalente des glycosylations de gp120 du VIH avec DC-SIGN. Une approche rationnelle a été employée dans le développement de ligands glycomimétiques hautement sélectifs pour DC-SIGN à partir de l’étude du site de liaison des deux CLRs. Puis, des plates-formes de présentations de ces glycomimétiques, de valences et de géométries différentes, sont comparées par SPR. Les améliorations spectaculaires d'affinités parfois observées sont liées à différents mécanismes d’interactions multivalentes responsables d’un phénomène d’avidité.Sur une des architecture de présentation sélectionnée (RODs), un travail de caractérisation fine des mécanismes responsables de ce gain d’affinité et/ou d’avidité a été conduit par la combinaison de plusieurs techniques biophysiques (SPR, ITC, polarisation de fluorescence et AUC). L’influence de la topologie de cette structure sur les mécanismes d’interactions est ainsi mise en évidence. Par les travaux menés, plusieurs ligands multivalents ont montré des affinités sans précédent pour DC SIGN atteignant des affinités du nanomolaire et représentant les meilleurs inhibiteurs connus à ce jour.Associé au développement d’antagonistes multivalents, une CLR (DCIR) a été identifiée récemment comme impliquée dans la dissémination du VIH, comme DC¬SIGN. Dans une perspective future de développement de glycomimétique, des travaux ont été menés sur la caractérisation structurale et fonctionnelle de ce nouvel acteur dans la problématique VIHThe innate and acquired immunity components work together to provide efficient protection of organisms. Dendritic cells, sentinel cells of the immunity, are able to capture pathogens through their receptors on the surface and they can present the antigens to lymphocytes T in order to stimulate specific adaptive immune responses. Among these receptors, there is a family named C-type lectin receptors (CLRs), which has an important role in the recognition of pathogenic oligosaccharide motifs. CLRs can be hijacked by many pathogens including HIV. DC-SIGN, one of the CLRs, interacts with the virus and promotes its dissemination. Unlike DC-SIGN, langerin, another CLR, has a protective role against the HIV infection. In this context, DC-SIGN became a promising therapeutic target but it shares ligand specificities with langerin.This work aims to develop highly specific antagonists against DC-SIGN in order to compete with the multivalent glycosylated gp120 protein of HIV. Using the study of the two lectins binding sites as starting point, a rational approach has been exploited to develop highly selective glycomimetics against DC SIGN. The SPR technique was used to investigate multivalent platforms with different valencies as well as ligand presentation in space. The amazing improvement of the affinity observed in some cases can be linked to different mechanisms of multivalent interactions, leading to an avidity phenomenon. On a selected scaffold (RODs), we characterized the different mechanisms responsible for the affinity and/or avidity gains, using a combination of different biophysical techniques (SPR, ITC, fluorescence polarization, AUC). In this work, we highlighted that the topology of this structure can influence the mechanisms of interactions. Overall, different multivalent ligands showed unique affinities for DC-SIGN, reaching the nanomolar affinity range, and they represent the best inhibitors to date.Finally, another CLR has been recently identified as one of the protein involved in the HIV infection as well as DC-SIGN. In a future perspective of glycomimetic development, structural and functional characterization has been done on this new actor involved in the HIV issue
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Benmoussa, Khaddouj. "Impact du peptide antimicrobien issu du venin de la fourmi Tetramorium bicarinatum P17 sur la polarisation et l'acquisition des fonctions antifongiques des macrophages humains vis-à-vis de Candida albicans." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30379/document.
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Les peptides antimicrobiens (PAMs) cationiques sont des molécules amphipatiques conservées chez une grande diversité d'espèces vivantes. Ils participent ainsi à la défense immunitaire de nombreux organismes incluant les bactéries, les insectes, les plantes et les vertébrés. En plus de leur activité microbicide directe dirigée contre un large spectre de pathogènes, la plupart des PAMs cationiques sont désormais connus pour exercer des fonctions immunomodulatrices sur les réponses innée et adaptative. Notre équipe a récemment découvert et isolé un nouveau PAM à partir du venin de la fourmi Tetramorium bicarinatum, nommé P17. Dans ce travail, nous avons étudié les propriétés immunomodulatrices du P17 sur la réponse immunitaire innée médiée par les macrophages. Nous nous sommes plus particulièrement intéressés à sa capacité à moduler la différenciation de macrophages dérivés de monocytes humains (h-MDM) ainsi que leurs fonctions fongicides associées vis-à-vis d'une levure opportuniste majeure Candida albicans (C. albicans). Nous avons ainsi pu mettre en évidence que le P17 oriente la différenciation des h-MDM vers un phénotype alternatif caractérisé par la surexpression des récepteurs lectine de type C (CLRs) tels que Dectine-1 et le récepteur mannose (MR). De manière intéressante, nous avons mis en évidence que la surexpression de ces deux récepteurs à la surface des h-MDM activés par le P17 nécessite la mobilisation de l'acide arachidonique et la production de leucotriène B4 (LTB4). Nous avons également démontré que ce métabolite de l'AA conduit à l'activation du récepteur nucléaire PPARƴ, facteur clé de l'activation alternative des macrophages et de l'expression des CLRs associée à ce phénotype. Au cours de ce travail, nous avons démontré que les h-MDM polarisés par le P17 présentent une meilleure capacité à éliminer C. albicans. En effet, ces h-MDM activés par le P17 ont une capacité de reconnaissance, par les CLRs Dectine-1 et MR, et de phagocytose de C. albicans augmentée. De plus, l'étude des mécanismes microbicides conduisant à l'élimination de C. albicans révèle que les h-MDM activés par le P17 produisent de fortes quantités d'espèces réactives de l'oxygène (ROS) et d'IL-1ß via l'inflammasome. Ainsi, ce travail met en évidence que l'induction de l'activité fongicide des h-MDM par le P17 est dépendante de l'axe LTB4/ PPARƴ/Dectine-1-MR. Nous avons finalement confirmé ces données in vivo sur un modèle de candidose gastro-intestinale induite chez des souris traitées par voie intra-péritonéale par P17 ou non. Les résultats obtenus ont révélé que les souris traitées par P17 étaient plus résistantes à l'infection gastro-intestinale à C. albicans. La diminution de la charge fongique au niveau du cæcum des souris traitées par le P17 est associée à une meilleure efficacité de leurs macrophages à phagocyter C. albicans, à produire des ROS et à tuer C. albicans. Ainsi, ces résultats identifient le P17 comme un activateur original des propriétés antifongiques des macrophages agissant en aval de la voie permettant l'induction de l'expression des CLRs via PPARƴ. Ces données révèlent pour la première fois l'implication d'un PAM dans le contrôle de la différenciation des macrophages et leurs fonctions microbicidesCationic antimicrobial peptides (AMPs) are evolutionary small and amphipatic conserved molecules which are involved in the immune defense of a wide range of organisms, including bacteria, insects, plants and vertebrates. Beside their direct microbicidal activity against pathogens, most of them are known to exert immunomodulatory functions on innate and adaptive immune cells. Here we evaluated the immunomodulatory properties of an original cationic AMP, named P17, discovered and isolated by our team from the ant Tetramorium bicarinatum venom. We have focused on its efficiency to modulate human monocyte-derived macrophages (h-MDM) differentiation and its capacity to provide them an antifungal activity against the main opportunistic yeast Candida albicans (C. albicans). We showed that P17 directed h-MDM polarization toward an alternative phenotype characterized by mannose (MR) and dectin-1 C-type lectin receptors (CLRs) upregulation. Interestingly, we demonstrated that this upregulation of MR and Dectin-1 in P17-treated h-MDM requires AA mobilization and leukotriene B4 (LTB4) synthesis, essential for PPAR activation. We also demonstrated that this AA metabolite led to the PPARƴ nuclear receptor activation which is a key factor of macrophages alternative activation and the associated CLRs expression. In this study, we observed that P17-activated h-MDM exhibited an improved capacity to eliminate C. albicans. Indeed, these P17-polarized macrophages displayed an increased ability to recognize and phacocyte yeasts. Furthermore, the study of microbicidal mechanisms leading to C. albicans clearance revealed that P17-activated h-MDM produced reactive oxygen species (ROS) and inflammasome-dependant IL-1ß in high amounts. These mechanisms induction in P17-polarized h-MDM was dependent on the LTB4/ PPARƴ/Dectin-1-MR axis. Finally, these data were supported by in vivo experiments demonstrating that P17-treated mice infected with C. albicans developed less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf C. albicans, to produce ROS and to kill yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts downstream the pathway leading to CLRs expression through PPARƴ activation
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Lo, Tsun Ho. "A Study on the C-Type Lectin Receptor CD302 Reveals a Role in Dendritic Cell Migration and Its Potential as A Therapeutic Target for Acute Myeloid Leukaemia." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18582.
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C-type lectin receptors (CLR) play important roles in immune cell interactions with the environment. We described CD302 as the simplest type I CLR, which is restricted to myeloid cells in human blood. CD302 colocalised with cell migratory structures including podosomes and lamellopodia, leading us to hypothesise that this CLR contributes to cell migration. This thesis describes the use of mouse models to obtain further insights into CD302 expression and immunological function. Akin to humans, mouse CD302 transcripts were highest in liver, lungs, lymph nodes (LN), spleen, and bone marrow. Detailed analysis of CD302 transcription in immune cells revealed high expression by macrophage (Mϕ), granulocytes and myeloid dendritic cells (mDC). Greater CD302 expression was found in migratory compared to resident mDC. We generated the first CD302 knockout (CD302KO) mouse and revealed a decrease in migratory mDC within LN of these animals. CD302KO migratory DC exhibited reduced in vivo migration into LN interfollicular channels, establishing a role for CD302 in mDC migration. CD169+ Mϕ in LN subcapsular sinus also showed irregular distribution. Monoclonal antibodies have been shown effective in the treatments of different haematological malignancies. However, acute myeloid leukaemia (AML) targets are currently limited so discovery of new targets would be beneficial to patients. We found expression of CD302 on the surface of blasts in the vast majority of AML patients. More importantly, CD302 was positive on leukaemic stem cells, the population responsible for relapse of the disease. Monoclonal antibodies targeting human CD302 were effective in mediating antibody dependent cell cytotoxicity and were internalised, making them amenable to toxin conjugation. Targeting CD302 with antibodies also limited in vivo engraftment of the leukaemic cell line HL-60 in NOD/SCID mice. These studies provide the foundation for studies examining CD302 as a potential therapeutic target for AML.
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Goyal, Surabhi [Verfasser]. "The Role of Single Nucleotide Polymorphisms in C-Type Lectin Receptors and the Signaling Molecules in their Pathways in Susceptibility towards developing Pulmonary Tuberculosis in an Indian Population / Surabhi Goyal." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1176636820/34.
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Eissing, Nathalie. "Charakterisierung von Subpopulationen Dendritischer Zellen und der Expression von C-Typ-Lektinrezeptoren in humanen Geweben mittels Immunfluoreszenzmikroskopie." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-78479.
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Dendritische Zellen (DCs) sind befähigt, als potenteste Antigen-präsentierende Zelle anti¬genspezifische Immunantworten zu initiieren und zu regulieren. Mittels in vivo Antigen¬beladung von spezifischen DC-Subpopulationen mit rekombinanten Antigen-gekoppelten Antikörpern gegen C-Typ-Lektinrezeptoren konnte im Mausmodell erfolgreich adaptive zelluläre und humorale Immunantworten hervorgerufen werden. Im Menschen kann dieser Ansatz therapeutisch noch nicht zum Einsatz kommen, da DC-Subpopulationen im humanen Gewebe momentan nicht ausreichend charakterisiert sind. Im Rahmen dieser Arbeit wurden humane Gewebe auf das Vorhandensein der im peripheren Blut beschriebenen DC-Subpopulationen (mDC-1 DCs: CD11c+BDCA1+, mDC-2 DCs: CD11clowBDCA3+ und pDCs: CD11c-CD123+BDCA2+) und die Expression von C-Typ-Lektinrezeptoren (DC-SIGN, MMR, Langerin, DCIR und DEC205) mittels Immun¬fluoreszenz untersucht. Anhand der vorge¬gebenen Marker im peripheren Blut konnten alle drei DC-Subpopulationen in der Milz, Thymus und Tonsillen detektiert werden. Zusätzlich konnte hier erstmalig eine vierte CD11c-CD123-BDCA2+ pDC-2 DC-Subpopulation in der Milz beschrieben werden, deren Funktion derzeit noch näher untersucht wird. Im Thymus konnte CD26 nach FACS-Analysen von Gordon Heidkamp als spezifischer Marker für mDC-2 DCs identifiziert und dies in der vorliegenden Arbeit auch durch Immun¬fluores¬zenzaufnahmen von Gewebeschnitten verifi¬ziert werden. CD26 stellt damit erstmalig einen Marker dar, der erfolgreich als alternativer Marker für BDCA3, welcher unspezifisch an Thrombomodulin bindet, zur Identifikation von mDC-2 DCs in der Immunfluoreszenz von Thymusproben eingesetzt werden könnte. Die getesteten Anti¬körper XCR-1 (monoklonal) und Clec9a (polyklonal) hingegen erschienen in der Immun¬fluoreszenz sowie in FACS-Analysen (Gordon Heidkamp) nicht geeignet. Weiterhin wurde die Expression ausgewählter C-Typ-Lektinrezeptoren (MMR, Langerin, DCIR, DC-SIGN und DEC205) im vorhandenen Gewebe näher betrachtet. Nach Auswertung der Immun¬fluoreszenzen konnte eine weit verbreitete Expression der untersuchten C-Typ-Lektin¬rezeptoren in humaner Milz und Thymus gefunden werden. Einzig hDCIR war auf vereinzelten Zellen exprimiert, und Langerin im Thymus nicht detektierbar. Um nicht verfügbare monoklonale Antikörper gegen C-Typ-Lektinrezeptoren zu produzieren und später Antigene an diese koppeln zu können, sollten lösliche Proteine einiger C-Typ-Lektinrezeptoren (humanes und murines Clec9a, Dectin-1 und -2, Langerin) produziert werden. Dabei gelang es bereits, lösliche Proteine der C-Typ-Lektinrezeptoren von humanem und murinem Dectin-1 zu generieren und diese zur weiteren Antikör¬per¬produktion einzusetzen.
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May, Frauke [Verfasser], and Bernhard [Akademischer Betreuer] Nieswandt. "The role of the (hem)ITAM-coupled receptors C-type lectin-like receptor 2 (CLEC-2) and Glycoprotein (GP) VI for platelet function: in vitro and in vivo studies in mice / Frauke May. Betreuer: Bernhard Nieswandt." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/103731140X/34.
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Ehrenspeck, Kirsten. "Charakterisierung von Stammzellen in humanen Geweben und deren Differenzierung in dendritische Zellen." Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-115812.
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Aus hämatopoetischen Stammzellen (HSCs) können sich neben allen anderen Zellen des
Immunsystems auch dendritische Zellen (DCs) entwickeln. DCs spielen eine zentrale Rolle
sowohl bei der Induktion von Immunantworten als auch bei der Aufrechterhaltung peripherer
Toleranz. Eine Beeinflussung von DCs zur therapeutischen Nutzung wäre wünschenswert,
erfordert aber ein noch tieferes Verständnis über deren Entwicklung im humanen
Organismus. Das erste Ziel dieser Arbeit war die Charakterisierung potentieller DC-Vorläuferzellen
in humanen lymphatischen Geweben. In Immunfluoreszenzaufnahmen von Thymus,
Milz und Tonsillen mit Stammzell-charakterisierenden Markern konnten sowohl die in
der Literatur als „Hämatopoetisches Stammzellkompartiment“ beschriebene Zellpopulation
als auch weitere Zwischenstufen der Entwicklungsreihe der HSCs detektiert werden. Als
Nächstes wurde untersucht, ob die im Gewebe identifizierten CD34+ Zellen in der in vitro
Kultur zu DCs differenziert werden konnten. Hierzu wurden zunächst Protokolle etabliert und
weiterentwickelt, in denen CD34+ Stammzellen des Nabelschnurbluts zu DCs gereift wurden.
In einem anschließenden Schritt wurde das Protokoll mit den besten Ausbeuten an DCs auf
Thymuszellen angewendet. Somit gelang es, aus Thymusstammzellen eine DCSubpopulation
zu generieren, die aufgrund ihrer Markerexpression den Langerhanszellen
ähnelt. Auf ihnen konnten außer Langerin auch andere C-Typ Lektinrezeptoren (Clec9a,
DCIR und CD205) detektiert werden. Diese Zellen sind daher interessante Ziele für Untersuchungen
zur Antigenbeladung von DCs und deren Präsentation an das adaptive Immunsystem.
Zur effektiven Antigenbeladung von DCs werden Antikörper gegen endozytotisch
wirksame Oberflächenmoleküle benötigt. Für deren Produktion wurden im weiteren Verlauf
der Arbeit His-tragende und Ig-Fusionsproteine von Clec9a, Langerin, Dectin-1 und Dectin-2
produziert, um diese zur Immunisierung und Antikörperproduktion einzusetzen. In Zukunft
können diese Antikörper zur Charakterisierung verschiedenster DC-Subpopulationen und
außerdem zur Antigenbeladung von DCs herangezogen werden.
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Nassanian, Hoorig. "The biology of the C-Type lectin receptor DC-SIGN." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1627802281&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Trimaglio, Giulia. "An orthotopic syngeneic mouse model to study the role of DCIR in colorectal cancer." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30053.
Full textAbstract:
Le cancer colorectal (CCR) est le troisième cancer le plus fréquent et le deuxième cancer le plus mortel dans le monde. En conséquence, de nouveaux biomarqueurs diagnostiques ainsi qu’une amélioration des traitements actuels sont nécessaires. Les tumeurs se développent dans des microenvironnements complexes où les cellules cancéreuses interagissent et modulent la réponse immunitaire locale pour persister et se multiplier. Les lectines de type C, exprimées notamment par les cellules de l’immunité, régulent la réponse anti-cancéreuse, et donc le développement tumoral. Parmi elles, l'immunorécepteur des cellules dendritiques (DCIR), a été montré comme jouant un rôle immunitaire majeur au cours des maladies infectieuses et auto-immunes. À l’inverse, son rôle dans l'immunité tumorale reste méconnu. L'analyse des données transcriptomiques de deux cohortes de patients atteints de CCR a révélé un lien entre une expression élevée de DCIR et une meilleure survie des patients. Dans ce contexte, l'objectif principal de ma thèse était de déterminer l'impact de DCIR sur le développement du CCR et la réponse immunitaire associée. Dans ce but, j’ai établi un modèle murin préclinique, orthotopique et syngénique du CCR consistant en l'injection intracaecale de cellules tumorales MC38 exprimant la luciférase (MC38-fLuc+) dans des souris C57BL/6. Le suivi de la croissance tumorale par bioluminescence a montré que, malgré l’acquisition initiale de tumeurs solides par toutes les souris, seulement 30% des souris ont développé un CCR progressif et mortel, tandis que les autres animaux ont spontanément rejeté leurs tumeurs. Aucun rejet des tumeurs CCR MC38 n'a été observé en l'absence d'immunité adaptative, ni lors de l'injection de cellules MC38 dans d'autres sites anatomiques. L'immunophénotypage par transcriptomique et cytométrie de flux a révélé que les souris développant des tumeurs progressives présentaient une réponse immunitaire pro-tumorale, définie par une signature caractéristique des lymphocytes T régulateurs, détectable peu après l'implantation tumorale, et par une infiltration de cellules myéloïdes suppressives connues pour favoriser la croissance tumorale. En revanche, les souris rejetant les tumeurs présentaient une signature pro-inflammatoire précoce et un microenvironnement anti-tumoral enrichi en lymphocytes T CD8+. Ainsi, nos résultats démontrent un rôle du microenvironnement spécifique du côlon dans la régulation de l'équilibre entre les réponses immunitaires anti- ou pro-tumorales et souligne l'importance d'utiliser des modèles murins orthotopiques pour les études in vivo. Dans la seconde partie de ma thèse, j’ai utilisé ce modèle murin de CCR pour comparer le développement tumoral dans des souris C57BL/6 de type sauvage ou des souris déficientes pour l’expression de mDcir1 (mDcir1-KO), un homologue murin du DCIR humain. Bien que l'absence de mDCIR1 n'ait aucune incidence sur le pourcentage de souris développant ou rejetant les tumeurs du CCR, nous avons observé que les animaux mDcir1-KO développaient des tumeurs plus importantes que les sauvages En accord avec ce résultat, nous avons constaté une infiltration plus faible de lymphocytes CD8+ cytotoxiques et une activation moindre des lymphocytes T CD4+ et CD8+ (c'est-à-dire T-BET+, CD44haut, CTLA-4+) dans les tumeurs des souris mDcir1-KO par rapport aux souris sauvages. Ainsi, nos données indiquent un rôle protecteur et anti-tumoral de DCIR pendant le développement du CCR, probablement dû à une dérégulation de l'équilibre existant entre la tumeur et la réponse immunitaire. Dans l'ensemble, cette étude ouvre la voie à la mise au point éventuelle de biomolécules pharmacologiques ciblant DCIR pour déclencher une réponse immunitaire anti-tumorale efficace dans le contexte du CCR et au-delàColorectal cancer (CRC) is the third most common and second deadliest cancer worldwide accounting for 900.000 deaths in 2018. Consequently, there is a strong need for new biomarkers as well as an improvement of the current treatments. Tumors develop in complex microenvironments where cancer cells constantly crosstalk with, and modulate, the local immune response to persist and replicate. C-type lectins receptors, expressed in particular by immune cells, actively regulate the immune response to cancer cells and, therefore, tumor development. Dendritic cell immunoreceptor (DCIR), a C-type lectin expressed by myeloid cells, has been shown to play a major role in immunity to infectious and autoimmune diseases. Yet, the role played by DCIR in tumor immunity remains unknown. Analysis of publicly available transcriptomic data from two cohorts of CRC patients revealed an association between high DCIR gene expression and improved survival of patients. In this context, the principal objective of my PhD thesis was to determine the role played by DCIR in the immune response during CRC development. First, I developed an orthotopic syngeneic pre-clinical CRC mouse model consisting in the intra-caecal injection of engineered MC38 tumor cells expressing firefly luciferase (MC38-fLuc+) in C57BL/6 mice. Monitoring of the tumor growth by bioluminescence revealed that, despite an initial growth of solid tumors in all the mice, only 30% of mice developed a progressive lethal CRC, while the remaining animals spontaneously rejected their solid tumor and survived more than 100 days. No rejection of tumors was observed in the absence of adaptive immunity, nor when MC38-fLuc+ cells were injected in other anatomical locations (i.e., liver and skin). Immunophenotyping by transcriptomic and flow cytometry showed that mice with progressive CRC tumors exhibited a pro-tumor immune response, characterized by a regulatory T cell pattern, discernible shortly post-tumor implantation, as well as myeloid suppressor cells that are well-known to favor tumor growth. By contrast, tumor-rejecting mice presented an early pro-inflammatory response and an anti-tumor microenvironment enriched with CD8+ T cells. Taken together, our results demonstrate a preponderant role of the colon-specific microenvironment in regulating the balance between anti- or pro-tumor immune responses and underline the importance of using orthotopic mouse models for in vivo studies. In a second part of my thesis, we used this CRC mouse model to compare the tumor development in wild-type (WT) C57BL/6 mice or mice deficient for mDcir1 (mDcir1-KO), a murine homologue of human DCIR. While the lack of mDCIR1 has no impact on the percentage of mice developing or rejecting CRC tumors, we observed that mDcir1-KO animals developed bigger tumors than their WT counterparts. In line with this result, we found a lower infiltration of cytotoxic CD8+ and decreased activation of both CD4+ and CD8+ T cells (i.e., T-BET+, CD44high, CTLA-4+) in CRC tumors from mDcir1-KO mice compared to WT mice. Altogether, our data point to a protective and anti-tumor role of DCIR during CRC development, probably due to a dysregulation of the balance existing between the tumor and the immune response. Overall, this study paves the way for the potential future development of pharmacological biomolecules targeting DCIR to trigger an efficient anti-tumor immune response in the context of CRC and beyond
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Marshall, Andrew. "The characterisation of a novel C-type lectin-like receptor MICL." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409114.
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Huysamen, Cristal. "The characterization of a novel C-type lectin-like receptor, CLEC9A." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/3060.
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Rogers, Sarah Louise. "Characterisation of C-type lectin-like receptor genes in the chicken MHC." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271871.
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Souto, Maior Mourão Sá D. "Characterisation of the C-type lectin receptor CLEC-2 : expression, ligands and functions." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302407/.
Full textAbstract:
Myeloid cells express a plethora of C-type lectin receptors (CLR) that can regulate inflammatory responses. Dectin-1 belongs to a sub-family of CLRs that possesses an extracellular C-type lectin domain (CTLD) and a single YxxL intracellular motif (hemITAM) that allows signalling via Syk kinase and induction of downstream functions. Based on consensus sequences for the CTLD and hemITAM, we identified CLEC-2 as a dectin-1-like receptor. CLEC-2 was previously characterised as a Syk-coupled platelet receptor able to induce platelet aggregation when targeted by the snake venom rhodocytin and by cells expressing the endogenous protein podoplanin. I generated monoclonal antibodies against mouse CLEC-2 and found that CLEC-2 is also expressed on lymphoid and myeloid cells, including dendritic cells (DC). Notably, treatment with LPS increases CLEC-2 expression by myeloid cells and synergises with CLEC-2 signaling to induce increased secretion of IL-10 but not IL-12. This increased IL-10 production is also observed in the serum of mice administered with anti-CLEC-2 mAb and LPS, and is dependent on the presence of macrophages and DCs. Furthermore, I generated a CLEC-2 conditional KO mouse line that will provide a tool to study CLEC-2 function in myeloid cells in vivo. Collectively, these data indicate that CLEC-2 expression is not restricted to platelets and that it plays a role on the vascular development and modulation of TLR responses.
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Mthembu, Nontobeko F. "Investigating the role of the Dendritic Cell Immunoactivating Receptor in the Immune Response during Pneumocystis murina." Master's thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32291.
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Pneumocystis jirovecii causes fungal pneumonia in immunocompromised patients and can be fatal if left untreated. The global mortality rate is estimated to be over 200 000 in AIDS patients. In non-AIDS patients there is an estimated mortality rate of 50 000 cases. This rate is increasing in developed countries, attributed to an increase in disorders which require immunotherapy. These include hematologic malignancies, organ transplant, inflammatory disorders and pre-existing lung disease. Immediate immunity is initiated by receptors that recognize pathogen associated molecular patterns on the surface of pathogenic fungi. Specifically, C-type lectin receptors (CLRs) have been shown to be the principal initiators of innate immune response during fungal infection. Limited studies have focused on the role of CLRs in Pneumocystis infection. Dectin1and Mincle have been shown to recognise Pneumocystis surface antigens with Dectin-1 recognizing β-glucans on the Pneumocystis cell wall leading to an effective immune response. However, the role of a newly described CLR, the Dendritic Cell Immunoactivating Receptor (DCAR) remains undefined. For this reason, we investigated the potential role of this receptor in a mouse model of Pneumocystis murina infection. Wild type and DCAR-deficient C57BL/6 mice were infected with P. murina organisms via intratracheal instillation. Fungal burden was measured in the lung using quantitative Polymerase Chain Reaction. DCAR-deficient mice had a significantly reduced burden compared to wild type mice at Day 7 and 14 post-infection. To identify the immune components involved in pathogen clearance in these mice we measured cellular recruitment and cytokine production at both early (48 hours) and late (7, 14 and 21 days) time points. Flow cytometry analysis showed an increase in alveolar macrophage, dendritic cells, inflammatory monocytes, eosinophils and T cell recruitment to the lung. While ELISA showed increased levels of IL-1β and IFN-γ at 48 hours, and later on in infection IL-1β and IL-12p40 levels were also elevated. Histology analysis determined the localization of the recruited cells, and v interestingly showed an increase in mucus production at day 21 in DCARdeficient mice. In conclusion, we have identified DCAR deficiency as a potential driver of protective immunity in mice during P. murina infection. This may be associated with increased levels of IL-1β in DCAR-deficient mice. Furthermore, DCAR may also be important in adaptive inflammatory response regulation, as DCAR-deficient mice have increased cellular recruitment and mucus production later in infection. The mechanism by which the deletion of this receptor affords these mice the ability to efficiently clear P. murina remains to be determined.
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Surovy, André Martin. "Toll like Receptor 2 is highly expressed in lesions of Acne Inversa and colocalizes with C-type Lectin Receptor expression /." Bern : [s.n.], 2007. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Hanske, Jonas [Verfasser]. "Investigation of the Structural Basis of Ligand Recognition of the C-Type Lectin Receptor Langerin / Jonas Hanske." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1121587895/34.
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Hanc, P. "Structural and biochemical characterisation of the C-type lectin receptor DNGR 1 and its binding to F-actin." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1472936/.
Full textAbstract:
DNGR-1 is a C-type lectin receptor that has been implicated in the regulation of endocytic trafficking and cross-presentation of dead cell-associated antigens. Dendritic cells deficient in DNGR-1 are impaired in priming effector T-cell responses against cytopathic viruses and other dead cell-associated antigens. The ligand for DNGR-1 is the polymerized form of actin (F-actin) revealed in dead cells upon loss of membrane integrity. In this study we set out to determine biophysical, biochemical, and structural properties of DNGR-1 and its interaction with F-actin. First, we describe a conformational change that occurs in the neck region of the receptor in a pH- and ionic strength-dependent manner. Notably, the conformational change happens between conditions corresponding to the extracellular environment and the environment present in the vesicles of the endosomal pathway respectively, suggesting a possible role in the spatial regulation of the DNGR-1 function. Second, in collaboration with Keichii Namba and Takashi Fujii (RIKEN Quantitative Biology Center, Osaka, Japan) we used electron cryomicroscopy to solve the structure of DNGR-1 bound to F-actin at 7.7 Å resolution. Interestingly, DNGR-1 binds into the groove between actin protofilaments, making contacts with three actin subunits that are helically arranged in the F-actin structure. We identify the residues directly involved in the interaction, confirm their contribution to the binding and demonstrate the importance of avidity of the multivalent interaction between DNGR-1 and F-actin. Additionally, in collaboration with David Sancho and Salvador Iborra (Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain) we formally demonstrate that ligand recognition is prerequisite for the biological function of DNGR-1 in dendritic cells. Third, by using heterodimeric DNGR-1 proteins in which one half of the dimer is incapable of binding to ligand, we demonstrate that DNGR-1 can bind with both ligand binding domains to a single actin filament, suggesting an exceptional flexibility of the neck region, and demonstrating an absence of rigid dimerization interface between the ligand-binding domains. In summary, we provide a comprehensive description of the structural and biophysical properties of DNGR-1, offering novel insights into its function and shedding light into innate immune mechanisms involved in recognition of cell death.
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Raziunaite, Ingrida. "Use of C-type lectin receptor probes and human monoclonal antibodies to map the dynamics of the fungal cell wall." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=238675.
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Straßer, Andreas Dominikus [Verfasser], Jürgen [Akademischer Betreuer] Ruland, and Bernhard [Akademischer Betreuer] Küster. "Analysis of C-type lectin receptor induced NF-kappaB signaling / Andreas Dominikus Straßer. Gutachter: Bernhard Küster ; Jürgen Ruland. Betreuer: Jürgen Ruland." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1052097340/34.
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Raulf, Marie-Kristin [Verfasser], Christina [Akademischer Betreuer] Strube, Bernd [Akademischer Betreuer] Lepenies, Maren von [Akademischer Betreuer] Köckritz-Blickwede, and Minka [Akademischer Betreuer] Breloer. "C-type lectin receptor recognition in parasitic infections / Marie-Kristin Raulf ; Christina Strube, Bernd Lepenies, Maren von Köckritz-Blickwede, Minka Breloer." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2021. http://d-nb.info/1237684927/34.
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Kielczewska, Agnieszka. "Natural killer cell receptors and their MHC ligand interactions in innate resistance to mouse cytomegalovirus." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111896.
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Le premier but de mon projet de doctorat a ete la caracterisation moleculaire de l'interface entre les recepteurs activateurs des cellules Natural Killer (NK) et de leurs ligands exprimes dans les cellules infectees ainsi que l'implication de cette interaction sur la reponse a l'infection par le cytomegalovirus (MCMV).J'ai tire un avantage de la variation naturelle au sein des membres lies aux recepteurs Ly49C ainsi que de la disponibilite des structures cristallines des Ly49 afin de comprendre les determinants moleculaires des interactions Ly49H-m157 et egalement identifier les residus des acides amines qui permettent de discriminer entre les recepteurs qui se lient et ceux qui ne se lient pas a m157. Mes decouvertes suggerent que le "site 2" du contact entre le CMH de classe I et Ly49 n'est visiblement pas implique dans la liaison avec m157. Au contraire, les residus localises au niveau de l'interface homodimere-recepteur seraient probablement critiques a la reconnaissance fonctionnelle de la glycoproteine m157. Notre approche fonctionnelle et de modelisation tridimensionnelle suggerent que l'architecture du dimere Ly49H est cruciale pour l'accessibilite de m157 mais non pour les molecules de CMH de classe I et relient la variabilite dans l'homodimerisation des Ly49 a la reconnaissance directe des produits pathogeniques.
Un autre mecanisme de la reponse de l'hote contre MCMV provient de l'etude de la souche de souris MA/My, laquelle, malgre l'absence du gene Ly49h ainsi que la proteine pour laquelle il code, y est hautement resistant. Des etudes anterieures ont demontre qu'une interaction epistatique entre un gene issu du groupe des genes Ly49 sur le chromosome 6 et le CMH (H2) sur le chromosome 17 est associee avec la resistance au virus. Utilisant une methode de co-culture de cellules reportrices NFAT-GFP exprimant les recepteurs activateurs Ly49 et de fibroblastes primaires infectes, j'ai montre que le recepteur activateur Ly49P des cellules NK reconnait specifiquement les cellules infectees par MCMV et que cette reconnaissance depend de la presence de l'haplotype H2k. Ce signal etait bloque par l'utilisation des anticorps anti-H2-D k mais non par anti-H2-Kk. Ces resultats indiquent l'existence d'un nouveau mecanisme des cellules NK implique dans la resistance au MCMV, lequel depend de l'interaction fonctionnelle entre le recepteur Ly49P et la molecule du MHC de classe I, H2-Dk, dans les cellules infectees par MCMV. Comme contribution directe de ce travail, nous avons demontre que la resistance chez MA/My est au moins partiellement dependante des interactions entre le recepteur Ly49P et la molecule H2-Dk modifiee par le virus dans les cellules infectees. Comme MCMV regule negativement l'expression des molecules du CMH de classe I, j'ai confirme la presence de H2-Dk dans les cellules infectees par l'utilisation d'un virus MCMV recombinant portant un gene rapporteur GFP. En permutant la plateforme peptidique de liaison, les domaines transmembranaires et intracellulaires entre les molecules H2-Db et H2-D k, j'ai demontre que la plateforme peptidique de liaison est critique pour la reconnaissance des cellules infectees. Par le criblage d'un panel de mutants MCMV portant des genes impliques dans l'evasion immune, j'ai demontre que l'infection de fibroblastes par le MCMV depourvu du gene m04 (Deltam04) abolit totalement l'activation de Ly49P. (Abstract shortened by UMI.)
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Andreev, Darja [Verfasser], Aline [Akademischer Betreuer] Bozec, and Falk [Gutachter] Nimmerjahn. "The impact of the C-type lectin receptor Mincle on osteoclast-mediated bone remodeling / Darja Andreev ; Gutachter: Falk Nimmerjahn ; Betreuer: Aline Bozec." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1222739461/34.
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Bulteau, François. "Ciblage in vivo des tumeurs via l'antigène Tn : Développement d'un cluster de Macrophage Galactose Lectine Human Macrophage Galactose-Type Lectin (MGL) Recognizes the Outer Core of Escherichia coli Lipooligosaccharide." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV048.
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L’ensemble des cellules, qu’elles soient procaryotes ou eucaryotes, est doté d’une couche de glycosylation externe riche et diversifiée, composant la face dominante immédiate en relation à leur environnement. Elles résultent de processus enzymatiques complexes liant les sucres entre eux et sur des protéines ou lipides. Des variations du « glycome » peuvent apparaître dans certaines pathologies. Les cancers sont les pathologies les plus fréquentes présentant des anomalies de ces glycosylations. Ces altérations sont quasi systématiques à la surface des cellules cancéreuses. Parmi celles-ci, l’antigène Thomsen-nouveau (Tn), un N-acétylgalactosamine (GalNAc) sur une sérine ou une thréonine, est fortement exprimé dans 90% des carcinomes mammaires ainsi que dans les cancers de la vessie, du col de l’utérus, de l’ovaire, du colon, de l’estomac et de la prostate. L’omniprésence de l’antigène Tn dans de nombreux cancers, associés à son absence dans les cellules saines, en fait une cible de choix pour la thérapie ciblée ou des vaccins synthétiques antitumoraux. Aucun anticorps ciblant l’antigène Tn n’est à ce jour disponible du fait de la difficulté à développer un anticorps avec une telle spécificité. Ainsi, nous nous sommes intéressés à une autre stratégie de ciblage, basée sur l’utilisation d’une molécule capable de reconnaître l’antigène Tn. Les lectines de type C sont une famille de protéines capables de se lier spécifiquement et de façon réversible à certains glucides, en présence de calcium. La macrophage galactose lectine (MGL) est une lectine de type C ayant une affinité très importante pour le GalNac et ses dérivés comme l’antigène Tn. Ce travail a consisté, dans un premier temps, à l’utilisation d’une forme recombinante soluble de la MGL pour valider le potentiel de cet outil pour le ciblage des cellules cancéreuses. Les différentes expériences, in vitro et in vivo, impliquant la MGL, ont démontré la capacité de cette dernière à cibler spécifiquement les tumeurs humaines via l’antigène Tn. La partie extracellulaire de la MGL est de ce fait un très bon candidat de vecteur pour le diagnostic et l’imagerie de tumeurs humaines et potentiellement pour l’administration de médicaments. Dans un deuxième temps, diverses stratégies de développement d’un outil bifonctionnel exploitant cette lectine ont été exploré. Le but était de créer une plateforme peptidique fonctionnalisable d’une part avec plusieurs domaines lectines, afin de contrôler l’affinité de reconnaissance, et d’autre part des groupements fonctionnels variable selon l’application recherché (diagnostique, thérapeutique, ...). Les différentes stratégies de couplage employées nous ont permis d’accrocher plusieurs CRD de lectine sur un support peptidique, cela en conservant l’état tridimensionnel et fonctionnel des protéines. Les caractérisations effectuées démontrent une importante augmentation de l’affinité directement fonction du nombre de lectine ajouté sur la plateforme. Ce travail ouvre la voie vers de nouveaux systèmes de ciblage des sucres modulable à façonAll cells, whether prokaryotic or eukaryotic, have a rich and diversified external glycosylation layer, forming the immediate dominant face in relation to their environment. They result from complex enzymatic processes linking sugars to each other and to proteins or lipids. Variations of the "glycome" can appear in certain pathologies. Cancers are the most frequent pathologies with abnormalities in these glycosylations. These alterations are almost systematic on the surface of cancer cells. Among them, the Thomsen-new antigen (Tn), an N-acetylgalactosamine (GalNAc) on a serine or threonine, is strongly expressed in 90% of mammary carcinomas as well as in cancers of the bladder, cervix, ovary, colon, stomach and prostate. The ubiquitous presence of the Tn antigen in many cancers, combined with its absence in healthy cells, makes it a target of choice for targeted therapy or synthetic anti-tumor vaccines. No antibody targeting the Tn antigen is currently available because of the difficulty in developing an antibody with such specificity. Thus, we were interested in an alternative targeting strategy, based on the use of a molecule capable of recognizing the Tn antigen. C-Type lectins are a family of proteins capable of specifically and reversibly binding to certain carbohydrates in the presence of calcium. Macrophage galactose lectin (MGL) is a C-type lectin with a high affinity for GalNac and its derivatives such as the Tn antigen. This work consisted, initially, in the use of a soluble recombinant form of MGL to validate the potential of this tool for the targeting of cancer cells. The different experiments, in vitro and in vivo, involving MGL, demonstrated the latter's ability to specifically target human tumors via the Tn antigen. The extracellular portion of MGL is therefore a very good vector candidate for the diagnosis and imaging of human tumors and potentially for drug delivery. In a second step, various strategies for the development of a bifunctional tool exploiting this lectin were explored. The goal was to create a peptide platform that could be functionalized on one hand with several lectin domains, in order to control recognition affinity, and on the other hand with functional groups that could be variable according to the application (diagnostic, therapeutic, ...). The different coupling strategies employed allowed us to attach several lectin CRDs to a peptide support, while preserving the three-dimensional and functional state of the proteins. The characterizations carried out show a significant increase in affinity directly related to the number of lectins added to the platform. This work paves the way to new customizable sugar-targeting systems
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Lorenz, Viola [Verfasser], and Bernhard [Gutachter] Nieswandt. "Cellular regulation of the hemITAM-coupled platelet receptor C-type lectin-like receptor 2 (CLEC-2): In vitro and in vivo studies in mice / Viola Lorenz ; Gutachter: Bernhard Nieswandt." Würzburg : Universität Würzburg, 2018. http://d-nb.info/1163536202/34.
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Andersson, Katja. "Intercellular protein transfer and regulation of inhibitory NK cell receptor accessibility /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-183-8/.
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Lindenwald, Dimitri Leonid [Verfasser], Bernd [Akademischer Betreuer] Lepenies, Silke [Akademischer Betreuer] Rautenschlein, Roland [Akademischer Betreuer] Lang, and Tina Sørensen [Gutachter] Dalgaard. "Veterinary Glycoimmunology: Generation and in vitro application of a novel sheep C-type lectin receptor fusion protein library / Dimitri Leonid Lindenwald ; Gutachter: Tina Sørensen Dalgaard ; Bernd Lepenies, Silke Rautenschlein, Roland Lang." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2020. http://d-nb.info/1224882903/34.
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Monteiro, João Gonçalo Tereno Verfasser], Bernd [Akademischer Betreuer] [Lepenies, Ralph Akademischer Betreuer] Goethe, and Reinhard [Akademischer Betreuer] [Schwartz-Albiez. "A C-type lectin receptor (CLR)-Fc fusion protein library as a toolbox to detect novel CLR ligands and the interplay of CLR/virus interactions / João Gonçalo Tereno Monteiro ; Bernd Lepenies, Ralph Goethe, Reinhard Schwartz-Albiez." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2019. http://d-nb.info/119175278X/34.
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Monteiro, João Gonçalo Tereno [Verfasser], Bernd [Akademischer Betreuer] Lepenies, Ralph [Akademischer Betreuer] Goethe, and Reinhard [Akademischer Betreuer] Schwartz-Albiez. "A C-type lectin receptor (CLR)-Fc fusion protein library as a toolbox to detect novel CLR ligands and the interplay of CLR/virus interactions / João Gonçalo Tereno Monteiro ; Bernd Lepenies, Ralph Goethe, Reinhard Schwartz-Albiez." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2019. http://d-nb.info/119175278X/34.
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Aouar, Besma. "Altération de la production d'interféron de type I par les cellules plasmacytoïdes dendritiques : ciblage de la voie de signalisation BCR-like." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5021.
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Les cellules dendritiques plasmacytoïdes sont les productrices majeures d’IFN de type I dans l’organisme humain. Durant les infections virales chroniques, telles que l’infection par le Virus de l’Hépatite C, les pDCs sont fonctionnellement altérées. L’efficacité dans plus de 50% des cas du traitement par IFN-α, utilisé jusqu’à récemment, suggère que la modulation de la fonction des pDCs serait une cible intéressante pour le traitement HCV. Les pDCs reconnaissent l’ARN du HCV par les récepteurs Toll-like, et disposent de plus d’un set de récepteurs dits régulateurs qui régulent la production d’IFN-I. L’activation de ces RR inhibe la production d’IFN-I par les pDCs stimulées par les agonistes de TLR7/9. Nous montrons ici que la glycoprotéine d’enveloppe E2 du HCV est un nouveau ligand des RR BDCA2 et DCIR des pDCs, et que cette liaison est responsable de l’inhibition d’IFN-I via l’activation de la voie de signalisation BCR-like. Nous avons ensuite voulu restaurer la production d’IFN-I dans les pDCs en ciblant les kinases décrites de la voie BCR-like, Syk et Mek. En inhibant Syk, l’IFN-I n’a été que partiellement restauré par les concentrations subliminales de l’inhibiteur; les concentrations élevées de cet inhibiteur ont bloqué la production d’IFN-I, suggérant l’implication de Syk dans la voie TLR7/9 comme montré pour l’activation des TLR dans les macrophages. En inhibant MEK, la restauration d’IFN-I est efficace. Les mécanismes de cette restauration sont explorés. Le ciblage pharmacologique de la signalisation BCR-like constituerait une nouvelle approche intéressante pour étudier les mécanismes de modulation de l’activation des pDCs dans les conditions physiopathologiquesPlasmacytoid dendritic cells are major producers of type I IFN in human organism. During chronic viral infections, such as Hepatitis C Virus infection, pDCs are functionally impaired. More than 50% efficiency of IFN-α treatment, until recently used, suggested that modulation of pDC function could be an important target for HCV treatment. pDCs recognize HCV RNA by Toll-like receptors, and dispose of a set of so-called regulatory receptors that regulate IFN-I production. Crosslinking of these RR such as BDCA-2 and ILT7 has been shown to inhibit IFN-I production by pDCs stimulated with TLR7/9 agonists. In this work we show that HCV envelope glycoprotein E2 is a novel ligand of pDC RR, BDCA-2 and DCIR, and that this binding is responsible for IFN-I inhibition via the activation of the BCR-like pathway. Then we assayed to restore IFN-I in pDCs with crosslinked RR by targeting well-known kinases of BCR-like pathway, Syk and Mek. When inhibiting Syk, IFN-I was only partially restored by subliminal concentrations of Syk inhibitor; high concentrations of Syk inhibitor effectively blocked IFN-I production, suggesting involvement of Syk in the TLR7/9 pathway as it was already demonstrated in TLR activation in macrophages. When inhibiting MEK, the restoration of type I IFN was effective. The underlying mechanisms leading to the restoration are further explored. Pharmacological targeting of BCR-like signaling may constitute an attractive new approach to study mechanisms of modulation of pDC activation in pathophysiological conditions
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Tsai, Shih-Han, and 蔡仕翰. "C-type lectin receptors on Dendritic cells and their influence on allergic response." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/99564277092907689941.
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碩士臺北醫學大學
醫學科學研究所
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Dendritic cells (DCs), a professional antigen-presenting cell type, are able to shape the immune response bridging the innate immunity and adaptive response. Now, allergic problem is more and more serious. Allergic diseases, such as asthma and food allergy, are characterized by elevated IgE/Th2 response and failed tolerance. C-type lectin receptors (CLRs) on DCs play a crucial role in determining either immunity or tolerance via recognition of specific carbohydrate moieties, but their role in the development and regulation of allergic responses has remained elusive. It was hypothesized that allergens containing complex glycan structures are natural ligands for CLRs on DCs, affecting subsequent DC’s and adaptive immune responses. I further hypothesized that differential DC responses to allergens can be found in a cohort of study subjects. Using monocyte-derived DCs (MDDCs) as a model, it was found that the carbohydrate structures on two model allergens, Der p 2 and BG60, are very important for the interaction with a member of the CLRs, DC-SIGN, and this interaction leads to the activation of Raf-1 kinase and p65 of NF-?羠 subunit to trigger the TNF-?? gene expression in MDDCs. Also, I found that MDDCs from certain individuals were not able to respond to allergen stimulation, which was associated with the lack of Raf-1 activation. Interestingly, MDDCs from all study individuals showed the induction of osteopontin, an anti-inflammatory and pro-inflammatory cytokine, following allergen stimulation. These results suggest that the glycan structures of allergens may serve as the “molecular pattern” in functional interaction with CLRs, and that the differential responses of MDDCs from different subjects may be a critical contributing factor to the expression of allergic responses.
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Hsu, Tzu-Yun, and 許資筠. "The Role of Syk-coupled C-type Lectin Receptors in Influenza Virus Infection." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/86078503124665890193.
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"Regulation of natural killer and cd4+T cell function by NKG2 C-type lectin-like receptors." Universitat Pompeu Fabra, 2009. http://www.tesisenxarxa.net/TDX-0612109-142651/.
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Wang, Lin, and 王玲. "Implications of TNF-α and C-type Lectin Receptors in the Pathogenesis of Dengue Hemorrhagic Fever." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/14715585026145927121.
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博士長庚大學
臨床醫學研究所
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Dengue virus (DEN) causes dengue fever (DF) or fatal dengue hemorrhagic fever (DHF), which threatens two-thirds of countries worldwide in the context of global warming. Dengue has been prevalent for many years in Kaohsiung. However, the pathogenesis of DHF is not clearly demonstrated. Immune dysregulation may play an important role on the pathogenesis of DHF. This study was conducted to study whether tumor necrosis factor α (TNF-α) and/or TNF receptors and C-type lectin receptor (DC-SIGN; CD209) polymorphism (SNP) were involved in the pathogenesis of DHF, and whether that variations in the CD209 gene might have a broad influence on viral replication and host immune responses. TNF-α produced by host immune response can activate regional macrophages; to increase vascular permeability systemically, resulting in the occurrence of DHF. We investigated dynamic changes among TNF-α, membrane TNF receptors (mTNFR1 and mTNFR2), and sTNFR1 and sTNFR2 levels in patients with DHF and DF during a DEN-2 outbreak in southern Taiwan in 2002. Patients with DHF showed the lowest levels of mTNFR1 and mTNFR2 expression on the surface of neutrophils. Multivariate analysis showed that a decrease in levels of mTNFR1 expression was the only factor significantly different between patients with DHF and those with DF. DEN is transmitted by mosquito bite in which the C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells for immune responses. We collected DNA samples in a case-control design to test whether the genetic variation in the promoter region of CD209 (-336 A/G; rs4804803) was associated with DHF. A strong association between GG/AG genotypes of rs4804803 and the risk of DHF was found when compared with DF, other non-dengue febrile illnesses (OFI) and controls. Moreover, using peripheral dendritic cells from normal individuals, we found that AG genotype with a higher cell surface DC-SIGN expression had a significantly higher TNF-α, IL-12p40, and IP-10 production, but a lower viral replication than those with AA genotype in response to DEN-2 infection In conclusion, these studies showed the involvement of innate immune responses at TNFR and CD209 levels in the pathogenesis of DHF. Lower membranous and higher soluble TNFR expression were correlated to DHF, and DC-SIGN polymorphisms were correlated to the susceptibility of DHF. Clarification of the gene polymorphisms of CD209, and cytokine TNF-α and TNFR expression in the DHF susceptibility may contribute to prevention and treatment of DHF.
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May, Frauke. "The role of the (hem)ITAM-coupled receptors C-type lectin-like receptor 2 (CLEC-2) and Glycoprotein (GP) VI for platelet function: in vitro and in vivo studies in mice." Doctoral thesis, 2011. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-65383.
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Die Thrombozytenaktivierung und –adhäsion sowie die nachfolgende Thrombusbildung ist ein essentieller Prozess in der primären Hämostase, der aber auch irreversible Gefäßverschlüsse und damit Herzinfarkt oder Schlaganfall verursachen kann. Erst kürzlich wurde beschrieben, dass der C-type lectin-like receptor 2 (CLEC-2) auf der Thrombozytenoberfläche exprimiert wird, jedoch wurde für diesen Rezeptor noch keine Funktion in den Prozessen der Hämostase und Thrombose gezeigt. In der vorliegenden Arbeit wurde die Rolle von CLEC-2 in der Thrombozytenfunktion und Thrombusbildung im Mausmodel untersucht. In dem ersten Teil dieser Arbeit konnte gezeigt werden, dass die Behandlung von Mäusen mit dem neu generierten monoklonalen Antikörper INU1, der gegen murines CLEC-2 gerichtet ist, zu dem vollständigen und hochspezifischen Verlust des Rezeptors in zirkulierenden Thrombozyten führte, ein Prozess, der als „Immundepletion“ bezeichnet wird. Die CLEC-2-defizienten Thrombozyten waren nicht mehr durch den CLEC-2-spezifischen Agonisten Rhodozytin aktivierbar, während die Aktivierung durch alle anderen getesteten Agonisten nicht beeinträchtigt war. Dieser selektive Defekt führte unter Flussbedingungen ex vivo zu stark verminderter Aggregatbildung der Thrombozyten. Außerdem zeigten in vivo-Thrombosestudien, dass die gebildeten Thromben instabil waren und vermehrt embolisierten. Infolgedessen war die CLEC-2 Defizienz mit einem deutlichen Schutz vor arterieller Thrombose verbunden. Außerdem ließ die in INU1-behandelten Mäusen beobachtete variable Verlängerung der Blutungszeit auf einen moderaten hämostatischen Defekt schließen. Diese Ergebnisse zeigen zum ersten Mal, dass CLEC-2 in vitro und in vivo signifikant zur Thrombusstabilität beiträgt und eine essentielle Rolle in der Hämostase und arteriellen Thrombose spielt. Daher stellt CLEC-2 eine potentiell neue antithrombotische Zielstruktur dar, die in vivo inaktiviert werden kann. Diese in vivo-Herabregulierung von Thrombozytenoberflächenrezeptoren könnte einen vielversprechenden Ansatz für zukünftige antithrombotische Therapien darstellen. Der zweite Teil dieser Arbeit behandelte den Effekt einer Doppelimmundepletion der immunoreceptor tyrosine-based activation motiv (ITAM)- und hemITAM-gekoppelten Rezeptoren Glykoprotein (GP) VI und CLEC-2 auf Hämostase und Thrombose mittels einer Kombination der GPVI- beziehungsweise CLEC-2-spezifischen Antikörper JAQ1 und INU1. Eine Einzeldepletion von GPVI oder CLEC-2 in vivo beeinträchtigte nicht die Expression und Funktion des jeweils anderen Rezeptors. Eine gleichzeitige Behandlung mit beiden Antikörpern führte jedoch zu dem nachhaltigen Verlust der GPVI- und CLEC-2-vermittelten Signale in Thrombozyten, während andere Signalwege nicht betroffen waren. Im Gegensatz zu den Einzeldefizienzen, wiesen die GPVI/CLEC-2 doppeldefizienten Mäuse einen schwerwiegenden Blutungsphänotyp auf. Außerdem führte die Behandlung zu einer starken Beeinträchtigung der arteriellen Thrombusbildung, die die Effekte der Einzeldefizienzen weit übertraf. Von Bedeutung ist auch, dass gleiche Ergebnisse in Gp6-/- Mäusen gefunden wurden, die mittels INU1-Behandlung CLEC-2-depletiert wurden. Dies veranschaulicht, dass der Blutungsphänotyp nicht durch Sekundäreffekte der kombinierten Antikörperbehandlung hervorgerufen wurde. Diese Daten deuten darauf hin, dass GPVI und CLEC-2 sowohl unabhängig voneinander als auch gleichzeitig in vivo von der Thrombozytenoberfläche herabreguliert werden können und lassen unerwartete redundante Funktionen der beiden Rezeptoren in Hämostase und Thrombose erkennen. Da beide Rezeptoren, GPVI und CLEC-2, als neue antithrombotische Zielstrukturen diskutiert werden, könnten diese Ergebnisse wichtige Auswirkungen auf die Entwicklung von anti-GPVI oder anti-CLEC-2-basierenden Antithrombotika habenPlatelet activation and adhesion results in thrombus formation that is essential for normal hemostasis, but can also cause irreversible vessel occlusion leading to myocardial infarction or stroke. The C-type lectin-like receptor 2 (CLEC-2) was recently identified to be expressed on the platelet surface, however, a role for this receptor in hemostasis and thrombosis had not been demonstrated. In the current study, the involvement of CLEC-2 in platelet function and thrombus formation was investigated using mice as a model system. In the first part of the thesis, it was found that treatment of mice with a newly generated monoclonal antibody against murine CLEC-2 (INU1) led to the complete and highly specific loss of the receptor in circulating platelets (a process termed “immunodepletion”). CLEC-2-deficient platelets were completely unresponsive to the CLEC-2-specific agonist rhodocytin, whereas activation induced by all other tested agonists was unaltered. This selective defect translated into severely decreased platelet aggregate formation under flow ex vivo; and in vivo thrombosis models revealed impaired stabilization of formed thrombi with enhanced embolization. Consequently, CLEC-2 deficiency profoundly protected mice from occlusive arterial thrombus formation. Furthermore, variable bleeding times in INU1-treated mice indicated a moderate hemostatic defect. This reveals for the first time that CLEC-2 significantly contributes to thrombus stability in vitro and in vivo and plays a crucial role in hemostasis and arterial thrombosis. Thus, CLEC-2 represents a potential novel anti-thrombotic target that can be functionally inactivated in vivo. This in vivo down-regulation of platelet surface receptors might be a promising approach for future anti-thrombotic therapy. The second part of the work investigated the effect of double-immunodepletion of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemITAM-coupled receptors, platelet glycoprotein (GP) VI and CLEC-2, on hemostasis and thrombosis using a combination of the GPVI- and CLEC-2-specific antibodies, JAQ1 and INU1, respectively. Isolated targeting of either GPVI or CLEC-2 in vivo did not affect expression or function of the respective other receptor. However, simultaneous treatment with both antibodies resulted in the sustained loss of GPVI and CLEC-2 signaling in platelets, while leaving other activation pathways intact. In contrast to single deficiency of either receptor, GPVI/CLEC-2 double-deficient mice displayed a dramatic hemostatic defect. Furthermore, this treatment resulted in profound impairment of arterial thrombus formation that far exceeded the effects seen in single-depleted animals. Importantly, similar results were obtained in Gp6-/- mice that were depleted of CLEC-2 by INU1-treatment, demonstrating that this severe bleeding phenotype was not caused by secondary effects of combined antibody treatment. These data suggest that GPVI and CLEC-2 can be independently or simultaneously down-regulated in platelets in vivo and reveal an unexpected functional redundancy of the two receptors in hemostasis and thrombosis. Since GPVI and CLEC-2 have intensively been discussed as potential anti-thrombotic targets, these results may have important implications for the development of novel, yet save anti-GPVI or anti-CLEC-2-based therapies