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1
Morley, Sarah Louise. "Molecular aspects of the humoral immune response against Neisseria meningitidis." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424765.
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Wong, Lik-wai Benny, and 黃力偉. "Immune response and signaling mechanisms of Helicobacter pylori induced gastritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43224313.
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Prabhala, Rao H. "Two different molecular pathways of immunomodulation by retinoids and carotenoids." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184676.
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Epidemiological studies suggest that both retinoid and carotenoid intakes are inversely correlated with the incidence of human cancers. Animal studies show that both retinoids and carotenoids inhibit tumor cell growth. Both retinoids and carotenoids activate the cytotoxicity function of macrophages in animal experiments. The purpose of this study is to evaluate the molecular mechanism for 13-cis retinoic acid (13-cRA) and beta-carotene (BC) induced immunomodulation which could explain their anti-cancer affects. The effects of 13-cRA and BC were studied on various subpopulations of T-lymphocytes both in vitro and in vivo. For in vitro studies, peripheral blood mononuclear cells (PBMC) were incubated with test compounds at clinically achievable concentrations (10⁻⁸M) for three days. Then the cells were stained with monoclonal antibodies followed by the analysis of flow cytometer. For in vivo studies, PBMC were collected from Barrett's esophagus or oral leukoplakia patients during treatment with 13-cRA (1mg/kg/day) or BC (30 mg/day), respectively. Then the cells were analyzed with monoclonal antibodies and flow cytometry. Both compounds showed the capability of stimulating different subpopulations of T-lymphocytes. 13-cRA predominantly increased the number of T-helper cells, their interleukin 2 (IL-2) receptors and their response to mitogens. Whereas, BC elevated the number of Natural Kill (NK) cells, their IL-2 receptors and their cytotoxicity against K562 target cells. Though these immunomodulatory effects appeared to be unaffected by the presence and cytotoxic functions of macrophages, cytokines seemed to have an important role in the retinoid- and carotenoid-induced immunomodulation. Plasma levels of IL-2 and tumor necrosis factor (TNF) measured by ELISA procedures were increased in patients treated for two months with 13-cRA and BC respectively. Anti-IL-2 and anti-TNF antibodies blocked the retinoic- and carotenoid-induced immunomodulation in in vitro studies. These results indicate that 13-cRA, activating T-helper cells with IL-2 production, and BC, activating NK cells with TNF release, induced immunostimulation which might be able to provide the anti-cancer affects in part seen in epidemiological studies.
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Swanson, Kara M., and n/a. "The bovine mammary gland immune response to Streptococcus uberis and its bacteriocins." University of Otago. Department of Microbiology & Immunology, 2008. http://adt.otago.ac.nz./public/adt-NZDU20080407.112302.
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Bovine mastitis is one of the most costly dairy-based diseases worldwide. Streptococcus uberis is a prevalent causative organism of mastitis and resides naturally in the environment of the dairy cow making prevention of the disease difficult. New strategies need to be developed to control this pathogen. However, a fundamental understanding of the complex relationships that exist between the cow, the pathogen and the environment are required in order to advance the development of prevention strategies. Microarray technology was used to evaluate the complex transcriptional changes which occur in the bovine mammary gland following the onset of clinical S. uberis mastitis. A 22,000 bovine cDNA microarray indicated that S. uberis mastitis led to the up-regulation of 1,283 genes and the down-regulation of 1,237 genes by greater than 1.5 fold. Gene ontology analysis demonstrated that S. uberis mastitis was typically associated with the up-regulation of genes that are involved in the immune response and homeostasis and a down-regulation of genes involved in lipid metabolism. Quantitative real-time analyses for a selection of genes associated with the immune response validated the microarray data. Mammary epithelial cell cultures did not show an increase in the expression of any of these immune factors in response to the same S. uberis strain used to induce clinical mastitis. This indicates that the expression of immune-related genes by mammary epithelial cells may be initiated by host factors and not S. uberis.
The application of bacteriocins, proteinaceous antimicrobials produced by bacteria which typically inhibit the same or closely-related species to that of the producer organism, has been suggested as one possible approach in the control of mastitis. S. uberis have been previously found to commonly produce bacteriocin-like inhibitory substances (BLIS). The BLIS activities of a set of fifteen S. uberis and S. bovis strains were assessed. The results confirmed the prolific and varied nature of BLIS production by S. uberis and S. bovis and also indicated that these strains may commonly produce more than one inhibitory agent. This survey of BLIS production led to the detection and characterisation of a novel circular bacteriocin, uberolysin, produced by S. uberis strains 233 and 42. The structural gene of uberolysin was subsequently identified in nine (64%) of the fifteen test strains.
Multiplex PCR analysis showed that 93% of 158 New Zealand S. uberis isolates contained the structural genes of at least one of the four known S. uberis bacteriocins (uberolysin, nisin U, ubericin A and ubericin 63). However, no apparent direct association was identified between any one of these bacteriocin-related loci and apparent ability to cause mastitis on New Zealand dairy farms. The uberolysin structural gene was detected in 91% of the isolates and this widespread distribution prompted the advancement and evaluation of a potential role for uberolysin in immunomodulation within the bovine mammary gland. Two different preparations of uberolysin were found to have different stimulatory effects on monocytes, neutrophils and epithelial cells. The less highly purified preparation appeared to diminish the production of TNF-α by monocytes in the presence of a bacterial stimulus and to decrease neutrophil phagocytosis. By contrast, the relatively more highly purified preparation of uberolysin itself induced a significant immune response by monocytes. Consistent with this, the purer preparation of uberolysin induced an increase in C3, IL-1β, IL-6, IL-8, the β-defensin LAP, the acute-phase protein MSAA, the calcium-binding protein S100A12 and TLR2 by quantitative real-time analysis.
Although currently only two S. uberis bacteriocins (uberolysin and nisin U) have been fully characterised, the present study has shown that this species may be an important source of novel antimicrobials. Furthermore, bacteriocin production by S. uberis may have an immunomodulation role within the mammary gland. A better understanding of the complex immune response initiated at the onset of clinical S. uberis mastitis and of the role that bacteriocins have in S. uberis pathogenesis may lead to development of improved strategies to combat this disease.
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Chakravarti, Sumone. "The cloning and functional characterisation of murine phosphatidylinositol 3-kinase gamma." Title page, table of contents and abstract only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phc4355.pdf.
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Mooney, John. "Molecular and cellular aspects of the humoral immune response in periodontal disease and other related conditions." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321510.
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Sumaria, Nital. "The relevance of specific molecular and cellular effectors during murine cytomegalovirus infection." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0116.
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[Truncated abstract] The design and development of effective anti-viral immunotherapies requires a comprehensive understanding of the cellular and molecular processes that are involved in the generation and regulation of immune responses. The fundamental objective of the immune system is to successfully complete the task of eliminating/controlling the invading pathogen without causing overt pathology. Cytomegaloviruses (CMVs) are large DNA viruses that are able to evade immune attack and persist lifelong within the host. In a healthy host, CMV causes an asymptomatic infection, but in instances of decreased immune functions, such as in newborns, acquired immunodeficiency syndrome (AIDS) patients and transplant recipients, the infection can result in serious morbidity and mortality. Thus, human CMV (HCMV) is a clinically important pathogen and an understanding of the pathogenesis, mechanisms of immune subversion and, importantly the cascade of immune events that ensue following infection is highly relevant. The studies presented in this thesis have provided useful insight into various aspects of viral immunity and it is hoped that they will assist in the design of more effective therapies against viruses of clinical importance. Genetic variability in humans can greatly influence anti-viral immune responses and the outcome of viral infection. ... Furthermore, these studies provide novel evidence that NK cells are also crucial for the control of virus in some organs of susceptible mice during early acute infection. The data reveals that both NK cells and CD8+ T cells utilise perforin- and IFN-? dependent control of MCMV. Furthermore, these studies provide novel evidence that protection mediated by Ly49H+ NK cells in resistant mice is dependent on perforin. Chapter 3 focuses on the biological relevance of Grz during MCMV infection. These studies found that GrzA and GrzB are essential components of the machinery involved in limiting MCMV during acute infection. These analyses also provide the first evidence suggesting that GrzM plays a role, albeit minor, in controlling MCMV replication. Furthermore, the current studies suggest that Grz can mediate direct antiviral activities independent of the induction of cell death in conjunction with perforin. Interestingly, in the absence of both GrzA and GrzB (GrzAB), mice were as susceptible to MCMV infection as perforin-deficient mice. However, unlike perforin-deficient mice, GrzAB-deficient mice controlled and survived the infection. In Chapter 4 the roles of perforin, GrzA and GrzB in anti-viral immunity and immunopathology during MCMV infection were examined. These studies show that NK cell-derived perforin is required to eliminate infected targets as well as activated effector cells, suggesting that NK cells are crucial not only in defensive immunity but also in limiting the immune activation that follows MCMV infection. In summary, the studies presented in this thesis define the significant role played by specific effector molecules in limiting MCMV replication during different stages of this viral infection. Furthermore, these studies provide novel evidence that perforin, GrzA and GrzB play distinct roles in defensive immunity and limiting immunopathology during MCMV infection.
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Andrews, Daniel Mark. "Effects of murine cytomegalovirus infection on dendritic cell functionality and natural killer cell responses." University of Western Australia. Centre for Ophthalmology and Visual Science, 2004. http://theses.library.uwa.edu.au/adt-WU2005.0003.
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Cytomegaloviruses (CMVs) are ubiquitous in nature, having evolved over many millenia with their hosts. While in healthy hosts most infections with CMV are asymptomatic, the virus can cause severe disease in immunocompromised hosts. Thus, the increase in organ transplantation and the HIV/AIDS pandemic have established human CMV (HCMV) as a clinically important pathogen. Indeed, HCMV infections are now the major cause of morbidity and mortality among immunocompromised patients, which has led to more research targeting CMV for effective anti-viral treatment. The discovery that cytomegaloviruses encode several genes which are involved in immune escape has prompted a new area of research, aimed at understanding immune escape mechanisms for exploitation as potential anti-viral therapeutics. By targeting the viral proteins directly, or their receptors in the host, it may be possible to treat CMV disease by agonistic/antagonistic therapy. The first part of this thesis describes the first demonstration of anti-NK1.1 staining in situ to identify NK cells using a modified in vivo perfusion/fixation method. Using this method, we have compared the acute NK1.1+ cellular response to wild-type MCMV infection in the visceral organs of genetically susceptible intra-NK complex recombinant BALB.B6-CT6 (Cmv1s, NK1.1+) mice with resistant C57B⁄J (Cmv1r, NK1.1+) and BALB.B6-Cmv1r mice (Cmv1r, NK1.1+). Expression of viral antigens and the consequences of infection on other cellular subsets, were also analyzed in this study. The data show that in susceptible mice (Cmv1s) MCMV infection is predominent in the marginal zone of splenic white pulp, resulting in local changes in various cellular constituents, including macrophages, NK cells and DC. In the liver, distinct foci of infection were comprised of large numbers of macrophages and NK1.1+ cells surrounding infected cytomegalic cells. In resistant mice (Cmv1r), 6 MCMV infection predominantly affected the red-pulp of the spleen and was associated with increased accumulation of NK1.1+ cells and macrophages at sites of viral infection
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Kodituwakku, Aruna Poojitha. "Antigen specific B cells in the immune response to Haemophilus influenzae type b PRP conjugate vaccine /." Title page, table of contents and summary only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phk769.pdf.
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Khong, Andrea. "Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0260.
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Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the worlds population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long in its host and can be reactivated following withdrawal of immune control. As such, it remains a serious clinical concern in individuals who are immunocompromised, such as newborns and neonates, transplant and/or chemotherapy recipients, and HIV/AIDS patients. CMV also has the ability to cause immunosuppression, the mechanisms of which include defective antigen presentation to T cells and interference with haematopoiesis in the bone marrow (BM). Due to strict species specificity, murine CMV (MCMV) provides a relevant model for the study of CMV modulation of the immune system in vivo in its natural host. The type I interferons (IFNs) represent a major family of cytokines involved in the early response to MCMV infection. Their anti-viral activity and regulation of NK cell activation and cytotoxicity are of significant interest in the context of MCMV infection, as genetic resistance to MCMV is mediated by the ability of Ly49H+ NK cells to directly recognise and lyse infected cells. Chapter 2 comprises an analysis of acute MCMV infection in the absence of type I IFN activity. These studies were conducted in IFNAR1 and IFNAR2 deficient mice, which lack components of the type I IFN receptor. Data obtained from these studies confirmed the essential requirement for type I IFN in controlling viral titres, promoting expansion of splenic Ly49H+ NK cells, and inducing early activation of NK cell cytotoxicity. In addition, our data depicted an accumulation of infected myeloid cells in the absence of effective NK cell-mediated control. This was paralleled by a significant increase in the level of serum TNF-a and IFN-¿, an effect which in some cases has been linked to serious pathological disease. Thus, the data described in this chapter provide an insight into the consequences arising from delayed NK cell responses to MCMV infection in the absence of type I IFN. vii Type I IFN can also potentially affect BM haematopoiesis. BM atrophy and impairment of myelopoiesis are serious consequences of CMV infection. During acute MCMV infection we consistently observed a profound loss of splenic dendritic cells (DCs) in BALB/c mice. Since all DC subsets are derived from BM haematopoietic progenitor cells, the possibility that MCMV might interfere with BM haematopoiesis and DC differentiation was explored. Chapters 3 and 4 describe the impact of acute MCMV infection on BM progenitors, with particular emphasis on the differentiation capabilities of these cells in ex vivo culture systems. Chapter 3 focuses on the effect of MCMV infection on BM cellularity and frequency of specific BM progenitor populations. A thorough analysis of contributing factors, such as viral infection of BM cells, involvement of type I and II IFNs, progenitor cell trafficking and NK cell activity in the BM compartment, was conducted. Our results showed that a severe loss of BM cellularity occurs in MCMV-infected mice. Furthermore, when BM cells from MCMV-infected mice were cultured ex vivo in granulocyte macrophage-colony stimulating factor (GM-CSF), there was an impairment in their ability to differentiate into DCs.
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Cheung, Ka-wa Benny, and 張嘉華. "Immune regulation in response to mycobacterial infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634206.
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Naor, Naftaly. "The immune response against p53 protein in cancer patients /." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69652.
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Mutations in the p53 gene are known to be associated with a wide range of human tumors. In some primary tumors and established cell lines, stable mutant p53 protein is expressed at high levels, whereas, in normal cells unstable wild-type p53 protein is expressed at very low levels. Sera from some patients with breast and colon tumors contain anti-p53 antibodies. It is unclear whether changes in p53 structure, or its increased level in tumors, causes p53 to become antigenic. In our study we tested sera from patients with various types of cancer for anti-p53 antibodies. Examination of the sera was made by Western blot, and the results were confirmed by rescreening sera with immunoprecipitation. Both techniques revealed the presence of anti-p53 antibodies in some sera from lung and ovary cancer patients, as well as in the sera from patients with breast or colon cancers. Clearly, patients with various cancer tumors are able to produce anti-p53 antibodies. It was unclear whether this humoral immune response is against mutant or wild type p53. To provide a better definition of this immune response, we have examined the anti-p53 response from cancer patients against mutant and wild type p53 in the native and denaturated state. Western blot and Immunoprecipitation analysis showed that the anti-p53 sera recognise both wild type and mutant p53 conformational and denaturation resistant epitopes. Taken together, these data demonstrate that the mutant p53 is not more antigenic than the wild type p53. This provides strong evidence that the antibody response is not directed solely against the altered conformation in mutant p53.
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Kendall, Elaine. "Molecular characterisation of the human major histocompatibility complex." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333402.
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Waight, Sharma Agnes Phyllis. "The intestinal immune response to Giardia in the rat." Title page, abstract and contents only, 1988. http://web4.library.adelaide.edu.au/theses/09PH/09phw138.pdf.
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Parsa, Venkata Laxmi Kishore. "Molecular mechanisms of host cell response to Francisella infection." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1195584597.
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Lange, Christina [Verfasser]. "Molecular analysis of the innate immune response in hydra / Christina Lange." Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1030344787/34.
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Cheung, Ka-wa Benny, and 張嘉華. "Mechanism of Bacillus Calmette Guerin-induced immune response." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29488989.
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Robinson, Stephen Paul. "Developmental aspects of normal and malignant dendritic cells." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325518.
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Dajani, Rana Basem. "Innate immune responses in the lung and liver." Diss., University of Iowa, 2005. http://ir.uiowa.edu/etd/103.
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Pascoe, E. W. "Cellular aspects of the immune response against Nematospiroides dubius in the mouse." Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374814.
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Burrows, Amanda Susan. "Cellular aspects of the immune response of the turbot, Scophthalmus maximus (L.)." Thesis, University of Plymouth, 1995. http://hdl.handle.net/10026.1/1990.
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Peripheral blood leucocytes of the turbot, Scophthalmus maximus, were characterised into 4 distinct groups following morphological, morphometric and histochemical examination. Total and differential cell counts were determined. Thrombocytes, the most abundant leucocyte type (52%), were highly mobile and encountered in several morphological forms. Granulocytes, representing 5.6% of the leucocyte population, histochemically most resembled the mammalian neutrophil. Both large and small lymphocytes (40.8%), were encountered. Monocytes were rarely observed (1.6%). Thrombocytes and monocytes were phagocytic in vitro at 12oc and 22oc, showing increased phagocytic activity at the higher temperature. The thymus was paired and consisted of a well developed outer cortex and an inner meduallary region. The spleen was bounded by a fibrous tissue capsule and contained a large volume of blood. Diffuse areas of red and white pulp, ellipsoids and melanomacrophage centres were apparent. Lymphocytes, thrombocytes and mature erythrocytes made up the cellular components. The kidney, located beneath the vertebral column contained haemopoietic tissue throughout. Excretory tubules were evident posteriorly. Cellular elements included developing granulocytes, large and small lymphocytes and melanomacrophages. Investigation of ontogenic development of the lymphoid tissue, from 24h post-hatch to the completion of metamorphosis (Day 63) revealed thymic, splenic and kidney rudiments all present at Day 4 with the first lymphoid cells appearing in thymus and kidney by Day 8. Splenic lymphoid cells and the development of areas of white pulp were apparent by Day 28. Differentiation of the thymus had occurred and melanomacrophage centres were seen in the spleen, completing structural lymphoid development by Day 63. Critical stages of lymphoid ontogeny were correlated with easily recognisable external morphological features. A study of the kinetics of carbon clearance by the reticuloendothelial system, revealed a phagocytic capacity in the spleen, kidney and heart. Splenic carbon was seen at 20min post injection, accumulating around ellipsoids and rising to a maximum level at 24h. By Day 5 carbon levels within phagocytes, by now more distant from the ellipsoids, had begun to decrease and carbon was seen within melanomacrophages. Levels of kidney carbon, present within large macrophage-like cells which increased in size forming larger aggregations, increased to a maximum at Day 3. Clearance appeared more rapid in the posterior kidney. Low level uptake was seen within the epicardium. Carbon uptake was not observed in the liver or gill. Kidney leucocyte migration in vitro was examined to a range of chemoattractants using a number of assays. 24h bacterial culture supernatants of Vibrio alginolyticus induced significant cellular responses. The under agarose assay demonstrated migration inhibition to 100%, 50% and 40% supernatant dilutions. Enhanced migration was detected to dilutions of 5-50% in the microchemotaxis chamber, being optimal at 20%. The leucocyte polarisation assay demonstrated cell orientation in response to I 00% culture filtrate and the capillary tube migration assay revealed cellular inhibition at concentrations of 10% & SO%. Leukotriene B4 (LTB4) also induced migration in the filter-based assay, being optimal at to-7M. Cellular migration and orientation were observed in filter and polarisation assays to turbot serum, with normal and activated serum inducing elevated responses in the filter based assay. No response was detected by any of the assay systems to n-formylmethionyl-leucyl- phenylalanine (FMLP) or casein at any concentration tested. Results are discussed in relation to the cellular defence mechanisms of fish.
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Sparkes, Andrew Howard. "Aspects of feline dermatophytosis and the immune response to Microsporum canis infection." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385524.
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Effertz, Bernard Stephen. "The humoral immune response to streptococcal cell wall-induced arthritis in the rat." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184877.
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I investigated the humoral immune response to streptococcal cell walls (SCW) in arthritis susceptible Lewis and resistant Fisher rats. All rats were given a single intraperitoneal injection of either SCW or saline (controls). Rats were sacrificed, three rats per time point, over an eleven week period and serum was collected for ELISA. SCW injected Lewis rats produced anti-SCW antibody, whereas control rats did not. Anti-SCW antibody was significantly elevated over controls between days 14-28 (post injection). Both saline and SCW injected Fisher rats produced anti-SCW antibody, but with different kinetics. Anti-SCW antibody increased by day 7 and remained elevated over controls till day 21, after which there was no difference. ELISA were designed to determine the SCW epitope(s) recognized by anti-SCW antibody. Formamide extracts of SCW, peptidoglycan and polysaccharide, were investigated along with the terminal epitope of polysaccharide, N-acetyl-D-glucosamine, and the peptidoglycan precursor peptide. The data revealed that anti-SCW antibody was directed against a combined SCW epitope, given the lack of significant binding to any of the SCW epitopes tested. Isotype analysis of anti-SCW antibody revealed that the Lewis response was composed primarily of IgG2a whereas the Fisher response was composed primarily of IgM. Binding of rat IgG isotypes to whole streptococcus, SCW, peptidoglycan, and polysaccharide was investigated, given the possibility of background binding by the streptococcal Fc-receptor. Streptococcal binding of rat IgG was specific for IgG2c and the polysaccharide portion of SCW was necessary for binding. Passive immunization of naive Lewis rats with antibody from rats with active arthritis was ineffective at transferring the disease. However, subcutaneous injection of affinity purified anti-SCW antibody or IgG into Lewis rats, followed twenty-four hours later by a single intraperitoneal injection of SCW, suppressed the acute phase and inhibited the chronic disease. IgM rheumatoid factor (RF) was present in the serum of both saline and SCW injected Lewis and Fisher rats. However, SCW injection only induced a significant increase in IgM RF (between days 3-7) in Lewis rats. Passive immunization of Fisher rats with affinity purified IgM RF (from Lewis serum), three days post SCW injection, was ineffective at inducing arthritis.
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吳越 and Yuet Wu. "The study of immune response to co-infection of influenza virus and Streptococcus pneumoniae." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193417.
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Influenza is a leading cause of respiratory disease worldwide. During pandemic and seasonal influenza, secondary Streptococcus pneumoniae infection is a severe complication that contributes to morbidity and mortality. With the clinical significance of this co-infection, it is imperative to understand the disease mechanisms and how our immune system would be modulated in dealing with the dual infection.
First, in vivo co-infection model was established. Mice were sequentially infected with influenza virus and then Streptococcus pneumoniae. Co-infected mice lost their body weight significantly and had 100% mortality, whereas mice infected with either influenza virus or pneumococcus alone lost their body weight transiently and all recovered from the infection.
Then, lung inflammatory response during the co-infection was examined. Although it is a common phenomenon that co-infection enhances inflammation, the kinetic of, and the relative contribution of influenza virus or pneumococcus to the lung inflammation is not well defined. Therefore, this study characterized the general lung inflammatory environment after co-infection. It was found that influenza virus and pneumococcus differentially modulated inflammatory response in terms of kinetics, leukocyte infiltration and cytokine production. At the early time point after co-infection, pneumococcal infection contributed more than the influenza virus infection to enhance inflammatory cytokine and neutrophil infiltrating the lung. At the later time point after co-infection, both influenza virus and pneumococcus contributed to synergistically increase inflammatory cytokine and macrophage infiltrating the lung. Influenza virus infection induced IFN-γ that contributed to the elevated IFN-γ level in co-infected mice. Influenza virus and pneumococcus synergistically increased Th2 associated cytokine including IL-4, IL-5, and IL-10. These up-regulated immune responses might contribute to the severe lung pathology.
Next, adaptive immunity to co-infection was examined. Literature studying co-infection often reports how prior influenza virus infection impairs the immune response against subsequent bacterial infection. However, whether and how secondary pneumococcal infection would affect the immunity to the initial influenza virus is unknown. Therefore this study investigated the modulation of immunity to influenza virus by secondary pneumococcal infection. It was found that co-infection significantly enhanced virus titer in lung and depleted the number of cell in spleen. Secondary pneumococcal infection after influenza decreased influenza virus specific IgG in the lung and peripheral blood. The reduced level of virus specific IgG was associated with the decrease in the number and the percentage of follicular B cell and CD4 T follicular helper cell through both pneumococcal capsular polysaccharide dependent and independent manner. Treating co-infected mice with immune serum containing influenza virus specific IgG successfully improved survival, which suggested the important protective function of virus specific IgG to the co-infection. Taken together, these data suggested that secondary pneumococcal infection impairs the antibody response to influenza virus, which might enhance mortality after co-infection.
In conclusion, this study provides new insight to understand the pathogenesis of co-infection, reveals the general lung inflammatory environment, highlights the negative role of pneumococcus to impair virus control and explores novel treatment for the co-infection.published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy
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Sowers, Kegan. "Decellularized Matrices Effect on the Adaptive Immune Response." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5698.
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Decellularized extracellular matrices have been a growing area of interest in the biomedical engineering fields of tissue engineering and regenerative medicine.As these materials move toward clinical applications, the immune response to these materials will be a driving force toward their success in clinical approaches. Fully digested decellularized matrix constructs derived from porcine liver, muscle and lung were created to test the adaptive immune response. Hydrogel characterization ensured that the materials had relatively similar stiffness levels to reduce variability, and in vitro studies were conducted. Each individual construct as well as a gelatin control were plated with a co-culture of macrophages and T-cells to measure T-cell proliferation. In addition standard markers of inflammation through qPCR were measured in the macrophage group. Constructs were then placed into animals for 3 and 7 days in addition to a second group that received constructs for 21 days before secondary constructs were placed. These groups were then sacrificed following 3, 7 and 14 days to measure the residual and memory-like response of the constructs. Our results showed that t-cell proliferation was increased with decellularized constructs, particularly in tissue with higher DNA content. In vivo, animals with secondary treatments showed extended inflammatory response, driven by Th1 and Th17 polarization suggesting a memory-like response due to recognition of peptides in the constructs from secondary placements.
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Shidrawi, Ray Georges. "Molecular immune aspects of coeliac disease : organ culture and peptide binding studies." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243337.
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Teng, Ooiean, and 丁瑋嫣. "Identification of CLEC5A in modulating host immune response after influenza A virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208615.
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Human infections with influenza A virus (IAV) exhibit mild to severe clinical outcomes as a result of differential virus-host interactions. C-type lectin receptors (CLRs) are pattern recognition receptors that may sense carbohydrates, proteins, or lipids derived from infected hosts or the invading microbes including bacteria, viruses, fungi, or parasites. CLR-viral interaction may lead to increased viral entry and spread; furthermore, their interactions have been reported to trigger downstream signaling that further modulates host’s innate immune responses through the induction of pro-inflammatory cytokines. To date, DC-SIGN and DC-SIGNR have been shown to mediate IAV entry; however, the potential interactions between other human transmembrane CLRs with IAV have not yet been systematically investigated. We utilized lentiviral-based pseudoparticles expressing influenza hemagglutinin (HA) to examine the binding potential between HA and a panel of human CLRs expressed in soluble form. CLEC5A was identified as a potential interacting target with the HA proteins derived from a highly pathogenic avian H5N1 virus A/VN/1203/04 (VN1203) or a human seasonal H1N1 virus A/HK/54/98 (HK5498), albeit at different binding intensity. Applying siRNA gene silencing, we confirmed that CLEC5A did not enhance influenza entry in human monocytic U937 cells that constitutively express CLEC5A or in the lentiviral-transduced stable CHO and CHO-Lec2 cells that overly expressed CLEC5A. To investigate downstream signaling upon engagement of CLEC5A to influenza virus, M-CSF or GM-CSF differentiated human macrophages with high expression levels of CLEC5A and DAP12, a known adaptor protein for CLEC5A upon phosphorylation to initiate signal transduction, was subjected to CLEC5A siRNA gene silencing followed by infection with recombinant A/PR/8/34 virus expressing HA and NA derived from either VN1203 (H5N1) or HK5498 (H1N1) viruses. RG-PR8xVN1203HA,NA (H5N1) exhibited a higher infectivity and induced higher levels of pro-inflammatory cytokines (TNF-( and IFN-α) and chemokines (IP-10, MCP-1, MIG and MIP-1α) secretion in M-CSF or GM-CSF differentiated macrophages while compared to that of the RG-PR8xHK5498HA,NA (H1N1) virus. Knocking-down CLEC5A in macrophages led to a universal reduction of cytokines and chemokines secretion after infection with either the RG-PR8xVN1203HA,NA, RG-PR8xHK5498HA,NA, RG-A/VN/1203/04 (H5N1) or A/Shanghai/2/2014 (H7N9) viruses, suggesting that CLEC5A plays a role as cytokine and chemokine amplifier after influenza infection. Since DAP12 phosphorylation is known to activate downstream signaling via Spleen tyrosine kinase (Syk), pre-incubation of M-CSF macrophages with a Syk inhibitor (Bay 61-3606) also lead to a significant reduction of TNF-α and IP-10 in infected macrophages. A higher mortality was observed in CLEC5A-/- mice while compared to the wild-type C57BL/6 mice after challenged with a lethal dose of RG-A/VN/1203/04 (H5N1) influenza virus suggesting that CLEC5A as a host innate response amplifier play a protective role upon influenza infection. In conclusion, we have identified CLEC5A as a novel host factor for influenza pathogenesis by modulating host innate inflammatory response.published_or_final_version
Public Health
Doctoral
Doctor of Philosophy
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Beltran, Caroline Gina Gracieuse. "A proteomic investigation of the immune response of the South African abalone, Haliotis midae." Doctoral thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/16483.
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Includes bibliographical referencesHaliotis midae is a commercially important abalone in South Africa, previously harvested from a stable, quota-managed fishery. However, the combined effects of overharvesting, increased illegal catches and negative environmental factors led to a collapse in wild populations in the mid-90s. Consequently, land-based aquaculture of H. midae has grown significantly in South Africa, to satisfy the global demand for abalone and alleviate pressure on wild stocks. Unfortunately, disease outbreaks have had a severe impact on the abalone aquaculture industry internationally and remain one of the single biggest factors contributing to economic loss. Understanding the effects of pathogen infection of abalone is therefore crucial to mitigating and controlling infection outbreaks on farms. Despite this, the molecular mechanisms underlying the immune response of H. midae remain obscure. High-throughput proteomics, a powerful tool to analyse global protein expression changes, can provide an integrated view of the immune system. Thus, this study aimed to elucidate the haemocyte proteome of H. midae and gain insight into regulatory molecular pathways underlying innate immunity. In this study, a comparative shotgun proteomics approach using isobaric tagging for relative and absolute quantification (iTRAQ) coupled with LC-MS/MS was employed to investigate H. midae proteome changes in response to Vibrio anguillarum challenge. A preliminary iTRAQ challenge trial was conducted which identified a putative early (1 and 2 hours post-injection) and late (48 hours post-injection) proteome response to bacterial-challenge. Using these time points, four independent challenge trials were conducted and analysed by iTRAQ and the results combined to produce a high-confidence dataset with good quantitative reproducibility for statistical analysis. A parallel set of experiments was conducted using mock-infected samples.
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Mee, Edward. "Manipulation of the immune response to malaria antigens using bacterial-derived lipoproteins." Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:c98c8f59-092d-482c-b159-6033b9844908.
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Pretorius, Alri. "Aspects of the immune response in ruminants to four protective Ehrlichia ruminantium gene products." Thesis, University of Pretoria, 2007. http://hdl.handle.net/2263/26758.
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In the search for a better vaccine against Ehrlichia ruminantium infection in ruminants, four E. ruminantium open reading frames (ORFs) derived from the Welgevonden isolate were tested using either DNA vaccination or DNA primemodified viral or DNA prime-recombinant protein boost strategies. Both the DNA vaccination and the DNA prime.recombinant protein boost strategy provided complete protection against E. ruminantium Welgevonden needle challenge, while the DNA prime.modified viral boost strategy only provided 90 % protection. The DNA prime.recombinant protein boost strategy also coincided with elevated cellular immunology as was evident from increased IFN-ã production. Furthermore, we could show that the 1H12 DNA vaccine could induce protection against heterologous needle challenge when animals were immunised with the Welgevonden-derived 1H12 ORFs and challenged with selected E. ruminantium stocks. Unfortunately the DNA only and the DNA prime.recombinant protein boost strategy were not protective in the field. Therefore, our results suggest that there is a vast difference between needle challenge and natural tick infestation and that E. ruminantium organisms transmitted by ticks have the ability to evade the protective immunity induced by immunization with the four 1H12 ORFs.Thesis (PhD)--University of Pretoria, 2007.
Veterinary Tropical Diseases
unrestricted
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Daniels, Brodie Belinda. "Molecular and cellular analysis of the interaction between soluble CD23 and CD11/CD18 integrins." Thesis, Nelson Mandela Metropolitan University, 2010. http://hdl.handle.net/10948/1217.
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The low affinity IgE receptor, CD23, is expressed by a wide variety of cells and cleaved from its original 45 kDa size to several smaller soluble CD23 proteins. Soluble CD23 function depends on the form of the protein and its interaction with various ligands. CD23 is believed to play an important role in regulating allergic responses and in inflammation, amongst others. β2 integrins are important in a variety of cell-adhesion reactions during immune-inflammatory mechanisms and the binding of their natural ligands generates outside-in cellular signalling, leading to cell activation. Although the binding of CD23 to β2 integrins contributes to this signalling in monocytes, the interaction site for CD23 is unknown. This study focused on the interaction of three soluble CD23 proteins with the β2 integrins CD11b/CD18 and CD11c/CD18. Differentiated HL60, THP1 and U937 monocytic cells were used to demonstrate the binding of three recombinant CD23 constructs (corresponding to 16, 25 and 33 kDa human soluble CD23) to upregulated CD11b/CD18 and CD11c/CD18. This binding was partially blocked by an antibody specific for the CD11b/CD18 αI domain, demonstrating that αI domains are involved in binding to CD23. Recombinant αI domain proteins of CD11b and CD11c were demonstrated to bind CD23 using ELISA and in surface plasmon resonance spectroscopy. The dissociation constants for CD23-CD11b/CD18 and CD23-CD11c/CD18 are comparable to other integrin ligands. This study has shown that CD23 interacts directly with the αI domains of β2 integrins and that the interaction surface likely spans the lectin domain as well as either the stalk and/or C-terminal tail of CD23. This study also looked at the effect that soluble CD23 proteins had on monocyte biology. It appears that iv sCD23 proteins have little effect on the phagocytic or chemotactic ability of monocytes, while an increase in oxidative burst was shown with the 16 kDa and 25 kDa CD23 proteins. Signalling pathways for the production of reactive oxygen species were investigated and it appears that the CD23 proteins signal mainly through the phosphoinositide-3 kinase pathway, although the mitogen activated protein kinase and Src kinase pathways may also play a role. These data suggest that sCD23 proteins induce outside-in signalling of β2 integrins and are able to change the activation state of CD11b/CD11c by stimulating oxidative burst. This needs to be further investigated by determining how the three sCD23 proteins are binding the CD11 proteins and investigating further leukocyte function and inflammatory responses by the cells.
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D'Souza, Sameer Dominic. "Response of human oligodendrocytes to immune-mediated injury : selective vulnerability and selective protection." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40343.
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This thesis studying the injury response of human central nervous system (CNS)-derived oligodendrocytes (OL) to immune mediated effector mechanisms and its relevance to protective strategies for OL, assessed the basis for the selective injury of OL, as occurs in the human demyelinating disease multiple sclerosis (MS). This thesis tested the postulate that selective target injury within the CNS may reflect target-cell rather than effector-cell properties. Differences in susceptibility of CNS neural cells to a common immune mediator or the cell-specific expression of a surface receptor for a putative injury mediator could result in specific target cell injury. With regard to the former possibility, OL amongst neural cells were selectively vulnerable to the cytokine tumor necrosis factor (TNF), death occurring via apoptosis. With regard to the latter possibility, the cytokines $ gamma$-interferon, TNF, and interlukin (IL)-1, selectively upregulated the expression of heat shock protein-72, a postulated ligand for cytolytic $ gamma delta$-T cells, on OL in mixed glial cell cultures via a final common pathway involving IL-1 binding to its receptor on OL. In addition, OL amongst other glial cells in vitro selectively expressed fas, a cell surface receptor that transduces apoptotic cell death signals when ligated by agonist antibodies or by fas ligand (FasL). Fas ligation on OL resulted in OL cell death via a novel apoptosis-independent lytic mechanism. Selective upregulation of fas on OL and FasL on microglia in MS lesions compared to control CNS tissue further implicated fas signalling as a potential contributor to OL pathology in MS. Only ciliary neurotrophic factor (CNTF) amongst an array of neurotrophic factors and cytokines protected OL from TNF-mediated apoptosis. CNTF did not protect other neural cells from TNF-mediated apoptosis, nor did it protect OL from lytic injury mediated by activated $ rm CD4 sp+$ T cells or by fas ligation. These data indicate that targe
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Lewis, Teresa D. "The specific immune response in rainbow trout: Somatic hypermutation and VH gene utilization." W&M ScholarWorks, 2000. https://scholarworks.wm.edu/etd/1539616739.
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The study of antibody responses in prominent aquaculture species such as the rainbow trout, Oncorhynchus mykiss, can facilitate vaccine development and contribute to producing useful paradigms of adaptive immunity in lower vertebrates. Thus, it is essential to identify genes responsible for antibody responses. In the mouse model, hybridoma technology allows for the association of monoclonal antibodies possessing various affinities for antigen with specific VH sequences, gene family utilization, and other molecular events (i.e. somatic hypermutation) that occur during the specific immune response. The absence of a comparable hybridoma technology in piscine systems has limited similar studies of fish immunogenetics to date. Molecular and serological experiments were performed in an attempt to obtain information regarding somatic mutation and VH gene utilization for trout antibodies without reliance on hybridoma technology. PCR primers recognizing consensus sequences of FR1 and FR3 were used to amplify antibody VH sequences from panned, antigen-specific B cells. to follow the development of the expressed VH repertoire, lymphocytes were obtained at weeks 0, 5, 10, and 20 post primary immunization with trinitrophenylated-keyhole limpet hemocyanin (TNP-KLH) or infectious hematopoietic necrosis virus (IHNV). Lymphocytes were also collected 10 weeks post secondary immunization (week 35). These studies were conducted in parallel with serological analyses of plasma antibodies obtained from the same sample in order to correlate molecular data with serological data from individual trout. Antigen-specific lymphocytes were processed to isolate RNA templates to produce cDNA which was cloned and sequenced. This sequence analysis allowed us to report, for the first time, the temporal accumulation of potential somatic variants that correlate to the development of new, high affinity antibody subpopulations during the immune response, some with the emergence of new antibody heavy chain isoelectropherotypes as identified by 2D-IEF/SDS-PAGE. Southern analysis and gene titration using various antigen-specific cDNA probes allowed us to correlate trout antibodies possessing various affinities for antigen with specific VH sequence and gene family utilization. Thus, trout Ig VH gene family utilization appears to follow the mouse model of differential use for specific immune response. These results reveal a capability for fine-tuning the piscine immune response previously not recognized.
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Angelopoulou, Katerina. "Immune response against the p53 tumor suppressor gene product, clinical studies and molecular mechanisms." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0014/NQ27598.pdf.
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Baxendale, Helen Elizabeth. "Analysis of the molecular basis of the immune response to streptococcus pneumoniae capsular polysaccharide." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252064.
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Pereira, Melanie Claire. "The molecular analysis of the interation surface between sCD23 and the B2-integrins, CD11b & CD11c." Thesis, Nelson Mandela Metropolitan University, 2012. http://hdl.handle.net/10948/d1014734.
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Both CD23 and the β2 integrins (also known as CD11/CD18) have very important immunological functions, especially during the allergic response where the binding of CD23 to β2 integrins contributes to various types of signalling in monocytes which can result in drastic sensitivities experienced by some allergic individuals. CD23, also known as the low affinity receptor for immunoglobulin E or (FcεRII), is a type II transmembrane glycoprotein which is synthesized by haematopoietic cells and has biological activity in both membrane-bound and freely soluble forms. It acts via a number of receptors, including the β2 integrins. β2 integrins are specifically found on leukocytes and they play important roles in cell–cell or cell–matrix adhesion via their ability to bind multiple ligands. These molecules occur as heterodimers consisting of an alpha (α) and beta (β) subunit. The α-subunits of β2 integrins contain an approximately 200-amino-acid inserted domain or I-domain which is implicated in ligand binding function. There are four different types of β2 integrins, namely CD11a, CD11b, CD11c and CD11d, all dimers with the common beta subunit, CD18. CD23 and CD11/18 are natural ligands of each other; however the interaction site for CD23 is unknown. It is postulated that the integrin recognizes a tripeptide motif in a small disulfide-bonded loop at the N-terminus of the lectin head region of CD23, which is focussed around Arg172, Lys173 and Cys174 (RKC). This study thus focused on the interaction between the I-domain of CD11 (b and c) and a recombinant 25kDa construct of sCD23. In order to understand the characteristics of ligand binding between the relevant proteins of interest, alanine substitutions on the RKC motif of CD23 were made via site-directed mutagenesis. Consequently, a recombinant form of the I-domain of CD11 (b and c) as well as a wild type (containing the RKC motif) and mutant form (containing an AAC motif) of sCD23 were expressed and purified. The CD11 recombinant proteins were purified via affinity chromatography and the CD23 recombinant proteins via gel filtration chromatography. In addition, synthetic (CD23 derived) peptides, one containing the RKC sequence and the other the AAC sequence, were designed and custom synthesized. The synthetic peptides as well as the recombinant CD23 proteins were then analyzed for their interaction with the CD11 I-domain via ELISA. Subsequent ELISA analyses showed that the native sCD23 and the RKC peptide were able to bind to the integrin α I-domain whereas the mutant sCD23 and the corresponding synthetic AAC peptide failed to bind. This interaction was also analysed via flow cytometry using differentiated U937 cells, yielding similar results. ELISA analyses for the sCD23-CD11b I-domain interaction showed a Kd of 0.36 ± 0.14 μM whereas the RKC-CD11b I-domain interaction yielded a Kd of 1.75 ± 0.58 μM. Similarly, the sCD23-CD11c I-domain interaction yielded a Kd of 0.39 ± 0.09 μM and 1.53 ± 0.72 μM for the RKC-CD11c I-domain interaction. Peptide inhibitory analysis, analysed via ELISA and flow cytometry, reinforced the fact that the RKC motif on sCD23 is a prerequisite for ligand binding of the CD11b/c I-domain.
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Wu, Yuet, and 吳越. "Immune response of human monocyte-derived dendritic cells to co-infection of influenza virus and Streptococcus pneumoniae." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45543732.
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Bowers, Desiree Ann. "Immune responses of patients with tuberculosis and healthy controls of different ages." Thesis, Stellenbosch : Stellenbosch University, 2003. http://hdl.handle.net/10019.1/53457.
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Thesis (MSc)--Stellenbosch University, 2003.ENGLISH ABSTRACT: The immune system matures progressively from infancy to adulthood, thus children may differ from adults in their immune function. The immature immune system demonstrates a higher naive to memory T cell ratio, defective macrophage function and antigen presentation which, cumulatively, results in diminished production of cytokines such as IFN-y. This cytokine has been shown to play a pivotal role in protection against Mycobacterium tuberculosis (M. tuberculosis) disease. Other cytokines, such as IL-12 and TNF-a, are also involved in the defence against M. tuberculosis. Epidemiological evidence suggests an agerelated incidence of tuberculosis (TB) irrespective of prevalence in a given region. Reports in the literature also demonstrate depressed immune responses in TB patients, at diagnosis, (before TB therapy) with subsequent improvement after TB therapy. The aims of this study were to optimise a whole blood assay in order to characterise immune responses, as measured by proliferation and cytokine production, in TB patients (after TB therapy) and healthy controls of different ages. Immune responses of TB patients would also be compared, before, and after TB therapy. A total of 68 subjects were included in this study. These comprised 27 TB patients and 41 healthy Mantoux positive controls. All subjects were stratified into two age groups: <12 years and >12 years. Diluted whole blood was cultured and stimulated with the mitogen, phytohaemagglutinin (PHA) and the specific mycobacterial antigen, purified protein derivative (PPD) to measure proliferation and IFN-y, IL-2, TNF-a and IL-10 production in the supernatant of cultures. Age was a significant variable for the following PHA-stimulated cytokines: IFN-y, TNF-a and IL-10. Proliferation and IL-2 production after PHA stimulation did not demonstrate any relationship with age. None of the PPD-stimulated proliferative or cytokine responses demonstrated any correlation with age. Concentrations of PHA- and PPD-induced IFN-y for all subjects (patients and controls) were increased “after therapy”, compared to “before therapy”. This phenomenon could possibly be due to maturation in the capacity of the immune system to produce this cytokine. Patients >12yrs demonstrated improvement in all proliferative and cytokine responses (except for PPD-induced IL-2 and TNF-a) “after therapy”, compared to “before therapy”. This is probably a valid finding and is thus in accordance with the literature. The whole blood assay is a simple, non-laborious assay that, according to the literature, produces results that seem to correlate well with that of conventionally used PBMCs. Age appears to be an important variable in the quantitative assessment of cellular immune responses (when the mitogen, PHA is used as a stimulant) and immune responses of older TB patients appear to improve after TB therapy, compared to before TB therapy.
AFRIKAANSE OPSOMMING: Die immuunsisteem matureer stelselmatig van kind na volwassene. Dus sal kinders se immuniteit verskil van volwassenes s’n. Die immature immuunsisteem het ‘n hoer nai'witeit vir geheue T-sel verhouding, defektiewe makrofaag funksie en antigeen presentering wat gesamentlik lei tot verminderde produksie van sitokiene soos byvoorbeeld IFN-y. Daar is bewys dat hierdie sitokien ‘n deurslaggewende rol speel in die beskerming teen Mycobacterium tuberculosis (M. tuberculosis). Ander sitokiene, soos IL-12 en TNF-a speel ook ‘n rol in die beskerming teen M. tuberculosis. Epidemiologiese data dui aan dat daar ‘n ouderdomverwante insidensie van tuberkulose (TB) is sonder dat dit beinvloed word deur die voorkoms van TB in ‘n sekere area. Verslae in die literatuur wys ook op onderdrukte immuniteitrespons in TB-pasiente by diagnose (voor TB-behandeling) met uiteindelike verbetering na TB-behandeling. Die doel van hierdie studie was om ’n volbloed metode te optimaliseer in ’n poging om die immuunrespons te karakteriseer soos gemeet met behulp van proliferasie en sitokien produksie by TB-pasiente (na TB-behandeling) en gesonde kontrole persone van verskillende ouderdomme. Die immuunrespons van TB-pasiente word ook vergelyk voor en na TBbehandeling. ‘n Totaal van 68 gevalle is vir die studie gebruik. Dit sluit in 27 TB-pasiente en 41 gesonde Mantoux positiewe kontroles. A1 die gevalle is in twee ouderdomsgroepe verdeel: <12 jaar en >12 jaar. Kulture is gemaak van verdunde volbloed en gestimuleer met phytohaemaglutinin (PHA) en gesuiwerde proteien derivaat (purified protein derivative-PPD) om proliferasie en IFN-y, IL- 2, TNF-a en IL-10- produksie in die supernatant van die kulture te meet. Ouderdom was ‘n beduidende veranderlike vir die volgende PHA-gestimuleerde sitokiene: IFN-y, TNF- a en IL-10. Daar was geen korrelasie tussen proliferasie en IL-2-produksie na PHA-stimulasie aan die een kant en ouderdom aan die ander kant nie. Geen van die PPDgestimuleerde proliferasie response of sitokien response het enige korrelasie met ouderdom getoon nie. Konsentrasies van PHA- en PPD-geinduseerde IFN-y vir alle gevalle (pasiente en kontrole) was verhoog “na behandeling”, vergeleke met “voor behandeling”. Hierdie fenomeen kan moontlik toegeskryf word aan maturasie in die vermoe van die immuunsisteem om sitokiene te vervaardig. Pasiente >12 jaar het bewyse getoon van verbetering in alle proliferasie en sitokien response (behalwe vir PPD-gei'nduseerde IL-2 en TNF-a) “na behandeling”, vergeleke met “voor behandeling”. Dit is waarskynlik ‘n geldige bevinding en is dus in ooreenstemming met verslae in die literatuur. Die volbloed metode is ‘n eenvoudige metode wat nie baie arbeidsintensief is nie, wat volgens die literatuur, resultate lewer wat goed korreleer met die konvensionele gebruik van perifere bloed mononukliere selle (PBMC’s). Dit wil voorkom asof ouderdom ‘n belangrike veranderlike is in die kwantitatiewe beoordeling van sellulere immuunrespons (wanneer PHA gebruik word as ‘n stimulant), en of die immuunrespons van ouer TB-pasiente verbeter na TB-behandeling in vergeleke met die respons voor TB-behandeling.
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Tsoi, Hoi-wah, and 蔡海華. "Effect of antibiotics on the immune response induced by live-attenuated Salmonella typhi." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31223540.
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Khan, Deena. "Molecular Basis of Upregulation of IL-17 in Estrogen Model of Inflammation." Diss., Virginia Tech, 2012. http://hdl.handle.net/10919/77129.
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Interleukin-17 (IL-17) plays a major role in inflammation by regulating the induction of various proinflammatory genes, which aid in the recruitment and activation of neutrophils. Although IL-17 is considered to be protective in infection, overproduction of IL-17 in conditions like autoimmune diseases has been shown to aggravate these diseases and contribute to tissue injury. One of the principal focus of our laboratory is to decipher molecular mechanisms involved in inflammatory cytokine regulation and response in inflammatory disorders. To study this aspect, we employ a murine model of pro-inflammation induced by exposure to a natural immunomodulator, estrogen. In this novel study, we have comprehensively investigated the effect of estrogen on IL-17 induction, an aspect not studied thus far. We are the first to demonstrate that estrogen increases the ability of lymphocytes to secrete IL-17A, and its isoforms IL-17F, IL-17A/F. In addition to the cytokine levels, the percentages of IL-17⁺ cells are also increased by estrogen. Impressively, we found that estrogen fine tunes the balance of multiple transcription factors/signaling pathways. Estrogen upregulates IL-17 by promoting the activity and expression of positive regulators (RORγt, RORα, NF-κB, JAK-2) and decreases the activity and/or expression of negative regulators (IRF8, ETS-1). In addition, we found that estrogen epigenetically regulates IL-17 induction by miRNAs (miR-326 and miR-223). We also found that majority of IL-17 positive cells are CD8⁺ suggesting that estrogen-mediated IL-17 induction is predominantly from Tc17 cells. This is possibly due to increased proliferation of CD8⁺ cells from estrogen-treated mice, as demonstrated by CFSE cell proliferation assay. Furthermore, estrogen also enhances the ability of IL-17-target cells to release proinflammatory molecules when exposed to IL-17. Together, this is the first study to comprehensively show that estrogen calibrates transcription factors and miRNAs to enhance IL-17 induction and promote IL-17 response. This dissertation work will provide a platform to continue further research in estrogen modulation of IL-17 in inflammation and disease conditions.Ph. D.
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Luo, Ying, and 羅英. "Hepatitis B virus: specific immune response after liver transplantation for chronic hepatitis B." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B3697724X.
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Yin, Han. "MOLECULAR ANALYSIS OF HTLV-2 APH-2 IN VIRAL TRANSFORMATION, PERSISTENCE AND HOST IMMUNE RESPONSE." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1322156034.
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Conley, Travis B. "Growth response to resistance exercise : influence of exercise device." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1395457.
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The purpose of this study was to compare the growth response elicited by an acute bout of resistance exercise (RE) conducted on a traditional weight stack device (WS) and a flywheel device (FW). Eight recreationally trained males (25 ± 9 y, 77 ± 27 kg) performed 4 sets of 7 repetitions of bilateral knee extension on each exercise device separated by 7 days. Muscle biopsies were obtained from the vastus lateralis at rest and 4 hrs post-exercise to examine the expression of selected myogenic and proteolytic genes. RE increased (P < 0.05) mRNA expression of Myogenin (3.6 vs. 3.6 fold), and MyoD (2.2 vs. 2.0 fold) and decreased (P < 0.05) expression of Myostatin (1.4 vs. 1.5 fold) to a similar degree on both exercise devices. There was no change in the expression of Atrogin-1, MuRF-1 or MRF4 following RE on either device. The only device mediated difference in the expression of the selected genes was observed in Atrogin-1 which was lower following RE on the FW versus the WS device. The current data shows that in the initial hrs following RE, use of the FW is as effective as the traditional resistance training devices (WS) in promoting the induction of genes involved with muscle remodeling and growth.School of Physical Education, Sport, and Exercise Science
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Green, Michelle G. "Respiratory Syncytial Virus Pathogenesis and Immune Response in the Cotton Rat Model." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492720984529555.
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Abebayehu, Daniel. "MODULATING THE INNATE IMMUNE RESPONSE TO ELECTROSPUN SCAFFOLDS AND POLYMER DEGRADATIVE BYPRODUCTS." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4739.
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Implanted biomaterials often induce inflammation that frequently leads to the foreign body response, fibrosis, and the failure of the implant. Thus, it is important to evaluate how cells interact with materials to promote a more regenerative response. It is critical to determine how to modulate the response of tissue resident innate immune cells, as they are among the first cells to interact with implanted materials. Among tissue resident innate immune cells are mast cells, which are inflammatory sentinels that degranulate and orchestrate the fate of other cell populations, such as monocytes/macrophages and lymphocytes. Mast cells have also been reported to play a vital role in the foreign body response of implanted biomaterials as well as angiogenesis. The goal of this study was to determine how to modulate mast cell responses to electrospun scaffolds by altering scaffold architecture and composition to promote anti-inflammatory and regenerative cell-scaffold interactions. Scaffold architecture was manipulated by changing either fiber diameter or pore diameter and mast cell responses were mediated by endogenous and exogenous DAMPs (i.e. IL-33 and LPS, respectively). Particularly in response to IL-33, scaffolds with increased fiber and pore diameter promoted less inflammatory cytokine and chemokine release while increasing angiogenic cytokine release. Additionally, taking scaffolds that promoted increased inflammatory cytokine expression and increasing the pore diameter alone dampened inflammatory cytokine expression. The next question we wanted to answer was how might the degradative byproducts of scaffolds alter mast cell inflammatory responses. Given the widespread use of polylactic acid, we decided to investigate this question using lactic acid as a degradative byproduct. In the presence of physiologically relevant levels of lactic acid, IL-33- and IgE-mediated inflammatory cytokines and chemokines are suppressed, while angiogenic cytokines are enhanced. This response was shown to be pH- and MCT1-dependent and was recapitulated in primary human skin mast cells as well as in vivo. In summary, scaffold architecture and the presence of select polymer degradative byproducts have the potential of selectively suppressing inflammatory cytokines and enhancing angiogenic cytokines.
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Schölvinck, Elisabeth Henriëtte. "The influence of age on the cellular immune response in patients with tuberculosis and healthy controls." Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53126.
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Thesis (PhD) -- Stellenbosch University, 2002.ENGLISH ABSTRACT: Children and adults may differ in their immune function. An adequate function of the individual's immune system is crucial to the risk for development of tuberculosis (TB) after infection with Mycobacterium tuberculosis (Mtb). Epidemiological evidence suggests an age-related incidence of TB. Furthermore, the prevailing clinical expression t ' of TB varies between age groups. -The aims of this study were to characterise the cellular immune response at different ages in TB patients and healthy individuals living in a region highly endemic for TB and to relate the findings to the clinical expression of TB in different age groups. A total of 150 persons of different ages were included in this study: 50 TB patients, (identified on the basis of clinical, radiological and microbiological characteristics), 49 healthy Mantoux positive (~15mm) and 51 healthy Mantoux negative (<15mm) subjects. All patients <12yrs were identified as having primary TB and postprimary TB was only diagnosed in patients ~12yrs. Haematologic indices were obtained from all the included subjects and found to be agerelated. With the exception of the absolute lymphocyte counts, all indices were significantly different in TB patients when compared to healthy controls. Whole blood was cultured and stimulated with PHA, PPD and ESAT -6 to measure lymphocyte proliferation and IFN-y, TNF-a, IL-2 and IL-10 production in the supernatants of the cultures. After stimulation with PHA, the production of IFN-y, TNF-a and IL-10 as well as lymphocyte proliferation were all age-related. After stimulation with PPD, age correlated positively with IFN-y production in healthy Mantoux positive subjects< 12yrs. In the age groups <20 yrs, patients produced similar amounts of IFN-y when compared to healthy age-related Mantoux positive controls. TNF-a and IL-2 production were not different between patients and controls. In this whole blood system, measuring any of these cytokines on their own did not differentiate patients from controls at all ages. The ratio of PPD stimulated IFN-y to TNF-a production was significantly less in patients with primary TB and postprimary TB when compared to Mantoux positive controls, irrespective of age. These findings indicate that calculated ratios between several cytokines may be useful markers of disease at all ages. ESA T -6 stimulated IFN -y production did not result in any significant correlation with age, but was significantly less in healthy Mantoux positive subjects ~12 yrs when compared to healthy Mantoux positive subjects <12 yrs and TB patients of all ages. This finding suggests that a positive immune response to ESAT -6 is indicative of recent immunological contact with Mtb. Total IgE was measured in serum. In children <12 yrs these values correlated with age and were highest in healthy Mantoux positive controls, thereby not confirming any inverse correlation between IgE and TB. Age should be recognised as a significant variable in quantitative measurements of cellular immune responses.
AFRIKAANSE OPSOMMING: Die immuunsisteem van kinders en volwassenes kan verskillend wees. Die mate van immuniteit van 'n individu is deurslaggewend vir die risiko om tuberkulose (TB) na infeksie met die Mycobacterium tuberculosis (M tb) te ontwikkel. Epidemiologiese bevindings suggereer dat die insidensie van TB ouderdomgebonde mag wees. V erder verskil die voorkomende kliniese beeld van TB ook tussen ouderdomsgroepe. Die doelstellings van hierdie studie was om die sellulere immuunrespons op verskillende ouderdomme by TB-pasiente en gesonde individue wat in 'n streek met hoogs endemiese TB-insidensie woon te vergelyk. Die doel was ook om vas te stel hoe hierdie bevindings by die kliniese beeld van TB by verskillende ouderdomsgroepe inpas. Daar is l50 persone van verskillende ouderdomme in hierdie studie ingesluit: 50 TBpasiente (geidentifiseer op grond van kliniese, radiologiese en mikrobiologiese karakteristieke), 49 gesonde Mantoux -positiewe (:2':l5mm) en 5l gesonde Mantouxnegatiewe (
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Hedin, Skogman Barbro. "Neuroborreliosis in childhood : Clinical, immunological and diagnostic aspects." Doctoral thesis, Linköpings universitet, Pediatrik, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-11520.
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Lyme Borreliosisis is a multi-organ infectious disease caused by the spirochete Borrelia burgdorferi. The spirochete is transmitted to humans by tick bites. Neuroborreliosis (NB) is a disseminated form of the disease, in which the spirochetes invade the nervous system. In children, subacute meningitis and facial nerve palsy are typical clinical manifestations of NB. The aim of this thesis was to study clinical, immunological and laboratory characteristics in children being evaluated for NB in a Lyme endemic area of Sweden, in order to identify factors of importance for prognosis and clinical recovery. A total of 250 patients and 220 controls were included during 1998-2005, with a prospective and a retrospective part. Less than half (41%) of children with signs and symptoms indicative of NB get the diagnosis confirmed by detection of Borrelia specific flagella antibodies in CSF (clinical routine method). Surprisingly few patients were diagnosed as having other infectious or neurologic diseases and consequently, many patients ended up with an uncertain diagnosis. However, four new Borrelia antigens (DbpA, BBK32, OspC, IR6) were evaluated and performed well in laboratory diagnostics. If they were combined in a panel, together with the flagella antigen, the sensitivity was 82% and the specificity 100%, leading to improved diagnostic accuracy in children with NB, as compared to using the routine flagella antibody test alone. Clinical recovery at the 6-month follow-up (n=177) was generally good and nonspecific symptoms, such as headache and fatigue, were not more frequently reported in patients than in controls. No patient was found to have recurrent or progressive neurologic symptoms. However, permanent facial nerve palsy was found in 22% of patients at the 2-year follow-up, with consequences such as eye-closing problems, excessive tear secretion, pronunciation difficulties and cosmetic complaints. When cellular immune responses were investigated, the number of Borrelia-specific IL-4 and IFN-γ secreting cells in CSF was found to be more prominent in children with NB than in controls. Furthermore, a much stronger IL-4 response in CSF was seen in children as compared to adults with NB. This cytokine profile of children with NB is believed to represent an effective and balanced type1/type2 response in a relevant compartment, and could contribute to the less severe course of the disease seen in children as compared to adults with NB. No prognostic factors were found to influence the outcome in patients with “Confirmed NB” or facial nerve palsy. Nor was any specific cytokine profile, or antibody response to new Borrelia antigens in CSF, correlated to a less favorable clinical outcome. An NB prediction score test, based on clinical variables at admission, is suggested to help physicians to determine whether to start early antibiotic treatment, before results from Borrelia antibody tests are available. Results in this thesis support the notion that mononuclear pleocytosis in CSF, in patients being evaluated for NB, indicates that they are true NB cases despite the fact that an antibody response cannot yet be visualized. with the routine flagella test. Consequently, early antibiotic treatment in NB seems to be the correct course of action and over-treatment is not a substantial problem.Borrelia-infektion hos barn och vuxna är den vanligaste fästingburna infektionen i Sverige och orsakas av en bakterie som heter Borrelia burgdorferi. Den sprids till människa via fästingbett och kan orsaka besvär från hud, leder, hjärtmuskel och nervsystem. När nervsystemet är infekterat kallas det Neuroborrelios. Denna avhandling handlar om Neuroborrelios hos barn i syd-östra Sverige, ett område med hög Borrelia-förekomst. Jag har studerat symtom, laborativa provsvar och tillfrisknande hos 250 barn med misstänkt Neuroborrelios under åren 1998-2005 och jämfört med friska barn. Dessutom har jag tittat närmare på vissa signalsubstanser inom immunförsvaret i blod och ryggvätska och vilken roll signalsubstanserna spelar för förlopp och utläkning av infektionen. Avhandlingen innehåller också en utvärdering av fyra nya diagnostiska test vid misstänkt Neuroborrelios hos barn. Det visar sig att mindre än hälften (41%) av barnen med misstänkt Neuroborrelios får diagnosen säkerställd med det befintliga Borrelia-testet (baserat på ett protein som kallas flagellin) som används rutinmässigt. Dock förblir diagnosen oklar för många barn (59%). De fyra nya Borrelia-testen (baserade på protein som kallas DbpA, BBK32, OspC och IR6) visar sig fungera bra och om man kombinerar dem med befintligt Borrelia-test, kan man säkerställa Neuroborrelios hos 82% av barnen med misstänkt infektion. Jag hoppas att dessa nya Borrelia-test i framtiden kan leda till förbättrad diagnostik hos barn som utreds för misstänkt Neuroborrelios. Immunförsvarets signalsubstanser, som analyserades i ryggvätska och blod, visade sig ha en viss profil hos barn med Neuroborrelios jämfört med barn utan Borrelia-infektion, men även jämfört med vuxna med Neuroborrelios. De immunologiska T cellerna producerade två olika sorters signalsubstanser, som kallas ”Interferon-γ” och ”Interleukin-4”. Denna immunologiska profil verkar fördelaktig och kan möjligen bidra till den i allmänhet goda utläkning av Neuroborrelios som man ser hos barn jämfört med vuxna. De vanligaste symtomen vid en Borrelia-infektion i nervsystemet är huvudvärk, trötthet, dålig aptit, feber och ont i nacken. Ansiktsförlamning är det vanligaste specifika neurologiska symtomet. Antibiotikabehandling ges till 69% av barnen och vid en 6 månaders uppföljning rapporterar patienterna god utläkning av de olika symtomen. Inget barn hade återkommande eller allvarliga neurologiska symtom vid uppföljningen. Däremot, barn med ansiktsförlamning visade sig få kvarstående besvär i viss utsträckning. När de undersöktes 2 år efter sin ansiktsförlamning förekom mild till måttlig kvarstående förlamning i 22% av fallen. Patienterna uppgav besvär av ökat tårflöde, sluddrigt tal, svårigheter med att stänga ögat och dessutom rapporterade många patienter att snedheten i ansiktet var kosmetiskt störande. Inga specifika symtom, laborativa prov, immunologiska signalsubstanser eller diagnostiska test visade sig vara kopplade till ökad risk för kvarstående besvär efter Neuroborrelios i allmänhet och inte eller hos patienter med ansiktsförlamning. En checklista har utarbetats med olika symtom som är typiska för barn med Neuroborrelios. Den föreslås kunna användas som beslutsunderlag för start av tidig antibiotikabehandling, redan innan svar på Borrelia-testen finns tillgängliga.
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Izadi, Shavakand Fariba. "A molecular genetic survey of immune response genes and biodiversity of industrial and non-industrial chickens." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36959.
Full textAbstract:
The current practices in industrial poultry breeding developed specialized production lines from very few breeds, resulting in reducting in genetic diversity. “Free run/free range” production systems (non-industrial) are a more recent trend in the poultry sector. Non-industrial chicken populations may differ genetically and have more diversity in disease resistance genes than industrial populations. To test this hypothesis, six chicken populations from non-industrial source; Silkies (SK), Taiwanese Cross (TC), Shiqi (SQ), Yellow Shiqi (YSQ), Yellow Wai-Chow (YW), and Agassiz Cross (AC), and industrial populations; Lohmann White (LW) and Lohmann Brown (LB), were sampled and three related experiments were carried out. First, I used 18 microsatellite markers to study genetic diversity within and among the chicken populations. The industrial population LB and the experimental cross AC which shared some common ancestors, were closely related. Non-industrial chickens SK and TC, with Chinese breed ancestry, were related to SQ, YSQ and YW. LW with White Leghorn ancestry, was not related to the non-industrial populations. Except for YSQ and SQ, STRUCTURE clustered these chicken populations to the genetically distinct groups.
Secondly, I used microsatellite marker (LEI0258), situated within the Major Histocompatibility Complex (MHC) region, to reflect the genetic variability of the adaptive immune system. Results indicated that the industrial chicken populations may have less genetic variability in the MHC compared to non-industrial populations but industrial populations may have higher frequency of certain alleles that were part of their selection history against specific pathogens. Finally, I used SNP markers to examine the genetic variation in candidate genes associated with the innate immune system (ChB6, Casp-1, IAP-1, TGF-β3, BMP-7, TLR4, MD-2, IFN-γ, iNOS, IL-2, Mx1, and TVB). There was no difference between industrial and non-industrial populations in genetic variability in this immune system. The results provided partial support for the hypothesis that industrial populations may have higher resistance to specific diseases, while non-industrial populations may have higher general disease resistance.
In conclusion, the results of this thesis research provided information on the genetic diversity of these chicken populations that can be used in decision making on conservation and in developing breeding stocks for free run/free range production.
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Didriksen, Nancy A. (Nancy Andrews). "The Effect of Examination Stress on Phagocytic Immune Functioning." Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc500983/.
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The purpose of this study was to determine whether psychological stress, specifically examination stress, would decrease immune system functioning. Twenty-five first-year master's and doctoral students who volunteered to participate in the study were psychologically and immunologically assessed during two high- and two low-stress periods. Immunological assessments included a white blood cell differential count and nitroblue tetrazolium test (NBT) to measure neutrophil functioning. Psychological instruments administered at each assessment period included Clinical Analysis Questionnaire (CAQ), Bender Gestalt Test, State- Trait Anxiety Inventory (STAI) and a Brief Stress Questionnaire. Stepwise discriminant function analysis of data revealed five variables which contributed significantly to change under stress and yielded an average canonical correlation of .79 (p < .002) providing evidence of support for the hypothesis that increased psychological stress will alter immune functioning and heighten psychological responses.
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Gangadharan, Bagirath. "Structural and functional aspects of factor viii in the initiation of the anti-factor viii immune response." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066257/document.
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L’apparition d’une réponse immunitaire contre le Facteur VIII (FVIII) de la coagulation est une complication majeur qui survient chez 30% des hémophile A sévères. Bien que des avancées importantes aient abouti au développement de nouvelles molécules de FVIII thérapeutiques, les mécanismes conduisant à l’apparition d’une réponse immunitaire anti-FVIII restent non élucidés. Des facteurs de risques génétiques et environnementaux ont été identifiés ou suggérés, mais une compréhension complète des processus immunologiques permettant l’initiation de cette réponse au dépend de l’induction de tolérance immune chez 30% des patients restent incomprise. Ma thèse porte sur les aspects fonctionnels et structurels du FVIII et leur rôle dans l’initiation de la réponse immunitaire anti-FVIII chez le modèle murin hémophile A. Le premier rôle du FVIII est sa participation à la cascade de la coagulation, et donc la première partie de ma thèse adresse le rôle du processus de coagulation dans l’initiation de la réponse immunitaire anti-FVIII. La seconde partie de ma thèse se concentre sur l’importance des résidus du domaine C2 impliqué dans la liaison aux phospholipides dans l’endocytose et la présentation du FVIII par les cellules présentatrices de l’antigène in vitro et discute de leur relevance in vivoImmunogenicity of Factor VIII (FVIII) is a major hurdle that affects about 30% of severe hemophilia A patients. Though a significant advancement has been accomplished in the development of newer FVIII molecules, the factors that drive FVIII immune responses remain elusive. Many genetic and environmental risk factors have been identified or suggested but a complete understanding of the immunological basis for the antibody formation and the mechanism(s) behind tolerance induction, in the 30% of the patients that never develop anti-FVIII antibodies, are not understood. My thesis involves overlapping aspects important for initiation of an anti-FVIII immune response in a mouse model of hemophilia A. The primary role of FVIII is its participation in coagulation-associated events and thus, the first part of my thesis addresses whether coagulation events per se are implicated in the initiation of anti-FVIII immune responses. The second part of my thesis focuses on the importance of the membrane binding residues within the C2 domain of FVIII in antigen uptake and presentation by antigen presenting cells in vitro and discusses its relevance in vivo