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1
Tjärnlund, Anna. "Mucosal Immunity in Mycobacterial infections." Doctoral thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-6782.
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More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB, caused by the bacterium Mycobacterium tuberculosis, is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, BCG, is administered parenterally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable.
The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA, in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Additionally, a role for IgA in modulation of immune responses is currently being revealed. In this work, we investigated the relevance of mucosal IgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor, the receptor responsible for mucosal secretions of IgA. Gene-targeted mice were more susceptible to mycobacterial infections in the respiratory tract and displayed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of immune cells to the site of infection.
Induction of optimal adaptive immune responses to combat mycobacterial infections requires prompt innate immune activation. Toll-like receptors (TLRs) are vital components of the innate branch of the immune system, ensuring early recognition of invading pathogens. Using TLR-deficient mice we demonstrated an important role for TLR2, and partly TLR4, in protection against mycobacterial infection in the respiratory tract. TLR2-deficient mice failed to induce proper proinflammatory responses at the site of infection, and macrophages derived from the knockout mice displayed impaired anti-mycobacterial activity.
Experimental evidence has concluded that the immune response upon an infection can influence the outcome of succeeding infections with other pathogens. Concurrent infections might additionally interfere with responses to vaccinations and have deleterious effects. We developed an in vitro model to study the effect of a malaria infection on a successive M. tuberculosis infection. Our results demonstrate that a malaria blood-stage infection enhances the innate immune response to a subsequent M. tuberculosis infection with a Th1 prone profile. Reduced infectivity of malaria-exposed dendritic cells implies that a malaria infection could impose relative resistance to ensuing M. tuberculosis infection. However, a prolonged Th1 response may interfere with malaria parasite control.
The outcome of this work emphasizes the importance of generating effective immune responses in the local mucosal environment upon respiratory mycobacterial infections. It furthermore puts new light on the immunological interaction between parasites and mycobacteria, which could have implications for future vaccine research.
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Rahman, Muhammad Jubayer. "Mucosal immunity against mycobacterial infection." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-39170.
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This thesis aimed to the identification of immune biomarkers of mycobacterial infection for better diagnosis of tuberculosis (TB) and also focused on new vaccination strategies with a particular emphasis on the immune responses in the respiratory tract using murine models. Since the lung is the natural habitat for the M. tuberculosis, we reasoned that immune responses detected locally in the lungs would be good correlates of infection (Paper I). Likewise, immune responses induced in the respiratory tract following immunization would be more effective against mycobacterial infection. We showed that cytokines (IL-12, TNF, and IFN-γ) and cytokine receptors (sTNFR1 and sTNFR2) together with specific antibodies in the respiratory tract correlated better with the bacterial burden in the organs. In Paper II, we investigated the role of the BCG vaccination as a priming vaccine in a heterologous prime-boost immunization protocol. The results showed that the neonatal BCG vaccination primed the immune system for a relevant antigen and showed a generalized adjuvant effect. Using this immunization protocol, protective immune responses in the lungs were generated independently of the route used for the booster immunization. In Paper III, We showed that exposure to mycobacterial antigens during the gestational period led to antigen transportation from the mother to the fetus and this resulted in an early priming of the fetal immune system. Immunization with the same antigen during the postnatal life increased antigen-specific recall IFN-γ responses and protection against infection. We examined the role of innate immunity for the induction of acquired immune responses upon immunization with mycobacterial antigens using TLR2 deficient mice (Paper IV). Our data indicated that suboptimal innate immune responses in the TLR2-/- mice might compromise the induction of acquired immune responses. Overall, the current findings suggested that a better understanding of the mucosal immunity would be useful for the improvement of diagnostic procedures and the development of efficient vaccines against TB.At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript
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Tjärnlund, Anna. "Mucosal Immunity in Mycobacterial infections /." Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm university, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-6782.
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Bailey, Jennifer Ruth. "Development of mucosal immunity in pigs." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500402.
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Smerud, Hilde Kloster. "IgA Nephropathy – Mucosal Immunity and Treatment Options." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-168631.
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In the present studies we have explored the link between food hypersensitivity and IgA nephropathy (IgAN) and evaluated treatment options in primary and recurrent disease. Approximately one third of our IgAN patients had a rectal mucosal sensitivity to gluten, as demonstrated by increased local mucosal nitric oxide production and/or myeloperoxidase release after gluten challenge. The gluten sensitivity seemed to be an innate immune reaction unrelated to the pathogenesis of celiac disease. Approximately half of the patients had a rectal mucosal sensitivity to soy or cow’s milk (CM). The levels of IgG antibodies to alfa-lactalbumin, beta-lactoglobulin and casein were significantly higher in CM sensitive as compared with non-sensitive IgAN patients, indicating that an adaptive immune response might be involved in addition to the innate immune reaction observed. With the knowledge of gastrointestinal reactivity enteric treatment was considered as a potential new treatment approach of IgAN. A 6-month prospective trial demonstrated proof-of-concept for the use of enteric budesonide targeted to the ileocaecal region of IgAN patients. We observed a modest, but significant reduction in urine albumin, a minor reduction of serum creatinine and a modest increase of eGFR calculated by the MDRD equation. eGFR calculated from the Cockcroft-Gault formula and cystatin C was not changed. In a retrospective study recurrence of IgAN and graft loss was evaluated in Norwegian and Swedish patients having received a primary renal transplant due to IgAN. Adjusting for relevant covariates, a multiple Cox-regression analysis on time to IgAN recurrence showed that use of statins was associated with reduced risk of recurrence and reduced risk of graft loss. The time lag from diagnosis to first transplantation and female gender were also associated with lower risk of recurrence. Improved graft survival was associated with related donor, low donor age and no or low number of acute rejection episodes.
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Alkazmi, Luay Mahmood M. A. "Mucosal immunity to the hookworm Ancylostoma ceylanicum." Thesis, University of Nottingham, 2004. http://eprints.nottingham.ac.uk/11876/.
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The host-parasite relationship of the hookworm Ancylostoma ceylanicum was explored in a hamster model system, focusing on intestinal mucosal responses to infection. Primary infection induced a rapid reduction in villous height culminating in excess of 75% reduction by day 35. Crypts of Lieberkuhn increased in depth achieving maximum depth by day 35. Mitotic figures in crypts and mast cells increased until day 28. Goblet cells increased continuously from background levels of 50 cell/mm² to exceed 300 cells/mm² by day 42. Paneth cell numbers declined in infected animals. Termination of infection by anthelmintic restored background values of intestinal architecture and goblet cell numbers within 7 days, but mast cells took longer and Paneth cell numbers increased beyond values in naïve controls. Mucosal changes are therefore dependent on the presence of worms, intensity of infection and change dramatically with time. Mucosal changes were studied in hamsters experiencing secondary infections following anthelmintic abbreviation of the immunizing infection, superimposed challenge infection and trickle infections. The kinetics of the responses were compared to animals experiencing primary infections and naive controls. Among the findings were: 1) continuous reduction in villous height and a marked increase in crypt depth from day 10 after challenge in abbreviated primary-challenged hamsters compared to little change in hamsters given superimposed challenge. 2) marked mast, goblet, and Paneth cell and eosinophil responses. 3) less intense mast cell responses in abbreviated primary-challenged compared to superimposed challenge animals 4) after a superimposed challenge poor goblet cell responses because levels were already high at the time of challenge, little change in Paneth cells but intense eosinophil responses 5) slower changes in mucosal architecture and mast cell responses in trickle-infected animals eventually exceeding those in primary infected animals. 6) less marked goblet and Paneth cell responses in trickle-infected groups but more intense, persistent increases in eosinophils Cyclosporin A's (CsA) usefulness as an immunosuppressive therapy for blocking T cell control of immunity was explored. However, CsA turned out to have marked anthelmintic properties and reductions in worm burden confounded the interpretation of mucosal changes.
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Philipson, Casandra Washington. "Systems analysis and characterization of mucosal immunity." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/74392.
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During acute and chronic infectious diseases hosts develop complex immune responses to cope with bacterial persistence. Depending on a variety of host and microbe factors, outcomes range from peaceful co-existence to detrimental disease. Mechanisms underlying immunity to bacterial stimuli span several spatiotemporal magnitudes and the summation of these hierarchical interactions plays a decisive role in pathogenic versus tolerogenic fate for the host. This dissertation integrates diverse data from immunoinformatics analyses, experimental validation and mathematical modeling to investigate a series of hypotheses driven by computational modeling to study mucosal immunity. Two contrasting microbes, enteroaggregative Escherichia coli and Helicobacter pylori, are used to perturb gut immunity in order to discover host-centric targets for modulating the host immune system. These findings have the potential to be broadly applicable to other infectious and immune-mediated diseases and could assist in the development of antibiotic-free and host-targeted treatments that modulate tolerance to prevent disease.Ph. D.
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Ye, Lilin. "FcRn mediated mucosal immunity and subunit vaccine delivery." College Park, Md.: University of Maryland, 2009. http://hdl.handle.net/1903/9815.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2009.Thesis research directed by: Virginia-Maryland Regional College of Veterinary Medicine. Maryland Campus. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Barton, John Roger. "Human gastrointestinal mucosal secretory immunity : investigation and regulation." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/19960.
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Current ideas of human gut immunity are derived heavily from animal studies; the few human studies have mainly addressed cellular aspects, and those on immunoglobulins and antibodies have used serum (or rarely jejunal aspirate) to investigate immune events at the gut level, assuming that these fluids are representative of the gut. The aims of this thesis were to develop, evaluate, and apply protocols for the study of gut secretions in man. Saliva was examined as a secretion in its own right, to investigate the relationship between systemic (serum) and mucosal antibodies, and as a potential mirror of immune events occurring more distally in the gut. Methods for the collection and processing of jejunal fluid, and intestinal fluid obtained via whole gut irrigation were then developed. Enzyme linked immunosorbent assay techniques were used to measure total immunoglobulin concentrations and antibody levels to three representative dietary protein antigens, in saliva, intestinal fluid, jejunal aspirate, and serum. Healthy subjects and groups of patients with a variety of gut diseases likely to have increased immunity were examined. There was great physiological variation in immunoglobulin concentrations and antibody levels in saliva, which were universally decreased by eating. In patients on a gluten-free or elemental diet, salivary antibody levels were maintained despite a lack of antigen stimulation. Neither saliva nor serum reflected immunity in gut lavage fluid, the only regularly observed relationship being a positive correlation between serum and saliva, especially after gut mucosal damage has occurred. Differences between control subjects and patients with coeliac disease were insufficient to allow the use of saliva as a diagnostic or clinical tool. Smoking strikingly influenced immunoglobulin concentrations, with a dose-dependent and reversible decrease in salivry IgA, and an increase in IgM. These alterations were not due to changes in the numbers of immunoglobulin-producing cells in the parotid gland. Smoking may also decrease IgA in lavage fluid.
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Ewing, Patricia A., and n/a. "Developmental profiles of mucosal immunity in pre-school children." University of Canberra. Human & Biomedical Sciences, 2000. http://erl.canberra.edu.au./public/adt-AUC20060707.154930.
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Previous studies of the ontogeny of the mucosal immune system have shown a
significant increase in salivary Immunoglobulin A levels occurring at about five years
of age. This study has monitored a group of 3 and 4 year old children during one year
of attendance at Pre-School to examine whether such an increase could be linked to
increased antigenic exposure associated with moving into a school like environment.
Saliva samples were collected at regular intervals and analysed for immunoglobulin and
total protein levels. Daily health records were maintained for each child, and a detailed
social and medical history was collected for each child at the beginning of the study.
The elevated mucosal immune response observed in previous studies involving children
in day care centres and attending school was not seen in this study. No significant
difference was observed between children who had previously attended Pre-School or
child care centres and those who were attending for the first time. However, a marked
seasonal increase in mean salivary IgA during the winter months was observed and this
increase correlated with an increase in respiratory infections. Hence, in studies of
developmental aspects of mucosal immune response it is essential that modifiers such as
season and infection be recorded.
11
Fowler, Sanna Margrethe. "The role of CD4'+ T cells in mucosal immunity." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393226.
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Croft, Nicholas Michael. "Investigation of gastrointestinal mucosal immunity and inflammation in children." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/21172.
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In this thesis I have introduced a new technique, whole gut lavage (WGL), for the study of gastrointestinal secretory immunity in children. Initially I arranged to collect specimens from control children, undergoing whole gut lavage prior to colonoscopy or surgery, at the Royal Hospital for Sick Children, Edinburgh. Whole gut lavage has been used to treat severe constipation and so I organised a study to look at the effectiveness of this, intending both these groups of children as immunologically normal controls. Analysis of specimens from the first five severely constipated children showed that the total IgA levels in all were very low. I went on to examine reasons for these low IgA levels including mucosal IgA deficiency, degradation and interference by other factors in the bowel lumen. Having collected specimens from control children I then arranged a study of intestinal secretory immunity in children with cystic fibrosis (CF). This was stimulated by a paper in the Lancet suggesting that CF children, taking high dose pancreatic enzyme supplements, had developed strictures of the ascending colon possibly due to direct toxic effects of these medications. As CF children have chronic lung infections I then studied the possible influence of respiratory secretions on assays of whole gut lavage fluid by measuring concentrations of immune factors in sputum. With the data from these patient groups I was able to analyse, in some detail, the clinical aspects of whole gut lavage in children. Although I had established that WGL could be an ethical and useful method for research in children it was clear, for clinical reasons, this could not be used for the study of acute diarrhoeal illness, one of the most common paediatric problems involving the gastrointestinal mucosal immune system. With the help of adult patients, I directly compared outputs of immune factors in faeces and whole gut lavage.
13
Brierley, Jennifer L. "Thermoregulation and mucosal immunity : the effects of environmental extremes." Thesis, Bangor University, 2013. https://research.bangor.ac.uk/portal/en/theses/thermoregulation-and-mucosal-immunity--the-effects-of-environmental-extremes(d5e98b6d-b1cf-45f7-8b99-bdf16b844c53).html.
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The main objectives of this thesis were to: 1. investigate the effects of acute and chronic hypoxia on human thermoregulation and mucosal inununity, specifically salivary immunoglobulin A (s-IgA) and salivary alpha-amylase during mild cold exposure at rest (Chapter 4 and 5), 2. identify the effectiveness of four practical field re-warming methods for the field treatment of cold casualties on thennoregulation and metabolism (Chapter 6), 3. examine the s-IgA response during and following mild hypothennia (Chapter 7) and 4. detelmine the efficacy of three field protection methods for the prevention of heat loss in non-shivering cold casualties using an ill vitro torso model exposed to - I8.5°C, O°C and 18.5°C for four hours (Chapter 8). Two hours of exposure to a simulated high altitude of 4000m, regardless of hypoxic acclimatisation, did not alter core or mean skin temperature during cold exposure. Nonetheless, hypoxia reduced metabolic heat production which may cause thel1110regulatory implications during longer bouts of cold exposure. Chronic hypoxia reduced thermal sensitivity to the cold which may lead individuals to neglect appropriate behavioural thelmoregulation and increase the risk of local and whole body cold injuries. Given s-IgA responses were unaffected by hypoxia in the cold before and following the 18 day mountaineering expedition suggests individuals are not at risk from URTI upon arrival to altitude. During a three hour ' awaiting rescue ' scenario following cold water immersion to reduce core temperature, a triple layered, metallised survival product with cells to trap heat and self-activating chemical heat pads was more superior at re-warming cold individuals compared to other methods tested. The insulative attribute of this survival bag may reduce possible shivering-induced fatigue and the subsequent increase in heat loss during more prolonged periods of cold exposure (> 4 hours). A reduction in core temperature (≥ 1.5°C) resulting from cold water immersion and subsequent cold air exposure suppressed the usual daily s-IgA response which may increase susceptibility to illness and infection (i.e. URTI, common colds, influenza) if re-warming is not initiated immediately. A non-shivering, in vitro torso model demonstrated that a triple-layered, metallised survival product with cells to trap heat and self-activating chemical heat pads was the most superior of three field cold protection methods to reduce heat loss during exposure to a variety of ambient temperatures (- 18.5°C, O°C and I8.5°C) for four hours. It would appear when individuals experience cold stress at sea level or altitude, a triple-layered, metallised survival product with cells to trap heat and self-activating chemical heat pads may be the optimal light-weight field treatment to counteract the potential onset of hypothennia. For nonshivering casualties, this survival product may greatly reduce heat loss creating a longer survival time while waiting for evacuation to superior medical treatments (e.g. hospitals). The overall aim of this thesis was to clarify the immediate health risks for individuals exposed to the extreme environments of cold and/or hypoxia, and if simple countermeasures which can be easily administered, offer suitable protection in the field to reduce such risks. The key message of this thesis is that individuals exposing themselves to cold and/or hypoxia when un-acclimatised to such conditions should carry self-administering survival bags and follow a specific programme of monitoring thermoregulation and upper respiratory symptoms in order to remain free of illness (e.g. rhinovirus, bronchitis) and peripheral or central cold injury (e.g. hypothermia and frostbite).
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Biswal, Jitendra Kumar. "Evaluation of mucosal immunity in FMDV vaccinated and infected cattle." Thesis, Royal Veterinary College (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572448.
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Vento, Kevin Leon. "Assessment of protective immunity following mucosal vaccination with Pseudomonas aeruginosa." Thesis, St George's, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408031.
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Tubau, Juni Nuria. "Characterization of Regulatory Mechanisms in Mucosal Immunity by Systems Immunology." Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/104250.
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The mucosal immunity of the gastrointestinal (GI) tract is constituted by a complex, highly specialized and dynamic system of immune components that aim to protect the gut from external threats. The sustained exposure of the mucosal immune system of the GI tract to an enormous number of lumen antigens, requires the constant upkeep of a highly regulated balance between initiation of immune responses against harmful agents and the generation of immune tolerance towards innocuous antigens. Therefore, the regulatory component is key to preserve tissue homeostasis and a normal functioning of the system. Indeed, defective regulatory responses lead to the development of pathological conditions, including unresolved infections, and inflammatory diseases. In this study, we aim to elucidate novel mechanisms involved in host-pathogen interactions during Helicobacter pylori and Clostridium difficile infections. Indeed, this work integrates preclinical in vivo and in vitro experimental approaches together with a bioinformatics pipeline to identify and characterize novel regulatory mechanisms and molecular targets of the mucosal immune system during enteric infections. Firstly, we identified a novel regulatory mechanism during H. pylori infection mediated by a specific subset of IL10-producing tissue resident macrophages. Secondly, we employed an ex vivo H. pylori co-culture with bone marrow derived macrophages, that together with a global transcriptomic analysis and a bioinformatics pipeline, lead to the discovery of promising regulatory genes based on expression kinetics. Lastly, we characterized the innate inflammatory responses induced during the course of C. difficile infection and identified IL-1ß, and its subsequent induction of neutrophil recruitment, as a key mediator of C. difficile-induced effectors responses. The characterized regulatory mechanisms in this work show promise to lead the generation of new host-centered therapeutics through the modulation of the immune response as promising alternative treatments for infectious diseases.Doctor of Philosophy
The immune system is responsible for protecting the human body from external threats. To achieve this goal, it must differentiate between harmless and harmful agents to only fight the latter. To combat these dangerous agents, the immune system induces highly controlled, inflammatory processes that aim to eliminate the external threat while minimizing the damage of human tissues and organs. The gastrointestinal tract is exposed to an enormous number of molecules, mostly harmless molecules from both the ingested food and the beneficial bacteria inhabiting the gut, but also from harmful bacteria and agents, only separated from the internal body structures by a thin layer called the epithelial barrier of the gut. The immune system responsible for the protection of the gastrointestinal tract includes an important regulatory component critical to maintain a proper gut function. This regulatory component regulates the generation of inflammatory processes to fight the dangerous agents, while blocking the responses against the inoffensive agents and preventing excessive tissue damage to maintain the integrity of the epithelial barrier. Indeed, a failure in the regulatory component results in severe consequences for the body's health, such as the inability to resolve infections. In this study, we aim to investigate the interaction between the human body and the enteric bacteria Helicobacter pylori and Clostridium difficile, to bring new insights in the regulatory component of the immune system of the gut. Moreover, the new mechanisms discovered in the regulatory system, might allow the development of new treatments for infectious diseases.
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McCluskie, Michael J. "Strategies for the induction of mucosal immunity against hepatitis B virus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0019/NQ45183.pdf.
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Davidson, Giles Andrew. "Aspects of mucosal immunity in rainbow trout, Oncorhynchus mykiss (Walbaum. 1792)." Thesis, University of Aberdeen, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305007.
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The immunological characteristics of the mucosae of rainbow trout, Oncorhynchus mykiss, were investigated. A technique for the isolation of viable cells from the intestinal and cutaneous mucosae was developed which enabled differential cell counts to be performed on suspensions of cells liberated from these sites. This was achieved using light and electron microscopical, enzyme histochemical and flow cytometric techniques. In cell suspensions derived from the intestinal mucosa, lymphocytes, macrophages and eosinophilic granulocytes (EGC) were present, lymphocytes being by far the most numerous. Goblet cells and epithelial cells were also present but neutrophils were not apparent. In cell suspensions derived from the cutaneous mucosa, lymphocytes, macrophages, neutrophils and several types of cell with hitherto undescribed morphologies were identified. In addition, goblet cells and epithelial cells were present. A small proportion of the cells from the cutaneous mucosa were leucocytes compared with cells from the intestinal mucosa. A small number (about 4%) of lymphocytes from the intestinal mucosa reacted with a monoclonal anti-trout immunoglobulin antibody, suggesting that these cells may be B cells. In the case of the intestinal mucosa it was found to be possible to enrich for certain cell types using Percoll gradients. Functional studies were performed using cells from the intestinal mucosa. These cells were capable of phagocytosing latex microspheres and releasing reactive oxygen species, although only in small quantities compared with cells from the head kidney. Intestinally-derived cells secreted a factor(s) with the ability to induce head kidney cells to migrate and this could be enhanced by treatment of the gut cells with calcium ionophore. Intestinal cells were unable to migrate themselves under the conditions investigated. In addition, intestinal cells were able to proliferate in response to stimulation by the T-cell mitogen phytohaemagglutinin, as determined by incorporation of triated thymidine. Cells isolated from the intestinal mucosa were also able to secrete a macrophage-activating factor (MAF) with the ability to upregulate the production of reactive oxygen species in normal head kidney macrophages.
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Dahele, Anna V. M. "Systemic and gut mucosal immunity to tissue transglutaminase in coeliac disease." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/23318.
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Lundqvist, Carina. "Human intraepithelial lymphocytes a comparative study of phenotype, morphology, and functional properties of intraepithelial lymphocytes in gut and oral mucosa /." Umeå, Sweden : Dept. of Immunology, Umeå University, 1995. http://books.google.com/books?id=TKppAAAAMAAJ.
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West, Nicholas Peter. "Exercise, Immunity and Illness." Thesis, Griffith University, 2011. http://hdl.handle.net/10072/367462.
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Identifying immune biomarkers in healthy humans that indicate an increased susceptibility to upper respiratory tract illness (URTI) is necessary to develop improved diagnostic and treatment strategies. URTI is associated with substantial socio-economic and personal cost. Small to moderate reductions in the severity and duration of illness could lead to substantial reductions in these costs. This thesis investigated the relationship between the immune system and URTI in healthy individuals utilising exercise as a model of stress. Chapter 2 (Section 2.2) reviews the effects of exercise on the immune system and URTI, with a particular focus on the way in which exercise can be used to better understand the role of the salivary antimicrobial proteins (AMPs) lactoferrin and lysozyme in host defence. Determining mucosal immune status, that is the condition of the immune system at body surfaces interfacing with the external environment, is necessary to understand the role of the immune system in host defence. Exercise-related disturbances in the immune system may increase susceptibility to URTI, particularly when prolonged intense exercise is undertaken frequently. Th e link between exercise-induced disturbances in immunity and URTI risk suggests that exercise may be a useful model by which to study the relationship between immunity and illness in healthy individuals.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Physiotherapy and Exercise Science
Griffith Health
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Shirreff, Lisa M. "Characterization of an M. marinum Vaccine| Examination of Both Mucosal Immunity and Systemic Immunity in a Fish Model." Thesis, University of Louisiana at Lafayette, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10163372.
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Mycobacterium marinum (Mm) shares at least 80% amino acid sequence identity with over 3,000 orthologous genes of Mycobacterium tuberculosis (Mtb) and is thus used as a surrogate pathogen for Mtb research. Our laboratory investigates mycobacteriosis using Japanese medaka ( Oryzias latipes) as an aquatic animal model. Mm disease presentation in medaka is similar to Mtb disease presentation in humans, including growth in macrophages, granulomatous lesions, and lifelong chronic disease. We have previously shown that a major route of infection in fish is through an oral route and have thus developed methods to infect medaka with Mm utilizing mosquito larvae as vectors. Recently, our lab was able to show that Mm is able to cross the gut epithelia of medaka in a relatively short-time frame and travel to the underlying submucosa. Therefore, Mm must have the ability to attach to the gut mucosal layer and evade killing by GALT immune cells. Mm is apparently able to exploit macrophages of the mucosal immune system to transport the bacteria to target organs like the head kidney, liver, and spleen for a systemic infection. Utilizing an Mm strain engineered to carry a deletion in the RD-1 region, known to include a number of virulence genes, our lab has shown that mucosal immunity against Mm can be induced in medaka. We have shown that exposure to the mutant RD-1 strain offers some protection against a chronic wild-type oral challenge. Since we know that mutant RD-1 can elicit a mucosal immune response, I tested to see if sensitizing mucosal immunity would also induce systemic immunity by first priming fish with mutant RD-1 and then subsequently challenging them with wild type Mm via an IP route. This thesis demonstrates that mucosal immunity is limited to the gut and thus does not appear to provide broad systemic immunity. Additionally, I tested to see if systemic vaccination would protect against a systemic virulent wild-type challenge by vaccinating and challenging fish via an IP route of infection. Results showed that systemic vaccination does not induce systemic immunity and thus does not protect against an IP injected virulent challenge. Collectively, results from this thesis have shown mutant RD-1 to only be effective as a vaccine against mycobacteriosis if given orally since it was shown to only induce a mucosal immune response and only be protective against an oral virulent wild type challenge.
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Rouxel, Ophélie. "Rôles des cellules MAIT (Mucosal Associated Invariant T) dans la physiopathologie du diabète de type 1." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB114.
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Le diabète de type 1 (DT1) est une maladie auto-immune caractérisée par la destruction sélective des cellules β pancréatiques entraînant une hyperglycémie et nécessitant un traitement par insulinothérapie à vie. La physiopathologie du DT1 est complexe et fait intervenir les cellules immunitaires innées et adaptatives dans la pathogenèse et la régulation du DT1. Alors que le développement du diabète peut être associé à des facteurs génétiques, des facteurs environnementaux sont également impliqués dans le déclenchement de cette maladie. Des études récentes ont mis en évidence le rôle du microbiote intestinal dans le développement ou la protection du DT1. Des modifications du microbiote ont par ailleurs été observées chez les patients DT1 avant le déclenchement de la maladie. Plusieurs études ont également décrit des altérations de la muqueuse intestinale chez les souris NOD et chez les patients DT1. Les cellules MAIT sont des lymphocytes T de type inné reconnaissant la molécule de MR1 et exprimant un TCR Va semi-invariant (Vα7.2-Jα33 chez l'homme et Vα19-Jα33 chez la souris). Les cellules MAIT sont activées par des métabolites bactériens, dérivés de la synthèse de la riboflavine. Leur particularité est de produire rapidement diverses cytokines telles que le TNF-α, l’IFN-γ et l’IL-17 et le granzyme B. La localisation et la fonction des cellules MAIT suggèrent qu'elles pourraient jouer un rôle clé dans le maintien de l'intégrité intestinale et le développement des réponses auto-immunes dirigées contre les cellules β. Dans l’ensemble, nos résultats chez les patients DT1 et chez les souris NOD montrent une activation anormale des cellules MAIT chez les patients DT1. Ces anomalies peuvent être détectées avant le déclenchement de la maladie. L'analyse des tissus périphériques de souris NOD souligne le rôle des cellules MAIT dans deux tissus, le pancréas et la muqueuse intestinale. Dans le pancréas, la fréquence des cellules MAIT est augmentée. Dans ce tissu les cellules MAIT semblent participer à la destruction des cellules β. Contrairement au pancréas, les cellules MAIT situées dans la muqueuse intestinale semblent jouer un rôle protecteur grâce à leur production de cytokines IL-22 et IL-17. Nos données chez les souris NOD Mr1-/-, dépourvues de cellules MAIT, soulignent le rôle protecteur des cellules MAIT lors du développement du DT1 en participant au maintien de l'intégrité intestinale. En outre, la présence d'altérations intestinales à mesure que la maladie progresse chez les souris NOD souligne l'importance des cellules MAIT dans le maintien de l'homéostasie intestinale. De manière intéressante, les cellules MAIT pourraient représenter un nouveau biomarqueur de la maladie et permettre de développer des stratégies thérapeutiques innovantes basées sur l’activation locale des cellules MAITType 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of pancreatic islet β cells resulting in hyperglycemia and requiring a life-long insulin replacement therapy. The physiopathology of T1D is complex and still not entirely understood. Both innate and adaptive immune cells are involved in the pathogenesis and the regulation of T1D. While diabetes development can clearly be associated with genetic inheritance, environmental factors were also implicated in this autoimmune diseases. Recent studies have highlighted the role of the intestinal microbiota in the development or protection against T1D. Gut microbiota analyses in patients have shown differences before the onset of T1D. Moreover, several studies also described gut mucosa alterations in NOD mice and in T1D patients. MAIT (Mucosal Associated Invariant T) cells are innate-like T cells recognizing the MR1 molecule and expressing a semi-invariant receptor Vα chain (Vα7.2-Jα33 and Vα19-Jα33 in mice). MAIT cells are activated by bacterial metabolites, derived from the synthesis of riboflavin. Their particularity is to rapidly produce various cytokines such as TNF-α IFN-γ, IL-17 and granzyme B. The localization and the function of MAIT cells suggest that they could exert a key role in the maintenance of gut integrity, thereby controlling the development of autoimmune responses against pancreatic β cells. To summarize, our results in T1D patients and in NOD mice indicate an abnormal MAIT cell activation in this pathology, which occurs before disease onset. The analysis of peripheral tissues from NOD mice highlights the role of MAIT cells in two tissues, the pancreas and the gut mucosa. In the pancreas, MAIT cells frequency is elevated and they could participate to the β cells death. In contrast to the pancreas, in the gut mucosa MAIT cells could play a protective role through their cytokines production of IL-22 and IL-17. Our data in Mr1-/- NOD mice, lacking MAIT cells, reveal that these cells play a protective role against diabetes development and in the maintenance of gut mucosa integrity. Moreover, the presence of gut alteration as T1D progress in NOD mice underscores the importance of MAIT cells in maintaining gut mucosa homeostasis. Interestingly, MAIT cells could represent a new biomarker towards T1D progression and open new avenues for innovative therapeutic strategies based on their local triggering
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Hu, Ke-Fei. "ISCOMs as delivery systems for mucosal immunization /." Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5417-4.pdf.
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Kay, R. A. "The mucosal regulation of the systemic immune response to cholera toxin." Thesis, University of Edinburgh, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380413.
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McDonald, John Leslie. "The Effects of Acupuncture on Mucosal Immunity in the Upper Respiratory Tract." Thesis, Griffith University, 2015. http://hdl.handle.net/10072/367594.
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Allergic rhinitis is a common disease in Australia, with an estimated 3.17 million Australians affected. Allergic rhinitis represents a significant burden to the community in quality of life and wellbeing, impaired performance, loss of productivity and health care costs. A review was undertaken firstly of the research literature on the efficacy and effectiveness of acupuncture for allergic rhinitis, then secondly of the research into the mechanisms of acupuncture in allergic rhinitis. A total of 4 systematic reviews, 15 randomised controlled trials (RCTs) and other non- randomised studies on acupuncture treatment for allergic rhinitis were reviewed. Acupuncture was reported to significantly reduce signs and symptoms of allergic rhinitis in both children and adults. Evidence of acupuncture efficacy for persistent (perennial) allergic rhinitis was reported to be stronger than for intermittent (seasonal) allergic rhinitis. Multiple physiological pathways appear to mediate the anti-inflammatory effects of acupuncture including the hypothalamic-pituitary-arenal (HPA) axis, sympathetic pathways, descending inhibitory pathways and possibly parasympathetic cholinergic pathways. Studies have also suggested that acupuncture may down-regulate pro- inflammatory neuropeptides and neurotrophins and may shift the Th1/Th2 balance in T helper cells and hence alter allergic status, however the evidence for these actions is inconclusive.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medicine
Griffith Health
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SIDOTI, MIGLIORE GIACOMO. "Bacterial lysate enhances protective mucosal immunity via increased expression of antimicrobial peptides." Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1047077.
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Polyvalent mechanical bacterial lysate (PMBL) has been reported to be effective in the prevention of common respiratory tract infections. PMBL are produced through a process that preserves the structure of the bacterial antigens and because of their immunogenic capabilities, increasing importance is given to its mechanism of action, not yet fully understood. Respiratory tract epithelial cells constitute a front-line physical barrier between the organism and the environment. They are able to sense pathogen associated molecular patterns and secrete a wide spectrum of protective factors. By using primary normal Human Bronchial Epithelial Cells (HBEpiCs), we observed that PMBL can improve epithelial barrier integrity via induction of adhesion molecules. Along with adhesion molecules, PMBL had a significant effect on epithelial cell proliferation increasing the expression of the autocrine growth factor Amphiregulin (AR). Moreover, treatment with PMBL promoted ex-novo gene expression of human beta-defensin 2 (HβD-2) on HBEpiCs and conferred them a direct antimicrobial activity. Epithelial cells are structural components of mucosal immunity that include also dendritic cells (DCs) and innate lymphoid cell-type 3 (ILC3s). PMBL induced IL-23 and IL-1β secretion by DCs that, in turn, activate ILC3s to produce IL-22, cytokine primarily involved in the induction of antimicrobial peptides (AMPs). Interestingly, IL-23 produced by DCs can also activate epithelial cells and lead to a boost of IL-22 production by ILC3s. Remarkably, HβD-2 and LL-37 AMPs can be induced in the saliva of normal subjects after administration of PMBL. Altogether, these results indicate that PMBL administration might support a critical barrier-protective immune pathway that originates from, and is orchestrated by airway epithelial cells and could be therapeutically exploited for the prevention of airway infections.
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Darwish, Ammar. "Systemic and mucosal immunity in patients with periampullary cancer, obstructive jaundice and chronic pancreatitis." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/systemic-and-mucosal-immunity-in-patients-with-periampullary-cancer-obstructive-jaundice-and-chronic-pancreatitis(b6e3ee83-3e4e-4b34-8c36-8eb75c3961cc).html.
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Introduction: Derangement of systemic and mucosal immunity, which are the integral components of the immune system, increases the risk of septic complications in patients postoperatively. The aims of this study were to investigate the integrity of systemic immunity as well as the mucosal immune system in patients with pancreatic cancer (PC), chronic pancreatitis (CP) and obstructive jaundice (OJ).Method: Healthy controls, as well as four groups of patients were studied. These included; jaundiced patients with PC, jaundiced patients secondary to benign disease (choledocholithiasis), non-jaundiced patients with PC and non-jaundiced patients with CP. The study evaluated the nutritional status including anthropometric measurements and the serum proteins: retinal binding protein (RBP), transferrin (TRF) and prealbumin (PALB). This study also evaluated systemic immunity in terms of total lymphocyte count, lymphocyte subsets (CD4+, CD8+, CD25+and CD56+), tumour necrosis factor alpha (TNF- alpha), interleukin-1alpha (IL-1 alpha) and complement components; and mucosal immunity in terms of CD3+, CD4+, CD8+, CD20+, CD57+, CD68+ and mast cells. Results: 78 patients were recruited (including 39 males) as follows: normal controls (n=17), benign OJ (n=9), patients with PC with jaundice (n=23), non-jaundiced patients with PC (n=20) and CP (n=9). Circulating CD25+ and CD4+ were significantly lower in the PC group whereas CD8+ showed increased levels in the same patients with a significant decrease in OJ patients when compared with controls. Circulating CD56+ showed no statistically significant difference between all four groups. In addition, IL-1 and TNF-alpha showed no statistically significant difference in all groups when compared with the control group. Also, C3 and CH50 showed significantly raised levels in PC with jaundice when compared with the control group. On the other hand mucosal lymphocyte subsets showed no statistically significant difference among all groups in comparison with the control group. As for prealbumin and transferrin, both showed significantly low levels in OJ, PC with jaundice and with PC when compared to healthy controls. Survival analysis for both PC groups was carried out and showed no difference in terms of age, however PC patients who survived over 13 months showed increased levels of prealbumin as well as low levels of CH50.Conclusion: Patients with PC both with and without jaundice showed some signs of altered and dysfunctional systemic immunity as well as a reduction in serum proteins. These findings may have implications on the disease progression and postoperative complications. This may warrant therapeutic interventions to restore nutrition and improve immunity before major surgical intervention is planned which could result in improving prognosis.
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Jackson, Courtney M. "Chorioamnionitis induces systemic and mucosal immune responses in the developing fetus." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592818915104982.
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Hou, Lin. "The distribution and characterization of protease-activated receptors in oral mucosa and skin." Thesis, Queen Mary, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286544.
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SPOSITO, BENEDETTA. "Type III Interferons: Running Interference with Mucosal Repair." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2023. https://hdl.handle.net/10281/402377.
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Gli interferoni (IFN) sono mediatori e regolatori fondamentali della risposta immunitaria dell'ospite a virus e ad altri agenti microbici. Gli IFN di tipo I e di tipo III (o IFN-λ) sono tra le prime citochine ad essere indotte in seguito a infezioni virali. Il legame tra gli IFN e i rispettivi recettori attiva vie di trasduzione del segnale simili tra loro che inducono l'espressione di geni stimolati dagli IFN (ISG) con funzioni antivirali. La caratteristica principale che rende ciascuna di queste famiglie di IFN unica e non ridondante è l'esistenza di recettori distinti che fanno sì che gli IFN-I attivino una risposta ubiquitaria e che gli IFN-III agiscano esclusivamente sulle cellule epiteliali e su un sottoinsieme di cellule immunitarie. Ulteriori distinzioni riguardano la natura meno infiammatoria degli IFN-III e la loro induzione solitamente anticipata rispetto a quella degli IFN-I. Pertanto gli IFN-III sono considerati i difensori di prima linea delle mucose con la capacità di attivare una risposta antivirale precoce senza causare danno tissutale. Se la loro azione risulta insufficiente a contenere l’infezione, il sistema passa all’induzione degli IFN-I, i quali generano una risposta antivirale e infiammatoria più potente e a livello sistemico, che tuttavia può portare ad immunopatologia. Nel corso della mia tesi ho verificato l'ipotesi secondo cui anche gli IFN-III possano causare immunopatologia, in particolare durante infezioni virali delle vie respiratorie e in contesti di danno all’epitelio gastrointestinale in malattie infiammatorie croniche intestinali e lesioni da radiazioni.
In primo luogo, io e i miei colleghi abbiamo dimostrato che in un polmone in cui è stata indotta una risposta antivirale, gli IFN-III prodotti dalle cellule dendritiche inibiscono la proliferazione delle cellule epiteliali portando ad una compromissione del rigenerazione della barriera e ad un aumento della suscettibilità ad infezioni batteriche. In seguito abbiamo analizzato la produzione di IFN lungo il tratto respiratorio di pazienti affetti da COVID-19. Abbiamo trovato che, nelle alte vie aeree, l'espressione di IFN-I/III correla con la carica virale e che negli anziani, che presentano un maggiore rischio di sviluppare una patologia severa, questa correlazione è più debole o assente. Una forte espressione di IFN-λ1, IFN-λ3 e ISG caratterizza le alte vie aeree di pazienti con sintomatologia lieve, mentre risultano fortemente espressi gli IFN-I, IFN-λ2 e un insieme di geni antiproliferativi e proapoptotici lungo tutto il tratto respiratorio di pazienti ospedalizzati, suggerendo che possano ostacolare il processo di riparazione dell’epitelio. Infine, abbiamo dimostrato che gli IFN-III ritardano la rigenerazione dell'intestino tenue e del colon in seguito a danno da radiazioni o da colite indotta da destrano sodio solfato, poiché contribuiscono a indurre la morte cellulare delle cellule epiteliali tramite la formazione di un complesso proteico costituito da Z-DNA binding protein (ZBP1) e gasdermin C (GSDMC).
I nostri risultati mettono in discussione il ruolo degli IFN-III come protettori delle mucose poiché indicano che quando non propriamente regolati possono causare immunopatologia. Queste evidenze portano alla necessità di progettare l’uso clinico degli IFN di tipo III in modo da evitare le loro funzioni dannose per i tessuti e massimizzarne gli effetti benefici.Interferons (IFNs) are fundamental mediators and regulators of the host immune response to viruses and other microbial agents. Type I and type III IFNs (also known as IFN-λ) are some of the first cytokines to be induced upon detection of viral infections. Signaling through their specific receptors leads to the activation of a similar signaling cascade that triggers the expression of a common set of IFN-stimulated genes (ISGs) with antiviral effector functions. The main feature that makes each of these families of IFNs unique and nonredundant is the existence of distinct receptors that differentiate them in their ability to act on virtually every cell type (type I IFNs) or exclusively on epithelial cells and a subset of immune cells (type III IFNs). Despite inducing a widely overlapping set of genes, IFN-I can mount a stronger proinflammatory response compared to IFN-III. This, coupled with the earlier induction of IFN-III upon infection, has led to the classification of IFN-III as front-line defenders of mucosal surfaces with the ability to initiate an early antiviral response with minimal tissue-damaging effects. If their response is insufficient the system shifts to the more potent and broader-acting antiviral and inflammatory IFN-I response that can cause immunopathology. In the course of my thesis, I have tested the hypothesis that also IFN-III contribute to immunopathology at barrier sites such as the respiratory and gastrointestinal epithelia during viral infections and inflammatory bowel disease/radiation-induced injury respectively. First, my colleagues and I found that in a mouse model where we mimicked the induction of antiviral responses in the respiratory tract, IFN-III produced by lung dendritic cells inhibited the proliferation of lung epithelial cells leading to an impairment in barrier restoration and an increase in susceptibility to bacterial infections. Then we measured IFN responses along the respiratory tract of COVID-19 patients. We uncovered that in the upper airways expression of IFN-I/III correlated with viral load and elderly patients, that have a higher risk of developing severe COVID-19, had a dysregulation in the IFN response. A strong expression of IFN-λ1, IFN-λ3 and ISGs characterized the upper airways of mild patients. IFN-I and IFN-λ2 together with antiproliferative and proapoptotic genes were upregulated along all the respiratory tract of severe COVID-19 patients, suggesting that they might contribute to the impairment of epithelium restitution. Finally, we demonstrated that IFN-III delayed colon and small intestine repair after dextran sulfate sodium-induced colitis and radiation-induced injury by triggering cell death of epithelial cells via the formation of a novel protein complex that includes Z-DNA binding protein (ZBP1) and gasdermin C (GSDMC). Our findings challenge the role of IFN-III as protectors of mucosal barriers as they indicate that a dysregulated IFN-III response holds the potential to contribute to immunopathology. Therefore, the clinical use of type III IFNs should be designed in such a way that their tissue-damaging functions are avoided and their beneficial effects are maximized.
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Da, Silva Clément. "Fonction des phagocytes de la plaque de Peyer dans la réponse immunitaire mucosale." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0251.
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Nous avons mis en évidence la présence des phagocytes exprimant le lysozyme dans les Plaque de Peyer chez l’Homme et montré que, comme chez la souris, elles sont principalement localisées dans le SED et sont distinctes des cDC. Dans un deuxième temps, nous avons étudié dans les PP de souris la fonction des différentes populations de phagocytes nouvellement caractérisées. Nous avons en particulier étudié l’impact de la détection d’un acide nucléique d’origine virale par les phagocytes en utilisant un agoniste synthétique du TLR7 : le R848. Bien que TLR7 soit exprimé par les cellules dérivées de monocytes et les DC plasmacytoïdes mais pas par les cDC, nous avons mis en évidence un processus d’activation rapide des cDC impliquant le TNF. Celui-ci conduit à une migration des cDC depuis les villosités adjacentes au dôme vers les IFR et à une forte augmentation de l’expression du CMH-II, des molécules co-stimulatrices ainsi que des gènes dépendants de l’interféron. L’activation du TLR7 induit également une forte expression de la sous unité p40 de l’IL-12 par les LysoDC et certains macrophages. De manière intéressante, nous avons également observé une forte expression d’IL-12 p40 par les LysoDC et certains macrophages peu de temps après le sevrage. Cela nous a conduits à étudier le rôle de cette cytokine dans la mise en place de la réponse immunitaire mucosale. Notre étude a donc des répercussions sur la compréhension des mécanismes conduisant à la mise en place de la réponse immunitaire mucosale en réponse à l’implantation du microbiote intestinal peu de temps après la naissanceIn this study, we first showed that lysozyme expressing cells are found in human PP and share features with their mouse counterpart, such as location and origin. Then, we investigated the behaviour of mouse PP phagocytes upon TLR7 stimulation, using the small synthetic agonist, R848. In PP TLR7 is expressed by monocyte derived cells and plasmacytoid DC, but not by cDC. Nevertheless, TLR7 stimulation triggers a quick activation of cDC. This activation relies on TNF secretion and leads to a massive migration of cDC from the dome associated villi to the IFR and to an increase of MHCII, co-stimulatory molecules and interferon-stimulated gene expression. Stimulation by TLR7 also induces a massive production of IL12p40 by LysoDC and some macrophages. Interestingly, we observed a similar increase of IL-12 p40 production by LysoDC and macrophages shortly after weaning. We thus investigated the impact of Il-12 p40 secretion on the development of the mucosal immune response. Therefore, our study provides clues on the mechanisms involved in the establishment of the mucosal immune response following microbiota colonization
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Gold, Matthew Joshua. "Role of group 2 innate lymphoid cells and SHIP-1 in mucosal immunity." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/51891.
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Mucosal surfaces present an important barrier between the host and environment. Maintenance of barrier function requires intricate cross-talk between a diverse array of immune cells and the epithelia, acting synergistically to respond to harmful antigens and maintain tolerance to innocuous antigens. In this thesis I utilized an array of transgenic animals to explore the cellular and molecular mechanisms that initiate adaptive immune responses in the lung and gut mucosa.
Recently, innate lymphoid cells have been characterized for their role in maintaining barrier immunity. Group 2 innate lymphoid cells (ILC2s) colonize the lung and provide a rapid source of IL-5 and IL-13 in a T and B cell independent manner in response to protease antigens. Using ILC2-deficient mice, I examined the role of these cells in mucosal inflammation using mouse models of allergic asthma and hypersensitivity pneumonitis (HP). ILC2s were critical in initiation of a Th2 response to locally, but not systemically delivered allergens and were completely dispensable for Th1 and Th17 dependent responses.
The PI3K pathway plays an important role in regulating leukocyte activation, survival, migration and cytokine release. It is negatively regulated by the lipid phosphatase Ship1, and Ship1-/- mice develop a wide array of hematological disorders leading to a reduced lifespan. The severe phenotype associated with loss of Ship1 throughout the immune systems masks subtler roles it plays in specific leukocyte subsets. Using a conditional deletion approach, I examined the role of Ship1 in T cells, B cells and dendritic cells (DCs) in mouse models of allergic asthma and helminth infection. While loss of Ship1 in B cells did not influence susceptibility to a HDM model of allergic asthma, loss of Ship1 in either the T cells or DCs protected from disease development due to an immune skewing to a Th1 response. Additionally, loss of Ship1 in DCs rendered mice susceptible to infection with the intestinal helminth Trichuris muris, further highlighting this Th1 immune skewing.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Mills, Jamie-Lee S. "Modelling natural immunity to streptococcal mucosal infections and novel approaches to vaccine delivery." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/414917.
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Streptococcus pyogenes causes significant global morbidity and mortally through a range of pathologies. The most common sites of infection are the upper respiratory tract and the skin, resulting in pharyngitis and impetigo respectively. Non-invasive infections are usually self-limiting; however, they have the potential to progress to life threatening invasive diseases such as toxic-shock syndrome and necrotizing fasciitis with a high rate of mortality. Furthermore, S. pyogenes infections can give rise to auto-immune sequelae of ARF/RHD and ASPGN that result in approximately 500 000 deaths each year. Despite global efforts that span decades, no human vaccine is approved for use. The major hurdles in vaccine development are the broad serotypic and antigenic diversity of S. pyogenes, the risk for potential auto-immune disease due to the molecular mimicry of the S. pyogenes M-protein (a prime vaccine target) and human cardiac myosin, and the ability of S. pyogenes to infect different body sites that require different protective immune mechanisms.
Previous research has shown that exposure to S. pyogenes can result in protective antibodies, though immunity is slow to develop and its role in preventing subsequent infections is poorly understood. In addition, there is a need to understand the mechanism of cross-compartment immunity to aid in guiding vaccine development to protect from multiple serotypes and also at various infection sites. To understand the mechanisms involved in site-specific and cross-compartment immunity, repeated mucosal exposures to S. pyogenes non-lethal infections in mice were performed to mimic endemic settings. Repeated homologous mucosal infections resulted in significant site-specific protection that endured for at least 9 weeks. Mice developed type-specific serum antibodies and antibody secreting cells (ASCs) that increased with increasing number of infections. These data indicate that the longevity of the antibody response is governed by the number of prior mucosal infections; however, no direct correlation with protection was established. Mucosal protection indicated a role for cell-mediated immunity. Repeated acute mucosal infections resulted in significant neutrophil recruitment to the local site of inflammation that correlated with protection.
Cytokine analysis suggested a role for IL-17A in mucosal protection, particularly for enduring protection. To assess the importance of IL-17, IL-17 knockout (IL-17-/-) mice were given repeated homologous mucosal infections. Unlike wild type BALB/c mice, IL-17-/- mice failed to generate mucosal protection with repeated exposures. Furthermore, IL-17-/- mice had significantly reduced M-protein type-specific salivary IgG, IgG and IgA-secreting cells in bone marrow, and neutrophil influx to the lung, correlating with lack of protection.
Mice required only one prior mucosal infection to develop significant and long-lasting protection against a homologous mucosal challenge. However, when cross-compartment protection at the skin was assessed, mice required a minimum of four repeated mucosal infections to generate significant protection. These data suggest that developing a protective immune response by repeated exposures is unlikely in a real-world setting. The literature indicates that multiple different S. pyogenes types move through communities, and people rarely encounter the same strain again within a short period of time. Realising these constraints in developing naturally acquired immunity to S. pyogenes, the next question was then asked: ‘could vaccine mediated immunity be boosted and broadened via natural exposures to S. pyogenes?’
Vaccine candidates based on the conserved C-terminal region of S. pyogenes M-protein (p145) have made considerable progress. The C-terminal region of the M protein is conserved across the majority of S. pyogenes strains, therefore forgoing the issue of serotype diversity. Two vaccine epitopes at the forefront of development, J8 and p*17, when conjugated to the carrier protein, diphtheria toxoid (DT), create J8-DT and p*17-DT.
p*17-DT delivered intramuscularly with the adjuvant, alum, (p*17-DT/Alum) has shown promising immunogenicity and protection against several S. pyogenes isolates; however, it does not protect mice against intranasal challenge with a hypervirulent covR/S mutant strain. To test the hypothesis that infection will boost vaccine-mediated immunity, mice received two vaccinations with p*17-DT/Alum, followed by repeated mucosal infections every three weeks with heterologous isolates. Mice that received vaccinations followed by sequential infections showed increasing protection against NALT (nasal associated lymphoid tissue) bacterial load with each subsequent infection when compared to naïve mice. Bacterial load in the NALT was significantly reduced in these mice following a covR/S mutant challenge. Antigen-specific ASCs were assessed as a determinant of humoral immunity. Although no increase in serum antibody levels or antibody avidity were observed between mice that received vaccination alone or when followed by repeated infections, the mice that received vaccination and sequential infections had significantly increased IgG secreting cells in the spleen. The ASCs, in combination with lung specific CD4+ T-cell responses may be contributing to increased protection seen in mice that were boosted with repeated heterologous infections. Although promising, the results were scattered, which may be attributed to the differences in sequence homology of p145 as well as characteristics of different isolates. These data suggest that vaccine-mediated immunity has the potential to be boosted with repeated exposures to S. pyogenes. However, it was demonstrated that there is room for improvement in vaccination strategy and alternative approaches should be explored. Therefore, the next aim was to assess if new delivery methods could be used to increase vaccine-mediated immunogenicity and protection.
Different methods of vaccine delivery can invoke varied immune responses. Skin-based immunisation routes have gained attention due to targeting of the epidermis and dermis layers rich in immune cells. Several advantages are associated with cutaneous routes, particularly when using high density/micro array patches (MAPs and HD-MAPs). These include dose sparing, enhanced thermostability, ease of administration, reduced generation of sharp-waste and risk of needle-stick injuries, good tolerability and enhanced acceptability in patients. HD-MAPs, developed by Vaxxas Pty Ltd, are at an advanced stage of development and have shown promising clinical trials results. The aim of his final study was to determine if the M-protein-based vaccine candidate J8-DT would have comparable immunogenicity and protection if delivered on the adjuvant free HD-MAP in comparison to intramuscular delivery.
The effect of dose sparing and the number of vaccinations on the antibody response profile of vaccinated mice were assessed. A reduction in the number of vaccinations (from three to two) with J8-DT/HD-MAP induced comparable antibody responses to three vaccinations with intramuscular J8-DT/Alum. J8-DT/HD-MAP vaccination led to a significant reduction in the number of S. pyogenes colony forming units in skin (92.9%) and blood (100%) compared to intramuscular vaccination with unadjuvanted J8-DT when assessed following skin challenge. J8-DT/HD-MAP induced a shift in the antibody isotype profile, with a bias towards Th1-related isotypes, compared to J8-DT/Alum (Th2 bias). Based on the results of this study, the use of J8-DT/HD-MAP should be considered in future clinical development and control programs against S. pyogenes.
The studies in this thesis demonstrate the constraints in developing naturally acquired immunity and highlight the importance for developing an effective vaccine against S. pyogenes.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Science, Environment, Engineering and Technology
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Permpoonpattana, Patima. "Clostridium difficile : infection and immunity." Thesis, Royal Holloway, University of London, 2013. http://repository.royalholloway.ac.uk/items/33009ec4-7815-0803-d39b-f968c8d9cdbb/7/.
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Clostridium difficile is a Gram positive pathogen of significant importance in the UK, Europe and the USA. No vaccine has been developed and current treatments are focused on hospital management and the use of antibiotics. The disease is spread in hospitals in the spore form and the role of spores in C. difficile infecton is poorly understood. In this project spores of C. difficile have been characterised. The proteins from the outermost layers of the spore were identified and the genes cloned. Three of these surface proteins have unique enzymatic properties that maybe important for symptoms of disease. The ability of C. difficile spores to adhere to intestinal cells was found to be far greater than with live cells and through this we have identified that the spore may play an important role in colonisation. The regulation of spore coat gene expression during sporulation was also examined and temporal phases of genes expression identified. A major part of this project was to develop a mucosal vaccine to C. difficile. The approach used was to clone the C-terminus of toxin A onto the surface of Bacillus subtilis spores and use these recombinant spores to immunise mice and hamsters. We found that oral delivery of these spores conferred 75% protection to C. difficile infection in a hamster model of infection. Further, parenteral immunisation of the same antigens (toxin A and B) failed to generate mucosal responses and this showed that mucosal immunisation is critical for good protection. Finally, we found that antibodies to the C-terminus of toxin A were cross reactive to the C-terminus of toxin B. This showed that mucosal delivery of just the C-terminus of toxin A is sufficient to confer protection in an animal model of infection. The outcome of this work is that we have shown the parameters for successful immunisation and vaccination against C. difficile.
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Ruberti, Maristela 1975. "Caracterização fenotípica e funcional das células imunocompetentes da mucosa intestinal envolvidas na tolerância oral a ovalbumina." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317404.
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Orientador: Wirla Maria da Silva Cunha TamashiroTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-20T10:43:40Z (GMT). No. of bitstreams: 1 Ruberti_Maristela_D.pdf: 10774061 bytes, checksum: 7afe7ee8aa8c7f97c1f80e66f0cd8bfa (MD5) Previous issue date: 2012
Resumo: Trabalhos anteriores de nosso laboratório mostraram que camundongos transgênicos DO11.10, cuja maioria dos linfócitos T expressam TCR específico para ovalbumina (OVA) no contexto de...Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital
Abstract: Previous work from our laboratory showed that DO11.10 transgenic mice, in which the most of T lymphocytes express TCR specific for ovalbumin (OVA) in the context of...Note: The complete abstract is available with the full electronic document
Doutorado
Imunologia
Doutor em Genetica e Biologia Molecular
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Martin, Tara L. "The STING Ligand 3’3’-cGAMP Effectively Elicits Mucosal and Systemic Immunity Following Sublingual Immunization." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461331044.
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Rodríguez, Ariane. "Mucosal immunity in the respiratory tract : The role of IgA in protection against intracellular pathogens." Doctoral thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-388.
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The lungs and upper airways are mucosal surfaces that are common site for infection with an enormous variety of inhaled pathogens. Therefore, induction of immune responses in the respiratory tract is crucial for protection against respiratory diseases.
One of the pathogens infecting the host via the respiratory tract is Mycobacterium Tuberculosis. The reported efficacy of the currently used Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis is highly variable, ranging from 50% against pulmonary tuberculosis to 80% against disseminated tuberculosis. Recently, the current route of vaccination (intradermal) has been considered as a possible factor influencing the protective capacity of the BCG vaccine. In this regard, intradermal route most likely induces protective systemic responses while it fails to induce optimal responses in the lungs. Therefore, our working hypothesis is that vaccination should be directed towards the respiratory mucosal immunity in order to improve the degree of host protection in the lungs.
In this thesis we studied the effect of the route of immunization as well as of different mucosal adjuvants on the induction of mucosal immune responses against the mycobacterial surface antigen PstS-1. We found that, the intranasal (i.n.) route of immunization was a more favorable route inducing strong local immune responses, than intraperitoneal (i.p.) route. Indeed, i.n. route immunization, unlike the i.p. route, elicited strong IgA responses in the lungs accompanied by a major influx of CD4+ T cells and a significant local production of IFN-gamma.
IgA, being the predominant Ig isotype at mucosal tissues, is considered a major effector molecule involved in defense mechanisms against viral and bacterial pathogens at these sites. Therefore, we investigated the possible role of IgA in the protection of the respiratory mucosa against mycobacterial infections, using mice deficient in IgA and in the polymeric Ig receptor. We show that, deficient mice are more susceptible to mycobacterial infections than wild type mice, thereby demonstrating a role for IgA in protection against mycobacteria. Importantly, our studies revealed a reduced production of protective factors, such as INF-gamma and TNF-alpha in the lungs of deficient mice that was associated with the higher susceptibility seen in these mice compared to wild-type mice. We also conducted challenge experiments against another respiratory pathogen, Chlamydia pneumoniae, using IgA deficient mice. Likewise to mycobacteria, our data support a role for IgA in the protection of the respiratory tract against C. pneumoniae infection.
Finally, we investigated the possible mechanisms explaining the reduced pro-inflammatory responses in IgA deficient mice. Our data indicated that IgA deficient mice present a defective response to stimulation with LPS or 19kDa which appears to be both, essentially due to suboptimal stimulation of macrophages and restricted to the lungs.
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Rodrʹiguez, Muñoz Ariane. "Mucosal immunity in the respiratory tract : the role of IgA in protection against intracellular pathogens /." Stockholm : Dept. of Immunology, The Wenner-Gren Institute, Stockholm University, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-388.
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Morris, Bruce C. "Intestinal Mucosal Mast Cell Immune Response and Pathogenesis of Two Eimeria Acervulina Isolates in Broiler Chickens." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/36228.
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Five experiments were conducted comparing differential intestinal immune responses to two isolates of Eimeria acervulina (EA), EA1 and EA2. In three experiments, broiler chicks were divided into control (non-challenged), EA1, or EA2 challenged (14 days of age) groups. On day 6 post-challenge (PC), changes in body weight were determined, intestinal lesions were scored, and duodenal tissue was evaluated for morphometric alterations and mucosal mast cell responses. EA1 produced duodenal lesions and reduced villus height to crypt depth ratios when compared to controls; however, no differences were found in mast cell counts. EA2 produced differing results, and observed data were suggestive of an intestinal secretory response when compared to EA1 or controls. In Experiment 4, tissues were analyzed from day 2 through day 6 PC. Villus atrophy and crypt hyperplasia were heightened on day 5 PC in both challenged groups. Mast cell counts were significantly greater on days 3 and 4 PC in EA1 birds. In Experiment 5, EA2 oocysts were cleaned with 5.25% sodium hypochlorite to evaluate the possibility of a bacterial contaminant contributing to the pathogenesis of intestinal alterations. Weight gains were decreased by challenge and villus heights and crypt depths were significantly altered in challenged birds, resulting in lower villus to crypt ratios, however, there were no differences in mast cell number. These data are indicative of differential host response and immunovariability between different isolates of the same Eimeria species and are suggestive of mast cell involvement in coccidial immunity in broiler chickens.Master of Science
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Srinivasan, N. "The role of inflammasomes in intestinal inflammation." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:04ad577c-a8dd-46eb-811a-79a3980ff806.
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Single Nucleotide Polymorphisms (SNPs) in the intracellular pattern recognition receptor gene NLRP3 are associated with susceptibility to Crohn’s disease, a form of inflammatory bowel disease (IBD). Following cell damage or infection, NLRP3 triggers the formation of inflammasomes, a multimolecular protein complex containing NLRP3, ASC and caspase-1, which mediate secretion of IL-1β and IL-18. NLRP3 inflammasome activation in macrophages has been implicated in protection against several pathogens, but whether NLRP3 activation in tissue cells contributes to protective immunity against bacterial pathogens is unknown. We show that upon infection with the attaching/effacing (A/E) intestinal pathogen Citrobacter rodentium, Nlrp3-/- and Asc-/- mice displayed higher bacterial colonization, more weight loss and exacerbated intestinal inflammation. We further show that Nlrp3 inflammasome activation in intestinal epithelial cells (IECs) acts rapidly after infection to limit bacterial replication and penetration, and inhibits the development of inflammatory pathology in the gut. We also show that epithelial Nlrp3-mediated protection is independent of the classical inflammasome cytokines IL-1β and IL-18. Thus an Nlrp3-Asc circuit in IECs regulates early defense against a mucosal pathogen and limits inflammation in the intestine. Nlrp3 inflammasome activation has also been implicated in protection in acute models of experimental colitis, but its role in chronic models of colitis is unknown. We found that Asc signaling is necessary for the development of innate chronic intestinal inflammation driven by Helicobacter hepaticus. Thus while deficient inflammasome signaling in tissue cells increases susceptibility towards enteric pathogens, excessive inflammasome activation can drive chronic intestinal inflammation.
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Ambrose, Zandrea. "Immune control of SHIV in macaques upon mucosal infection of immunization /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/9290.
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Clever, David C. Clever. "T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519.
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Junior, Andrés Jimenez Galisteo. "Toxoplasma gondii vs radiação ionizante: imunidade humoral e celular em baço e intestino de camundongos isogênicos imunizados com taquizoítos irradiados por Cobalto 60." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-17082009-173434/.
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Toxoplasma gondii vs radiação ionizante: Imunidade humoral e celular em baço e intestino de camundongos isogênicos imunizados com taquizoítos irradiados por Cobalto 60 Andrés Jimenez Galisteo Jr. Estudamos o desenvolvimento de uma vacina para toxoplasmose utilizando a radiação ionizante como ferramenta. Aqui avaliamos o desenvolvimento da imunidade sistêmica e intestinal e a resistência à infecção, em diferentes camundongos imunizados, por via oral e parenteral, com taquizoítos irradiados a 255 Gy e desafiados com cistos da cepa ME49. Camundongos C57Bl/6j, BALB/c e C57Bl/6j IFN--/- foram imunizados com 107 taquizoitos de T. gondii irradiados a 255Gy por diferentes vias. As preparações de taquizoítos irradiados, por via oral e parenteral, induziram produção de imunoglobulinas IgG e IgA no soro de camundongos, sendo predominante a subclasse de IgG2b, determinadas por ELISA. A produção de IgM foi mínima. Os animais imunizados pela via parenteral, apresentaram uma maturação mais rápida da avidez de anticorpos IgG que os animais imunizados por via oral. Houve excreção de IgG, IgA e IgM nas fezes dos animais imunizados, mais intensa nos animais imunizados por via oral. No estudo da imunidade celular induzida por antígeno e detectada for real-time PCR, houve uma grande produção de IFN- por células esplênicas, menor por células das placas de Peyer intestinais, onde houve maior produção de IL-2. Houve proteção em todos os nossos esquemas avaliados, maior nos animais BALB/c. Os animais deficientes de IFN-, não foram afetados pelo processo de imunização e apresentaram produção de IgG e IgA sérico e excreção de S-IgA e S-IgM nas fezes, com menor numero de cistos cerebrais em animais imunizados por via parenteral. Todos nossos dados apontam para a possibilidade do desenvolvimento de uma vacina oral para toxoplasmose, utilizando taquizoítos irradiados, com aplicação prática na imunização de felinos domésticos e selvagens.We are developing a vaccine for toxoplasmosis, using ionizing radiation as a tool. Here we analyzed the production of sytemic and intestinal immunity, with protection studies, in several strains of inbred mice, by oral or parenteral route, using 255 Gy irradiated tachyzoites of T. gondii RH strain, with challenge with cysts of ME- 49 strain. C57Bl/6j, BALB/c and C57Bl/6j IFN--/- mice were immunized with 107 irradiated tachyzoites, be parenteral or oral route. Those preparations, both by parenteral or oral routes, induced the production of specific IgG, mainly of the IgG2b subclass, and IgA immunoglobulins in serum, , as determined by ELISA. IgM production was negligible. Parenteral immunized mice showed higher IgG avidity maturation, as compared to oral immunized mice. Fecal excretion of IgG, IgA and IgM was detected in stools of immunized animals, more intense in oral immunized mice. In cellular immunity studies, induced by antigen, with detection of cytokine production by quantitative real-time PCR, there are a great production of IFN- by spleen cells, with lower levels in Peyer patches cells, where there are a greater IL-2 production. Challenge studies in immunized mice demonstrated protection to infection in all used schedules, greater in BALB/c mice. C57Bl/6j IFN--/- mice, when immunized, showed no signs of disease and produced similar or greater levels of antibodies than wild type mice. They also excreted S-IgA and S-IgM in stools, but with low numbers of brain cysts in parenteral immunized mice, despite similar mortality. Our data points to a fair possibility of use of those irradiated parasites as an oral vaccine, devised to use for veterinary or wild felines vaccination, reducing the production of oocysts by those hosts and interrupting the chain transmission of human toxoplasmosis.
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Liang, Bin. "Characterisation of the mucosal immunity in the nasal-associated lymphoid tissue following influenza A virus infection." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271049.
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Ohue, Ryuji. "Studies on the regulatory responses of mucosal immunity to the environmental changes in the gastrointestinal tract." Kyoto University, 2012. http://hdl.handle.net/2433/157716.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第16925号
農博第1941号
新制||農||1001(附属図書館)
学位論文||H24||N4686(農学部図書室)
29600
京都大学大学院農学研究科食品生物科学専攻
(主査)教授 谷 史人, 教授 伏木 亨, 教授 井上 國世
学位規則第4条第1項該当
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Stoicov, Calin. "Pathogenesis of the Helicobacter Induced Mucosal Disease: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/477.
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Helicobacter pylori causes chronic gastritis, peptic ulceration and gastric cancer. This bacterium is one of the most prevalent in the world, but affects mostly the populations with a lower socioeconomical status. While it causes gastric and duodenal ulcers in only 20% of infected patients, less then 1% will develop gastric adenocarcinoma. In fact, H. pylori is the most important risk factor in developing gastric cancer. Epidemiological studies have shown that 80% of gastric cancer patients are H. pylori positive. The outcome of the infection with this bacterium depends on bacterial factors, diet, genetic background of the host, and coinfection with other microorganisms. The most important cofactor in H. pylori induced disease is the host immune response, even though the exact mechanism of how the bacterium is causing disease is unknown.
The structural complexity of Helicobacter bacteria makes us believe that different bacterial factors interact with different components of the innate immunity. However, as a whole bacterium it may need mainly the TLR2 receptor to trigger an immune response. The type of adaptive immunity developed in response to Helicobacter is crucial in determining the consequences of infection. It is now known for decades that a susceptible host will follow the infection with a strong Th1 immune response. IFNγ, IL-12, IL-1β and TNF-α are the key components of a strong adaptive Th1 response. This is further supported by our work, where deficient T-bet (a master regulator for Th1 response) mice were protected against gastric cancer, despite maintaining an infection at similar levels to wild type mice. On the other hand, a host that is resistant to Helicobacter develops an infection that is followed by a Th2 response sparing the mucosa from severe inflammation. Human studies looking at single nucleotide polymorphism of cytokines, like IL-1β, IL-10 and TNF-α have clearly demonstrated how genotypes that result in high levels of IL-1β and TNF-α, but low IL-10 expression may confer a 50-fold higher risk in developing gastric cancer.
The outcome of Helicobacter infection clearly relies on the immune response and genetic background, however the coinfection of the host with other pathogens should not be ignored as this may result in modulation of the adaptive immunity. In studying this, we took advantage of the Balb/C mice that are known to be protected against Helicobacter induced inflammation by mounting a strong Th2 polarization. We were able to switch their adaptive immunity to Th1 by coinfected them with a T. gondii infection (a well known Th1 infection in mice). The dual infected mice developed severe gastritis, parietal cell loss and metaplastic changes. These experiments have clearly shown how unrelated pathogens may interact and result in different clinical outcomes of the infected host.
A strong immune response that results in severe inflammation will also cause a cascade of apoptotic changes in the mucosa. A strict balance between proliferation and apoptosis is needed, as its disruption may result in uncontrolled proliferation, transformation and metaplasia. The Fas Ag pathway is the leading cause of apoptosis in the Helicobacter-induced inflammation. One mechanism for escaping Fas mediating apoptosis is upregulation of MHCII receptor. Fas Ag and MHCII receptor interaction inhibits Fas mediated apoptosis by an impairment of the Fas Ag receptor aggregation when stimulated by Fas ligand. Because H. pylori infection is associated with an upregulation of the MHCII levels on gastric epithelial cells, this indeed may be one mechanism by which cells escape apoptosis.
The link between chronic inflammation and cancer is well known since the past century. Helicobacter infection is a prime example how a chronic inflammatory state is causing uncontrolled cell proliferation that results in cancer. The cell biology of “cancer” is regarded not as an accumulation of cells that divide without any control, but rather as an organ formed of cancer stem cells, tumor stromal support cells, myofibroblasts and endothelial cells, which function as a group. The properties of the cancer stem cells are to self-renew and differentiate into tumor cells thus maintaining the tumor grow, emphasizing that a striking similarity exists between cancer stem cells and tissue stem cells.
We looked into what role would BMDCs play in chronic inflammation that causes cancer. Using the mouse model of Helicobacter induced adenocarcinoma we discovered that gastric cancer originates from a mesenchymal stem cell coming from bone marrow. We believe that chronic inflammation, in our case of the stomach, sets up the perfect stage for bone marrow stem cells to migrate to the stomach where they are exposed to inflammatory stimuli and transform into cancer stem cells. One of the mechanism by which the MSC migrate to the inflammation site is the CXCR4/SDF-1 axis.
Our work sheds new light on Helicobacter induced gastric cancer pathogenesis. I hope that our findings will promote the development of new therapies in the fight against this deadly disease.
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Nosralla, Liara Nogueira Petrechen. "Níveis e complexidade de IgA contra estreptococos orais em amostra de colostro humano." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17144/tde-29032017-165520/.
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Após o nascimento, os recém-nascidos são expostos a vários tipos de micro-organismos, que podem determinar um processo infeccioso devido a sua imaturidade imunológica. Dentro deste processo, a amamentação tem um papel importante pela transferência passiva de imunoglobulina A (IgA). A cavidade oral é a principal porta de entrada destes agentes, especialmente os estreptococos, sendo que alguns colonizam inicialmente como Streptococcus gordonii (SGO), S. sanguinis (SSA) e S. mitis (SMI) e outros podem causar doenças, como S. mutans (SM), por ser o principal agente etiológico da cárie dentária. Pouco se sabe sobre a especificidade de IgA do colostro contra antígenos importantes destes estreptococos, o que pode ajudar na investigação dos mecanismos de estimulação antigênica e desenvolvimento da resposta imune de mucosa. Para tanto, foi avaliado no presente estudo, a especificidade e os níveis de IgA três antígenos de virulência de SM: glucan binding protein B (gbpB), glicosiltransferase (GTF) e antígeno I/II (Ag I/II) envolvidos na capacidade destas bactérias de aderir e acumular no biofilme. Além disso, as glicosiltransferases: 153 kDa de SGO e 170 kDa de SSA e IgA1- protease de SMI (220 kDa) em amostras de colostro humano. Um total de 77 amostras de colostro foram analisadas quanto aos níveis de immunoglobulian A, M e G por ELISA. A complexidade da IgA contra as bactérias foram analisadas por Western blot. Os resultados mostraram que a concentração média de IgA foi de 2850,2 (±2567,2) mg/100 mL sendo estatisticamente maior (p<0.05) dos níveis de IgM e de IgG (respectivamente 321,8±90,3 e 88,3± 51,5 mg/100 mL). A maioria das amostras tiveram níveis detectáveis de anticorpos IgA para extratos de antígenos de bactérias e seus antígenos de virulência, apresentando um elevado número de bandas reativas. Não houve diferença estatisticamente significante no número médio de IgA reativas a Ags entre os antígenos (p>0.4). A detecção de gbpB foi significativamente menor do que os outros antígenos de SM (p<0.05). Assim, o leite materno das primeiras horas após o nascimento apresentou níveis significativos de IgA contra importantes antígenos de virulência dos estreptococos orais estudados, que pode sugerir que a amamentação antes da erupção dos dentes pode interferir no processo de instalação e acumulação destes microorganismos na cavidade oral.After birth, newborn babies are exposed to several types of microorganisms that can determine an infectious process due to their immunological immaturity. In this case, the feeding plays an important role by passive transfering of immunoglobulin A (IgA). The oral cavity is the main gateway of these agents, especially streptococci, some initially colonize as Streptococcus gordonii (SGO), S. sanguinis (SSA) and S. mitis (SMI) and others can cause diseases such as S. mutans (SM), as the main agent of tooth decay. Little is known about the specific IgA against major antigens of these streptococci which can help in the investigation of antigenic stimulation mechanisms and development of mucosal immune response. Therefore, we evaluated in this study, the specificity and levels of IgA from colostrum against three SM virulence antigens: glucan binding protein B (gbpB), glycosyltransferase (GTF) and antigen I/II (Ag I/II) involved in capacity these bacteria to adhere to and accumulate in the biofilm. Also, the glycosyltransferases: 153 kDa-SGO and 170 kDa-SSA and IgA1- protease of SMI (220 kDa). This study involved 77 samples of colostrum that were analyzed for levels of immunoglobulian A, M and G by Elisa. The specificity of IgA against extracts of SM and initials colonizators (SSA, SMI, SGO) were analyzed by the western blot. The mean concentration of IgA was 2850.2 (± 2567.2) mg/100ml followed by IgM and IgG (respectively 321.8 ± 90.3 and 88.3 ± 51.5), statistically different (p<0.05). Results showed that the majority of samples had detectable levels of IgA antibodies to extracts of bacteria antigens and theirs virulence antigens. To SM, the GbpB was significantly lower detected than others antigens of SM (p<0.05). High complexities of response to Ags were identified in the samples. There were no significant differences in the mean number of IgA-reactive Ags between the antigens (p>0.4). So, the breast milk from first hours after birth presented significant levels of IgA specific against important virulence of antigens those oral streptococci, which can disrupt the installation and accumulation process of these microorganisms in the oral cavity.
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O’Meara, Connor Patrick. "The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/61614/1/Connor_O%27Meara_Thesis.pdf.
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Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants.
In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge.
The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.
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Bonnardel, Johnny. "Caractérisation phénotypique, ontogénique et fonctionnelle du système phagocytaire mononucléé des plaques de Peyer." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4048.
Full textAbstract:
Les plaques de Peyer (PP) sont les principaux sites inducteurs de la réponse immunitaire mucosale.L’épithélium associé aux follicules comprend des cellules épithéliales spécifiques, appelées cellules M et spécialisées dans le transport du matériel présent dans la lumière intestinale vers le dôme sous épithélial (SED) où il sera pris en charge par les cellules du système phagocytaire mononuclée (MPS) qui orchestreront ensuite les réponses immunitaires mucosales.Nous avons effectué une analyse complète du phénotype, de la distribution, de l’ontogénie, de la fonction et des profils transcriptomiques du MPS des PP. Nous avons montré que les monocytes donnent naissance à deux populations: les lysoDC et les lysoMac. La première exprime de fort niveau de CMH-II et de molécules de costimulation, a une courte durée de vie et est capable d’activer les lymphocytes T naïfs pour sécréter de l’IFNγ tandis que la deuxième exprime faiblement le CMH-II, à une longue durée de vie et n’est pas capable d’activer les LT naïfs. Ces deux populations ont toutefois des propriétés communes de phagocytose et de défense innée contre les virus et les bactéries entéropathogènes. Nous avons identifié deux populations distinctes de lysoMac selon l’expression de Tim4: les lysoMac Tim4+ situés dans l’IFR et la partie inférieure du follicule ; les lysoMac Tim4- situés dans le SED et la partie supérieure du follicule. Nous avons aussi déterminé 4 états de maturation pour les lysoDC suivant l’expression d’Emb, Jam-A et CD24. Nous avons également redéfini la localisation de chaque population du MPS des PP fournissant ainsi une base solide pour étudier le rôle de chacun de ses membres dans l’immunité mucosalePeyer’s patches (PPs) are primary inductive sites of mucosal immunity. The follicle-associated epithelium contains specialized epithelial cells, called M cells, that bind and rapidly transport microorganisms from the lumen to the subepithelial dome (SED) where they are internalized by cells of the mononuclear phagocyte system (MPS) which are involved in the initiation of the mucosal immune responses. MPS comprise monocytes, macrophages (Mφ) and dendritic cells (DC). Here, we provide a comprehensive analysis of the phenotype, distribution, ontogeny, function, and transcriptional profile of PP MPS. We show that monocyte give rise to two different cell populations named lysoDC and lysoMac. The former express high levels of MHCII and costimulatory molecules, have a short half life and are able to prime naïve T cells for IFNγ production while the latter display low levels of MHCII, have a long half life and are unable to prime naïve T cells efficiently. However, these two cell populations share common features such as phagocytosis and antimicrobial defense mechanisms. LysoMac can be separated in two subpopulations according to Tim4 expression: Tim4+ lysoMac located in the IFR and the lower part of the follicle; Tim4- lysoMac located in the SED and upper part of the follicle. LysoDC can be separated in four different maturation stages according to Emb, Jam-A and CD24 expression. Finally, we redefined the location of each PP MPS population. In summary, we provide a comprehensive map of the PP MPS which will allow to study its role in mucosal immune response initiation and regulation