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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Markers of chronic immune activation and T-cell function in hyperglycaemia

Nyambuya, Tawanda Maurice January 2017 (has links)
Thesis (MTech (Biomedical Sciences))--Cape Peninsula University of Technology, 2017. / Type 2 diabetes mellitus (T2DM) is a chronic inflammatory condition characterised by hyperglycaemia; continuous activation of T-lymphocytes and immune dysregulation. Although the exact mechanisms of these phenomena are not fully understood, there is strong evidence suggesting the involvement of T-cells in the chronic inflammatory environment which could predispose diabetics to infections and thrombotic events. The effect of hyperglycaemia on cells of the innate immune system in T2DM has been well described and implicated in the progression of the disorder and the development of its complications. However, studies investigating the adaptive immune response still remain scarce and controversial. Thus, investigating T-cells in hyperglycaemic conditions could provide further insight into the immune dysfunction observed in T2DM and assist in identifying pathways which could be targeted in the disease management and treatment. Therefore, this study aimed to investigate chronic immune activation by measuring the expression of T-cell activation markers in hyperglycaemia and compare the results to those in the normoglycaemic group.
2

Investigation of Novel LncRNAs Harboring Risk SNPs Associated with Celiac and Crohn's Disease

Shearer, Alyssa January 2022 (has links)
Long non-coding RNAs (lncRNAs) have been implicated as important regulators of inflammation through various mechanisms in both the innate and adaptive immune systems of mice and humans. The majority of SNPs identified by GWAS to be associated with autoimmune disorders lie within non-coding areas of the genome, including genes for lncRNAs. To identify lncRNAs with relevancy to inflammation and autoimmunity, a discovery pipeline was used to find lncRNAs differentially expressed in TLR4 activated murine macrophages, conserved between mice and humans, and harboring GWAS identified SNPs associated with autoimmune disorders. Two of the six candidate lncRNAs identified, Lnc15 and Lnc13, are decreased in activated macrophages and are associated with both celiac and Crohn’s disease. To further explore the regulation and influence of these two lncRNAs during inflammation and its resolution, a variety of in vitro and in vivo techniques were utilized, including novel mouse knockout models. An investigation of Lnc15 was conducted in cells of both the innate and adaptive immune system, where the dominant isoform of Lnc15 was identified to be a ~1.4 kb transcript localized to the cytoplasm in both murine macrophages and T cells. Analysis of Lnc15 regulation was conducted in activated murine macrophages, focused on TLR signaling. Through stimulating macrophages with specific TLR ligands, Lnc15 was found to be decreased by TLR2, TLR3, and TLR4 signaling, likely dependent upon both MYD88 and TRIF. While not dependent upon NF-κB, protein synthesis is required for TLR induced decreases in Lnc15 levels. Conversely, activated neutrophils significantly increase Lnc15 levels, although the mechanism of regulation is not yet known. Mice lacking Lnc15 globally were found to be more susceptible to DSS induced colitis, which is likely dependent upon a defect in the innate immune system. In the adaptive immune system, Lnc15 was found to be specifically upregulated in Tregs compared to other T cell subsets. Lnc15 deficient Tregs had a reduced suppressive capacity in vitro, but not in vivo in a T cell induced model of colitis. These findings suggest Lnc15 plays a role in Treg suppressive capacity under certain conditions, but the exact mechanism influenced remains to be identified. Additionally, overexpression of Lnc15 in a murine T cell line resulted in a decrease in Rorc expression. A Lnc15 RNA pulldown experiment identified USF2, a transcription factor known to regulate Rorc expression, and UBR5, a ubiquitin-protein ligase known to influence RORyt stability, as protein interactors of Lnc15. These data indicate that Lnc15 can influence aspects of RORyt biology, which implicates Lnc15 as a regulator of either the plasticity between Tregs and Th17 cells, or Treg ability to suppress inflammatory Th17 cells. An investigation into Lnc13 regulation by disease relevant cytokines was conducted with a series of macrophage stimulation experiments. Lnc13 was found to be positively regulated by cytokines with an anti-inflammatory capacity, including IL-6, IL-4 and IL-10. When Lnc13 deficient macrophages were polarized, a higher expression of Il6 was detected in both M1 and M2 macrophages, suggesting a regulatory connection between Lnc13 and IL-6 across macrophage activation states. Previously identified Lnc13 target genes displayed a quicker transcriptional response to LPS stimulation in Lnc13 deficient macrophages. Additionally, when the Lnc13 mouse was crossed with the DQ8 transgenic mouse model and challenged to gluten, the ileum tissue of Lnc13 deficient mice expressed higher amounts of Il12 and Ifng, cytokines directly relevant to celiac disease. These findings provide support for Lnc13 as a novel regulator of macrophage response and cytokine expression in response to disease relevant stimuli.
3

Immunopathological mechanisms of inflammatory reaction in Chinese patients with type 2 diabetic nephropathy: clinical and in vitro studies.

January 2007 (has links)
Ho, Wing-Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 115-131). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abbreviations --- p.iii / Abstract --- p.v / 摘要 --- p.ix / Publications --- p.xii / Table of Contents --- p.xiv / Chapter 1. --- General Introduction / Chapter 1.1. --- Diabetes Mellitus (DM) and Diabetic Nephropathy --- p.1 / Chapter 1.1.1. --- "Prevalence, Diagnosis and Classification of DM" --- p.1 / Chapter 1.1.2. --- Type 2 DM and its Complications: Diabetic Nephropathy --- p.5 / Chapter 1.1.3. --- Diagnosis and Impacts of Diabetic Nephropathy --- p.7 / Chapter 1.1.4. --- Current Treatment of Type 2 DM and Diabetic Nephropathy --- p.8 / Chapter 1.2. --- Cytokines and Chemokines --- p.9 / Chapter 1.2.1. --- Types and Properties --- p.9 / Chapter 1.2.2. --- Cytokines and chemokines in Type 2 DM and Diabetic Nephropathy --- p.13 / Chapter 1.3. --- T Lymphocyte Costimulatory Molecules --- p.15 / Chapter 1.3.1. --- Types and Properties --- p.15 / Chapter 1.3.2. --- T Lymphocyte Costimulatory Molecules in Type 2 DM and Diabetic Nephropathy --- p.16 / Chapter 1.4. --- Adhesion Molecules --- p.18 / Chapter 1.4.1. --- Types and Properties --- p.18 / Chapter 1.4.2. --- Adhesion Molecules in Type 2 DM and Diabetic Nephropathy --- p.20 / Chapter 1.5. --- Intracellular Signaling Pathways --- p.21 / Chapter 1.5.1. --- Types and Properties --- p.21 / Chapter 1.5.2. --- Intracellular Signaling Pathways in Type 2 DM and Diabetic Nephropathy --- p.23 / Chapter 1.6. --- Objectives of Our Study --- p.24 / Chapter 2. --- Materials and Methods / Chapter 2.1. --- Materials --- p.26 / Chapter 2.1.1. --- "Patients, Control Subjects and Blood Samples" --- p.26 / Chapter 2.1.2. --- Cell Line --- p.27 / Chapter 2.1.3. --- "Cell Culture Media, Buffers and Other Reagents" --- p.28 / Chapter 2.1.4. --- "Recombinant Human Cytokines, Inhibitors and Other Stimulators" --- p.30 / Chapter 2.1.5. --- Reagents and Buffers for Flow Cytometric Analysis --- p.31 / Chapter 2.1.5.1. --- Cytometric Bead Array (CBA) of Cytokines and Chemokines --- p.33 / Chapter 2.1.5.2. --- Multiplex Fluorescent Bead Immunoassay (FBI) of Soluble Adhesion Molecules --- p.33 / Chapter 2.1.5.3. --- Phosphorylation State Analysis of Signaling Molecules --- p.34 / Chapter 2.1.5.4. --- Immunofluorescent Staining of Cell Surface Molecules --- p.36 / Chapter 2.1.6. --- Reagents and Buffers for Protein Array Analysis --- p.37 / Chapter 2.1.7. --- "Reagents and Buffers for 3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenylytetrazolium Bromide (MTT) Assay" --- p.37 / Chapter 2.1.8. --- Reagents for Human Enzyme-Linked Immunosorbent Assay (ELISA) --- p.37 / Chapter 2.2. --- Methods --- p.38 / Chapter 2.2.1. --- Whole Blood Culture Experiments --- p.38 / Chapter 2.2.2. --- "Collection of Serum and Plasma, and Purification of PBMC from EDTA-Blood" --- p.39 / Chapter 2.2.3. --- HK-2 Cell Cultures --- p.39 / Chapter 2.2.4. --- HK-2 Cell Treatments --- p.40 / Chapter 2.2.5. --- Flow Cytometric Analysis --- p.41 / Chapter 2.2.5.1. --- CBA of Cytokines and Chemokines --- p.41 / Chapter 2.2.5.2. --- Multiplex FBI of Soluble Adhesion Molecules --- p.41 / Chapter 2.2.5.3. --- Phosphorylation State Analysis of Signaling Molecules --- p.42 / Chapter 2.2.5.4. --- Immunofluorescent Staining of Cell Surface Molecules --- p.43 / Chapter 2.2.6. --- Protein Array Analysis --- p.44 / Chapter 2.2.7. --- MTT Assay --- p.44 / Chapter 2.2.8. --- ELISA --- p.45 / Chapter 2.2.9. --- Statistical Analysis --- p.46 / Chapter 3. --- "Clinical Study on the Expressions of Cytokines, Chemokines, Co-stimulatory Molecules, Phosphorylated Signaling Molecules in Patients with Diabetic Nephropathy" / Chapter 3.1. --- Introduction --- p.47 / Chapter 3.2. --- Results --- p.49 / Chapter 3.2.1. --- Demographic Data of Participants --- p.49 / Chapter 3.2.2. --- Expression Profile in Plasma of Patients --- p.49 / Chapter 3.2.2.1. --- Cytokines and Chemokines --- p.49 / Chapter 3.2.2.2. --- Soluble Costimulatory Molecules --- p.55 / Chapter 3.2.2.3. --- Soluble Adhesion Molecules --- p.55 / Chapter 3.2.2.4. --- "Correlations between Plasma Concentrations of Cytokines, Chemokines, soluble Costimulatory Molecules and soluble Adhesion Molecules and UACR in Patients" --- p.60 / Chapter 3.2.3. --- Effects ofTNF-α and IL-18 on the ex vivo Production from Whole Blood of Patients --- p.65 / Chapter 3.2.3.1. --- Ex vivo Production of Cytokines and Chemokines --- p.65 / Chapter 3.2.3.2. --- Ex vivo Production of Soluble Costimulatory Molecules --- p.70 / Chapter 3.2.4. --- "Expression of Phosphorylated p38 MAPK, JNK and ERK in PBMC of Patients" --- p.73 / Chapter 3.3. --- Discussion --- p.77 / Chapter 3.3.1. --- "Cytokines, Chemokines and Diabetic Nephropathy" --- p.77 / Chapter 3.3.2. --- Soluble Costimulatory Molecules and Diabetic Nephropathy --- p.80 / Chapter 3.3.3. --- Soluble Adhesion Molecules and Diabetic Nephropathy --- p.83 / Chapter 3.3.4. --- Intracellular Signaling and Diabetic Nephropathy --- p.87 / Chapter 4. --- In vitro Study on the Signal Transduction Mechanism Regulating the Expression of CCL2 and Cell Surface Adhesion Molecules in Tumour Necrosis Factor (TNF)-α-Stimulated HK-2 Cells / Chapter 4.1. --- Introduction --- p.90 / Chapter 4.2. --- Results --- p.93 / Chapter 4.2.1. --- Expression Profile of Cytokines and Chemokines of TNF-α-activated HK-2 Cells --- p.93 / Chapter 4.2.2. --- "TNF-α Upregulated CCL2, ICAM-1 and VCAM-1 Expression in HK-2 Cells" --- p.95 / Chapter 4.2.3. --- "TNF-α Activated the p38 MAPK, JNK and ERK Signaling Pathways in HK-2 Cells" --- p.96 / Chapter 4.2.4. --- Cytotoxicity of MAPK Inhibitors --- p.96 / Chapter 4.2.5. --- "Effects of p38 MAPK, JNK and ERK Inhibitors on TNF-α-induced Expressions of CCL2, ICAM-1 and VCAM-1" --- p.100 / Chapter 4.3. --- Discussion --- p.102 / Chapter 5. --- Conclusion and Future Prospects / Chapter 5.1. --- Conclusion --- p.107 / Chapter 5.2. --- Future Prospects --- p.111 / References --- p.115
4

Modulatory actions of HMGB1 on TLR4 and rage in the primary afferent sensory neuron

Allette, Yohance Mandela 02 April 2015 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Damage Associated Molecular Patterns (DAMPs) act largely as endogenous ligands to initiate and maintain the signaling of both inflammatory processes and the acquired immune response. Prolonged action of these endogenous signals are thought to play a significant role sterile inflammation which may be integral to the development of chronic inflammation pathology. HMGB1 (High Mobility Group Box 1) is a highly conserved non-acetylated protein which is among the most important chromatin proteins and serves to organize DNA and regulate transcription. Following stress or injury to the cell, hyperacetylation of lysine residues causes translocation of HMGB1 and eventual release into the extracellular environment where it can take the form of a DAMP and interact with cell types bearing either the Receptor for Advanced Glycation End-products (RAGE) or Toll-Like Receptor 4 (TLR4). Activation of these surface receptors contribute directly to both acute and chronic inflammation. This project investigated the role of HMGB1 through its receptors Receptor for Advanced Glycation End-products (RAGE) and Toll-Like Receptor 4 (TLR4) as it pertained to the development of chronic inflammation and pathology in small diameter, nociceptive sensory neurons. It was demonstrated that the neuronal signaling associated with exposure to HMGB1 is dependent upon the ligands conformational states, as the state dictates its affinity and types of neuronal response. Neuronal activation by bacterial endotoxin or the disulfide state of HMGB1 is dependent on TLR4 and the associated signaling adapter protein, Myeloid differentiation primary response gene 88 (MYD88). Interruption of the receptor-mediated signaling cascade associated with MyD88 was shown to be sufficient to mitigate ligand-dependent neuronal activation and demonstrated significant behavioral findings. Further downstream signaling of HMGB1 in the neuron has yet to be identified, however important steps have been taken to elucidate the role of chronic neuroinflammation with hopes of eventual translational adaptation for clinical therapeutic modalities.
5

Functional caracterisation of formyl peptide receptor 3 and its peptidic ligand F2L in the development of physiological and pathological inflammatory responses / Caractérisation fonctionnelle du récepteur FPR3 et de son ligand peptidique F2L dans le développement de réponses inflammatoires physiologiques et pathologiques

Devosse, Thalie 22 December 2010 (has links)
Tous les êtres vivants présentent un arsenal de défenses contre les pathogènes, et la réponse inflammatoire constitue le processus initial de cette défense, qui s’achève par la réparation des tissus lésés. Paradoxalement, un processus inflammatoire prolongé est également associé à de nombreuses pathologies comme l’athérosclérose, l’asthme, les maladies auto-immunes mais aussi certains cancers. Le recrutement excessif de leucocytes au site de l’inflammation est un processus commun à ces pathologies. Dès lors, la compréhension et la maîtrise du phénomène complexe et finement orchestré de la migration sélective des populations leucocytaires, appelée chimiotactisme, sont des enjeux majeurs de la recherche médicale contemporaine. <p>Les récepteurs aux peptides formylés bactériens et mitochondriaux (FPRs) forment la première famille de récepteurs chimiotactiques identifiée. Elle comprend trois membres, FPR1, 2 et 3, présentant un haut niveau de similitude et partageant certains de leurs multiples ligands. Le troisième membre de ce groupe, FPR3, reste actuellement le moins bien connu. Récemment, un agoniste de FPR3, affin et spécifique, a été identifié dans le laboratoire. Il s’agit du peptide F2L, qui correspond aux 21 premiers acides aminés de la protéine intracellulaire HEBP1.<p><p>Dans le cadre de ce travail de thèse, nous nous sommes attelé à la caractérisation approfondie du récepteur FPR3 et son ligand peptidique F2L. <p>Dans un premier temps, et à l’aide d’anticorps validés dans le cadre de ce travail, nous avons montré que le peptide F2L induit le chimiotactisme d’un ensemble de populations leucocytaires qui expriment FPR3, dont les sous-populations de macrophages des poumons, du colon et de la peau, les éosinophiles et les cellules dendritiques plasmacytoïdes. Cette distribution suggère, pour FPR3, une fonction dans la réponse inflammatoire. <p>Nous avons pu montrer ensuite que F2L peut être généré par la protéolyse de son précurseur, HEBP1, sous l’action de la cathepsine D des macrophages. La cathepsine D est une aspartique protéase lysosomiale impliquée dans l’homéostasie cellulaire, les processus apoptotiques et inflammatoires physiologiques et pathologiques, et dans le développement tumoral. Il s’agit désormais d’identifier dans quel compartiment et sous quelles conditions F2L est produit et sécrété. <p>Enfin, parallèlement à ces travaux, nous avons démontré que la cathepsine G, une sérine protéase contenue dans les granules azurophiles des neutrophiles, active également le récepteur FPR3. Des résultats préliminaires suggèrent un mode d’activation alternatif du récepteur, impliquant la protéolyse d’un troisième partenaire et la génération d’un agoniste actuellement non identifié. <p><p>Le couple FPR3-F2L semble dès lors impliqué dans l’induction ou la résolution de la réponse inflammatoire en recrutant les éosinophiles, monocytes, macrophages et cellules dendritiques au site de la lésion. / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished
6

Intracellular signaling mechanisms regulating the mast cell-mediated allergic inflammation.

January 2007 (has links)
Ng Sin Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 120-135). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abbreviations --- p.iii / Abstract --- p.vi / 撮要 --- p.ix / Publications --- p.xi / Table of contents --- p.xiii / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- Allergic Diseases and Allergic Inflammation --- p.1 / Chapter 1.1.1 --- Prevalence of Allergic Diseases --- p.1 / Chapter 1.1.2 --- Common Allergic Diseases: Allergic Asthma --- p.1 / Chapter 1.1.3 --- Common Allergic Diseases: Atopic Dermatitis --- p.2 / Chapter 1.1.4 --- Allergic Inflammation --- p.3 / Chapter 1.2 --- The Inflammatory Leukocytes: Mast Cells and Eosinophils --- p.6 / Chapter 1.2.1 --- Characteristics of Mast Cells --- p.6 / Chapter 1.2.2 --- Mast Cells Distribution --- p.8 / Chapter 1.2.3 --- Mast Cells Subtypes --- p.8 / Chapter 1.2.4 --- HMC-1 Cells --- p.9 / Chapter 1.2.5 --- Characteristics of Eosinophils --- p.12 / Chapter 1.3 --- Adhesion Molecules in Allergic Diseases --- p.15 / Chapter 1.3.1 --- Adhesion Molecules and Leukocyte Migration --- p.15 / Chapter 1.3.2 --- Selectin --- p.17 / Chapter 1.3.3 --- Intermolecular Adhesion Molecules --- p.17 / Chapter 1.3.4 --- Integrin --- p.18 / Chapter 1.4 --- Cytokines and Chemokines in Allergic Diseases --- p.18 / Chapter 1.4.1 --- IL-6 --- p.20 / Chapter 1.4.2 --- CXCL1 --- p.21 / Chapter 1.4.3 --- CXCL8 --- p.21 / Chapter 1.4.3 --- CCL2 --- p.22 / Chapter 1.5 --- Intercellular Signal Transduction Pathways in Inflammation --- p.24 / Chapter 1.5.1 --- RAS-RAF-mitogen-activated Protein Kinases --- p.24 / Chapter 1.5.2 --- Janus Kinase/ Signal Transducers and Activators of Transcriptions Pathway --- p.27 / Chapter 1.5.3 --- Nuclear Factor-KB Pathway --- p.29 / Chapter 1.5.4 --- Phosphoinositide 3-Kinase Pathway --- p.31 / Chapter 1.6 --- Aims and Scope of the Study --- p.33 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Materials --- p.35 / Chapter 2.1.1 --- HMC-1 Cell Line --- p.35 / Chapter 2.1.2 --- Human Buffer Coat --- p.35 / Chapter 2.1.3 --- Human Mast Cell Chymase and TLR ligands --- p.35 / Chapter 2.1.4 --- Media and Reagents for Cell Culture --- p.36 / Chapter 2.1.5 --- Reagents and Buffers for Purification of Human Eosinophils --- p.37 / Chapter 2.1.6 --- Reagents and Buffers for Flow Cytmetry --- p.38 / Chapter 2.1.7 --- Reagents and Buffers for Total RNA Extraction --- p.41 / Chapter 2.1.8 --- Reagents and Buffers for Reverse Transcription-Polymerase Chain Reaction (RT-PCR) --- p.42 / Chapter 2.1.9 --- Reagents and Buffers for Agarose Gel Electrophoresis --- p.45 / Chapter 2.1.10 --- Reagents and Buffers for Sodium Dodecyl Sulfate -polyacrylamide Gel Electrophoresis (SDS-PAGE) --- p.46 / Chapter 2.1.11 --- Reagents and Buffers for Western Blot Analysis --- p.48 / Chapter 2.1.12 --- Chemotactic Migration --- p.51 / Chapter 2.1.13 --- Signaling Transduction Inhibitors and Protein Synthesis Inhibitors --- p.51 / Chapter 2.2 --- Methods --- p.52 / Chapter 2.2.1 --- HMC-1 Cell Cultures --- p.52 / Chapter 2.2.2 --- Purification of Buffy Coat Eosinophils by MACS and Eosinophil Culture --- p.52 / Chapter 2.2.3 --- Total Cellular RNA Extraction --- p.53 / Chapter 2.2.4 --- RT-PCR --- p.54 / Chapter 2.2.5 --- Agarose Gel Electrophoresis --- p.55 / Chapter 2.2.6 --- Flow Cytometry Analysis --- p.55 / Chapter 2.2.7 --- Protein Array Analysis of Cytokine Release --- p.57 / Chapter 2.2.8 --- Quantitative Analysis ofCXCLl --- p.58 / Chapter 2.2.9 --- Total Protein Extraction --- p.58 / Chapter 2.2.10 --- SDS-PAGE --- p.58 / Chapter 2.2.11 --- Western Blot Analysis --- p.59 / Chapter 2.2.12 --- Chemotactic Migration Analysis --- p.60 / Chapter 2.2.13 --- Statistical Analysis --- p.60 / Chapter Chapter 3 --- Effects of Mast Cell Derived Chymase on Human Eosinophils and the Signaling Mechanisms: Implication in Allergic Inflammation / Chapter 3.1 --- Introduction --- p.61 / Chapter 3.2 --- Results --- p.65 / Chapter 3.2.1 --- Effects of Chymase on Eosinophil Survival --- p.65 / Chapter 3.2.2 --- Effects of Chymase on the Adhesion Molecule Expression of Eosinophils --- p.68 / Chapter 3.2.3 --- Effects of Chymase on the Chemokinetic Properties on Eosinophils --- p.71 / Chapter 3.2.4 --- Effects of Chymase on the Release of Chemokines and IL-6 from Eosinophils --- p.73 / Chapter 3.2.5 --- Signal Transduction Mechanism Involved in Regulating Chymase-induced Effects on Eosinophils --- p.78 / Chapter 3.3 --- Discussion --- p.71 / Chapter Chapter 4 --- TLR-mediated Effects and Signal Transduction Mechanism of HMC-1 Cells / Chapter 4.1 --- Introduction --- p.92 / Chapter 4.2 --- Results --- p.97 / Chapter 4.2.1 --- Expression of Adhesion Molecules on HMC-1 Cells --- p.95 / Chapter 4.2.2 --- TLR Expression Profile on HMC-1 Cells --- p.97 / Chapter 4.2.3 --- Effects of TLR ligands on HMC-1 Cell Adhesion Molecule Expressions --- p.99 / Chapter 4.2.4 --- TLR7-induced Phosphorylation of ERK and Effects of PD98059 on TLR7-induced ERK Phosphorylation --- p.104 / Chapter 4.2.5 --- Effect of TLR7 Ligand on HMC-1 Cells Cytokine Release --- p.108 / Chapter 4.3 --- Discussion --- p.110 / Chapter Chapter 5 --- Conclusions and Future Perspectives / Chapter 5.1 --- Conclusions --- p.115 / Chapter 5.2 --- Future Perspectives --- p.117 / References --- p.120 / Appendix --- p.136
7

Impact of clinical factors on inflammaging and Toll-like receptors responses in old age

Compte, Nathalie 17 December 2014 (has links)
Le vieillissement s’accompagne d’une altération globale des fonctions physiologiques notamment celles de l’immunité :on parle « d’immunosénescence ». Ce processus se traduit entre autre par l’installation d’un état inflammatoire chronique caractérisé par une augmentation des taux sériques de cytokines telles que l’interleukine(IL)-6 et des protéines de la phase aigüe. Cet état proinflammatoire serait incriminé dans le déclin des fonctions physiologiques, la fragilité et les syndromes gériatriques. Par ailleurs, les maladies cardiovasculaires, la dépression et l’infection chronique par le Cytomégalovirus (CMV) sont également associés à un état inflammatoire chronique. La prévalence de ces comorbidités étant importante chez les patients gériatriques, ces maladies pourraient donc contribuer à l’association observée entre marqueurs de l’inflammation et les syndromes gériatriques.<p>Les infections représentent un problème majeur en gériatrie. Les cellules du système immunitaire inné jouent un rôle important dans les défenses contre les agents pathogènes. La reconnaissance de ceux-ci par les cellules dendritiques, les macrophages ou les monocytes fait intervenir une série de molécules telles que les récepteurs de la famille Toll (TLR). Certains travaux suggèrent que la fonction des cellules de l’immunité innée pourrait être perturbée chez les individus âgés mais ces données restent controversées.<p>Dans ce travail, nous souhaitons aborder les hypothèses suivantes :<p>•\ / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished
8

Transcription factors in the development of Th9 cells

Goswami, Ritobrata 07 October 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Cytokines are extracellular proteins that mediate communication between cells. T helper cell subsets secrete specific cytokines that promote the development of inflammation. Naïve CD4+ T cells activated and primed in the presence of TGF-β and IL-4 predominantly secrete IL-9, a cytokine that acts as a growth factor for T cells and mast cells, and promotes allergic inflammation. The transcription factors downstream of TGF-β- and IL-4-induced signaling, and that are required for expression of IL-9, have not been previously examined. IL-4 signaling induces the expression of IRF4, a transcription factor required for the development of Th9 cells. IL-4 and the downstream-activated factor STAT6 also interfere with the expression of the transcription factors T-bet and Foxp3 that inhibit IL-9 production from Th9 cells. The TGF-β pathway induces the expression of PU.1, another transcription factor required for Th9 development. In the absence of PU.1 there is increased association of a subset of histone deacetylases to the Il9 promoter. In developing Th9 cells, PU.1 can bind to the Il9 promoter and recruit specific histone acetyltransferases, including Gcn5 to the Il9 gene. Gcn5 functionally contributes to Il9 expression as IL-9 production is diminished when Gcn5 expression is reduced, although other cytokines expressed by Th9 cells are not affected. While Gcn5 is not required for PU.1 or IRF4 binding to Il9, it is important for controlling histone acetylation at the Il9 gene promoter. Together these data define the STAT6-dependent transcription factor network in Th9 cells and the mechanism of PU.1-dependent IL-9 induction in Th9 cells and might indicate that targeting IL-9 regulation is a viable approach for treating inflammatory disease.
9

Régulation de la réponse immunitaire adaptative par les cellules dendritiques conventionnelles et inflammatoires

Hespel, Cindy 19 March 2012 (has links)
Les cellules dendritiques décrites depuis les années 60 ont instantanément capté l’intérêt des scientifiques qui ont pu mettre en évidence leur rôle indispensable dans l’initiation des réponses immunitaires adaptatives et leur ont attribué le surnom « d’adjuvant naturel ». De manière surprenante, les cellules dendritiques conventionnelles sont aussi indispensables dans le maintien de la tolérance et peuvent présenter naturellement ou acquérir une fonction suppressive. Parmi les mécanismes capables de contrôler les réponses de type Th1, l’enzyme indoléamine 2,3-dioxygénase (IDO) a particulièrement attiré notre attention. Cette enzyme initiant la première étape de dégradation du tryptophane et sa transformation en catabolites toxiques nommés kynurénines semble jouer un rôle primordial dans la tolérance envers les fœtus allogéniques et dans l’échappement des tumeurs à la réponse immunitaire. <p><p>Nous avons donc évalué le rôle de l’IDO exprimé par les cellules dendritiques conventionnelles dans la régulation de la réponse adaptative. L’ensemble des résultats in vitro révèle que l’expression d’IDO par les cellules dendritiques conventionnelles au cours de leur maturation n’influence celle-ci ni au niveau de l’expression des molécules MHCII et CD86 ni au niveau de leur capacité à induire la différenciation des lymphocytes Th1. De plus, dans des modèles d’immunisation in vivo par transfert de cellules dendritiques conventionnelles, l’expression d’IDO par ces dernières ne semble pas leur permettre de contrôler les réponses T CD4+ ou T CD8+. Cependant, nous avons constaté qu’en absence de lymphocytes T régulateurs naturels l’expression d’IDO par les cellules de l’hôte constitue un mécanisme important limitant la réponse Th1. <p><p>En cas d’inflammation ou d’infection, de profonds changements affectent le compartiment des cellules dendritiques où émerge une nouvelle sous-population qui se différencie à partir des monocytes inflammatoires du sang et qui portent le nom de cellules dendritiques inflammatoires. Alors que les cellules dendritiques conventionnelles forment une population hétérogène où chaque sous-population semble se spécialiser dans la différenciation d’un type particulier de lymphocyte T auxiliaire ou « helper », la littérature met en évidence une incroyable plasticité phénotypique des cellules dendritiques inflammatoires qui les rend capables de s’adapter au type d’infection auquel l’hôte est confronté en intervenant directement au niveau de la réponse innée mais aussi en participant à l’initiation et la régulation de la réponse T la plus adaptée. <p><p>Le modèle d’immunisation in vivo par transfert de cellules dendritiques inflammatoires présentant l’antigène OVA nous a permis de démontrer la capacité de ces cellules à promouvoir spécifiquement la différenciation de lymphocytes de type Th17. Dans le cadre d’une immunisation classique par un adjuvant, le défaut dans le recrutement des cellules dendritiques inflammatoires dans les souris CCR2-/- nous a permis de mettre en évidence le rôle indispensable des cellules dendritiques inflammatoires pour l’induction des réponses Th1 et Th17. Finalement, envisageant la possibilité d’une collaboration entre DCs conventionnelles et inflammatoires pour l’induction des réponses de type Th17, nous avons constaté que le transfert de cellules dendritiques conventionnelles présentant l’antigène KLH provoque in vivo le recrutement de cellules dendritiques inflammatoires au sein des ganglions drainant le site d’injection et que ces cellules dendritiques inflammatoires semblent nécessaires pour la différenciation des lymphocytes de type Th17.<p><p>La collaboration entre cellules dendritiques via le transfert d’informations pourrait être un évènement fréquent permettant de réguler la réponse immunitaire adaptative à trois niveaux principaux :au niveau quantitatif, en augmentant le nombre de cellules dendritiques présentant l’antigène, au niveau de la durée, en transmettant l’information aux cellules dendritiques inflammatoires colonisant les tissus desquels les cellules dendritiques conventionnelles disparaissent après activation/maturation et au niveau qualitatif, en combinant les propriétés intrinsèques des différentes sous-populations de cellules dendritiques afin de réguler la différenciation des lymphocytes T helper.<p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
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Etude du rôle de l'Interleukine 17A dans la réponse immunitaire contre Mycobacterium tuberculosis dans le modèle murin et applications vaccinales / Role of Interleukin-17A in the immune response to Mycobacterium tuberculosis in mice and vaccine applications

Freches, Danielle 28 June 2012 (has links)
La tuberculose est une maladie contagieuse causée par une infection avec M. tuberculosis. Son incidence globale élevée, des traitements longs et coûteux, l’apparition de souches résistantes aux antibiotiques disponibles et la co-infection avec le VIH en font un problème de santé publique de premier plan. En effet, l’Organisation Mondiale de la Santé estime qu’un tiers de la population mondiale est infectée de façon latente par M. tuberculosis. La mise au point d’un vaccin efficace serait un des moyens de mieux contrôler cette maladie et pour cela une meilleure compréhension de la réponse immunitaire contre M. tuberculosis est indispensable. Il est cependant clair que la réponse Th1 et l’IFN-γ sont essentiels pour la protection contre M. tuberculosis. Cependant, beaucoup d’aspects de cette immunité restent encore indéterminés dont le rôle de la réponse IL-17A. Dans ce travail, nous avons analysé la susceptibilité de souris génétiquement déficientes pour la sous-unité A du récepteur de l’IL-17A à une infection par M. tuberculosis. Nous montrons que la signalisation induite par l’IL-17A est indispensable pour le contrôle à long terme de l’infection et ce malgré une augmentation de la réponse IFN-γ.<p>Dans la deuxième partie du travail, nous avons analysé l’effet de la neutralisation de l’IL-12 sur la susceptibilité de souris préalablement vaccinées avec le Bacille de Calmette et Guérin (BCG) à une infection par M. tuberculosis. La neutralisation de l’IL-12 a été réalisée en utilisant un auto-vaccin anti-IL-12. Les résultats ont confirmé le rôle essentiel de l’IL-12 dans la protection contre une infection primaire avec M. tuberculosis ;ils ont cependant également permis de démontrer que la neutralisation de l’IL-12 n’exerce qu’un effet très modeste sur la protection conférée par le vaccin BCG. Ainsi, la diminution d’IFN-γ induite par la neutralisation de l’IL-12 semble être compensée par une augmentation de la production de TNF-α, d’IL-6 et plus particulièrement de l’IL-17A.<p>En conclusion, notre travail indique que la réponse IL-17A est importante pour la protection contre M. tuberculosis que ce soit lors d’une infection primaire ou en cas de réponse mémoire. De plus, nos observations renforcent l’idée de plus en plus communément admise que l’IFN-γ seul n’est pas suffisant pour protéger contre M. tuberculosis/Tuberculosis is a contagious disease caused by infection with M. tuberculosis. Due to its high global incidence, the length and cost of antibiotic treatments, the emergence of antibiotics resistant strains and co-infection with HIV, Tuberculosis remains a major health problem. In addition, World Health Organization estimates that one-third of the world population is latently infected with M. tuberculosis. The development of an efficient vaccine could lead to a better control of this disease, but for that purpose a better understanding of the protective immune response against M. tuberculosis is essential. It is clear that Th1 immunity and IFN-γ play an essential role in protection against M. tuberculosis. However, numerous aspects of this immune response are still poorly understood, such as the role of the IL-17A response. <p>In this work, we have analyzed the susceptibility to M. tuberculosis infection in mice genetically inactivated in the IL-17 receptor.A subunit. We have shown that IL-17A signalling is required for long-term control of M. tuberculosis infection, even if the IFN-γ response is increased. <p>In the second part of this work, we have analyzed the effect of IL-12 in resistance against M. tuberculosis infection and in the protection conferred by the BCG vaccine. For that purpose, IL-12 was neutralized using an anti-IL-12 auto-vaccine. Our results confirm the essential role of IL-12 in the protection against a primary M. tuberculosis infection. Nevertheless, these results also demonstrate that IL-12 neutralization only marginally affect the protection conferred by the BCG vaccine. Indeed, the decreased IFN-γ production induced by IL-12 neutralization in BCG-vaccinated mice seems compensated by increased TNF-α, IL-6 and more specifically IL-17A production.<p>In conclusion, our data indicate that the IL-17A response is important in protection against M. tuberculosis, both in primary infection or in the case of memory responses. Moreover, our results emphasize the emerging idea that a functional IFN-γ response alone is not sufficient to protect against M. tuberculosis.<p><p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

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