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ROLE OF ARYL HYDROCARBON RECEPTOR IN CHRONIC INFLAMMATORY DISEASESArsenescu, Violeta 01 January 2009 (has links)
Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging.
The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice' visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA.
In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status.
These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases.
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The role of NLRs in induction and resolution of intestinal inflammationSong-Zhao, George Xiaoxi January 2012 (has links)
Innate immune activation is thought to play a central role in IBD pathogenesis because genetic polymorphisms in NOD2 and NLRP3, cytosolic innate immune receptors belonging to the NLR family, have been associated with IBD susceptibility. However, the mechanisms through which NLR mutations predispose to IBD remain unclear. The aim of this project was to dissect the functional roles of different NLRs in intestinal inflammation. Using the well-established DSS-induced colitis model as well as experimental models of IBD based on infection with Helicobacter hepaticus, we found that Nod2 expression was significantly increased at the peak of intestinal inflammation, and remained elevated throughout the resolution process. This observation suggests a possible role for Nod2 in the resolution of inflammation. Conversely, upon infection with the acute intestinal pathogen Citrobacter rodentium, Nlrp3-/- mice suffered from increased bacterial colonization as early as 3 days post infection, resulting in exacerbated intestinal inflammation and severe weight loss. Analysis of irradiation bone marrow chimeras showed that the protection required Nlrp3 activation in the non-haematopoietic compartment. Furthermore, this protective mechanism was independent of the inflammasome-associated cytokines IL-1β or IL-18. Therefore, this study implicates Nlrp3 activation in intestinal tissue cells as having a crucial role in controlling pathogenic bacterial colonization, providing a potential mechanism by which NLRP3 polymorphisms could lead to increased susceptibility to IBD.
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Upplevelser av att leva med inflammatorisk tarmsjukdom (IBD) : En litteraturstudieFranzén, Sofie, Ohlsson, Spire January 2016 (has links)
Bakgrund: Inflammatorisk tarmsjukdom (IBD) innefattar sjukdomarna Ulcerös kolit och Morbus Crohn. Miljöfaktorer och förändrade kostvanor tros vara anledningar till att IBD-fallen ökat i USA och västra Europa på kort tid. I Sverige drabbas cirka 500 personer av Morbus Crohn varje år och Ulcerös kolit drabbar ca 900 personer per år. Sjukdomen yttrar sig i fysiska symtom som diarré, smärta och viktnedgång men påverkar även individen psykosocialt. Syfte: Syftet var att beskriva människors upplevelser av att leva med inflammatorisk tarmsjukdom samt att presentera vilken undersökningsgrupp som beskrivits i de inkluderade vetenskapliga artiklarna. Metod: Studien är en beskrivande litteraturstudie där 11 kvalitativa artiklar användes. Databaserna PubMed och Cinahl användes för att söka artiklar. Sökorden som användes var: Inflammatory Bowel Diseases, Qualitative, Everyday life och Lived experiences. Huvudresultat: IBD är en kronisk sjukdom. Fysiska symtom som illamående, viktnedgång, smärta och trötthet vilket även ses som ett psykiskt symtom. Oro, depression och dålig självkänsla upplevdes också. Sjukdomen visade sig påverka individens vardagsliv, kostvanor, familjeliv, och sociala relationer. Alla inkluderade artiklar presenterade undersökningsgruppen. Slutsats: IBD blir allt vanligare i världen. Symtomen är både fysiska och psykosociala och påverkar den drabbades vardagsliv, sociala liv och kosthållning. Sjuksköterskan möter en stor utmaning i att kunna bemöta och vårda dessa patienter då varje enskild individ har olika upplevelser av samma diagnos. / Background: Inflammatory bowel disease (IBD) includes the diseases Ulcerative Colitis and Morbus Crohn. Environmental factors and changing diets are thought to be reasons for IBD cases has increased in the US and Western Europe in a short time. It is in Sweden about 500 people affected of Morbus Crohn every year and Ulcerative colitis affects about 900 people per year. The disease has physical symptoms such as diarrhea, pain and weight loss, but also affects an individual psychosocial. Aim: The aim was to describe people's experiences of living with inflammatory bowel disease, and to present the study group as described in the included articles. Methods: This study is a descriptive literature study and 11 qualitative articles were used. PubMed and Cinahl were used to search for articles. Keywords used were: Inflammatory Bowel Diseases, Qualitative, Everyday Life and Lived Experiences. Main results: IBD is a chronic disease. Physical symptoms such as nausea, pain and fatigue which is also seen as a mental symptoms. The disease was found to influence the individual's daily life, eating habits, family life, and social relationships. All included articles presented the study group. Conclusion: IBD are becoming more common in the world. The symptoms are both physical and psychosocial and affects the afflicted person everyday life, social life and diet. Nurses face a big challenge in being able to confronting and care for these patients, since each individual has different perceptions of the same diagnosis.
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Role slizniční imunity a střevní mikroflóry při vývoji zánětlivých onemocnění / Role slizniční imunity a střevní mikroflóry při vývoji zánětlivých onemocněníMálková, Jana January 2014 (has links)
Gut microbiota is important for our health and well-being, but when its composition is disrupted, it can induce or perpetuate several chronic inflammatory disorders, including inflammatory bowel diseases (IBD). The mechanisms which distinguish protective microbes from the deleterious or indifferent ones are largely unknown. The aim of this thesis was to study the interaction of the immune system with microbes that have different relationships to IBD pathogenesis. Escherichia coli is a predominant aerobic microorganism of the gastrointestinal tract. This species includes microbes implicated in induction of IBD as well as in its therapy. Four E. coli strains with different relations to IBD were selected for our experiments: E. coli Nissle 1917 (EcN), which has been successfully used in IBD therapy, E. coli strains LF82 and p19A, which have been implicated in the pathogenesis of IBD, and E. coli strain K6, which has neither been implicated in pathogenesis nor in protection from this disease. The experiments were performed both with living bacteria and inactivated ones. As the mode of inactivation may change the microbial antigenic structure, we measured how different methods of inactivation, i.e. 1% formaldehyde, exposure to heat or UV irradiation, influence the microbe's immunogenicity. First, we...
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The function of innate immune genes in Crohn's diseaseBaker, John Summers January 2010 (has links)
Crohn's Disease (CD) is a debilitating condition characterised by chronic intermittent intestinal inflammation. More than 90 genetic polymorphisms are associated with CD susceptibility, including several in genes of the innate immune system. Here I present a series of experiments designed to enhance our knowledge of the roles of CD-associated polymorphisms in pathogenesis. Many therapeutic regimens are employed in CD treatment, but patients' responses to treatment and disease progression vary widely. There is great interest in studying whether analysis of patients' genotype at CD-associated polymorphisms can be used to predict their disease course, and guide clinical decision-making. To answer these questions, it is essential to be able routinely and cost- effectively to genotype patients at the full range of known CD-associated polymorphisms. The first project presented here describes the design and initial successful testing of a CD-specific genotyping microarray for use in genotype-phenotype studies. The polymorphism most strongly associated with CD susceptibility is in the pattern recognition receptor NOD2; the remaining experiments presented here study the function of NOD2 in primary human monocyte-derived Dendritic Cells (DCs). First, a microarray study is presented which characterises global transcriptional responses to NOD2 stimulation in DCs. NOD2 stimulation is shown to enhance transcriptional changes induced by Toll-Like Receptor 2 stimulation, and NOD2-mediated transcriptional regulation is shown to be lost in DCs expressing CD-associated NOD2 variants. Second, experiments are presented which describe development of a new protocol for proteomic analysis of post-translational protein modifications, and which identify a number of novel candidate targets of NOD2 signalling in DCs. Finally, a project is presented which demonstrates for the first time that NOD2 stimulation induces autophagy in DCs, in an NF-kB and RIPK2-dependent pathway. CD-associated polymorphisms in NOD2 and ATG 16Ll abolish NOD2-mediated autophagy induction, resulting in impaired bacterial handling and antigen presentation.
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Saccharomyces boulardii reverte a resposta inflamatÃria e funcional presente na mucosite intestinal induzida por 5-fluorouracil em camundongos. / Saccharomyces boulardii ameliorates the inflammation and gastric dysmotility presents in intestinal mucositis induced by 5-fluorouracil in mice.Priscilla Fernanda Campos Justino 20 June 2011 (has links)
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / IntroduÃÃo: A mucosite induzida por antineoplÃsicos à um fator limitante na terapia anticÃncer. O trato gastrintestinal à vulnerÃvel por causa da alta proliferaÃÃo e frequÃncia de renovaÃÃo celular. Saccharomyces boulardii (SB) à uma levedura probiÃtica que à utilizado para proteger a microflora gastrintestinal do desequilÃbrio e de distÃrbios gastrintestinais associados. Objetivos: Avaliar o efeito do tratamento com SB na resposta inflamatÃria e nas alteraÃÃes da motilidade digestiva no curso da mucosite intestinal experimental induzida por 5-FU. MÃtodos: Camundongos machos Swiss (25-30g) foram tratados com 5-FU (450mg/Kg, i.p.) ou com soluÃÃo salina (controle). Outros grupos receberam durante 3 ou 6 dias SB (800mg/Kg, gavagem) atà o dia do sacrifÃcio, diariamente. Um grupo prÃ-tratado recebeu o SB por 3 dias antes e 3 dias depois da administraÃÃo do 5-FU (SB 6D) e outro grupo recebeu SB somente 3 dias apÃs a administraÃÃo do 5-FU (SB 3D). No 3 dia apÃs o 5-FU ou 5-FU+SB (3D ou 6D), os animais foram sacrificados, amostras de jejuno e Ãleo foram retiradas para avaliar a injÃria epitelial por morfometria, escores histolÃgicos, atividade de MPO, nÃveis de nitrito e concentraÃÃo de GSH. Para avaliaÃÃo de citocinas pelo mÃtodo de ELISA foi determinada a concentraÃÃo de IL-1β e CXCL1. Jà na tÃcnica de esvaziamento gÃstrico os animais receberam o mesmo tratamento descrito anteriormente. Posteriormente, foram deixados em jejum de 18 horas. No 7 dia foram administrados 0,3 ml da soluÃÃo glicosada (5%) contendo vermelho de fenol (VF) a 0,75 mg/ml em cada animal. ApÃs 20 min, os animais foram sacrificados e submetidos a uma laparotomia mediana. O intestino delgado foi exposto e divido em 3 partes iguais: proximal, medial e distal. Com o auxÃlio de uma proveta contendo uma soluÃÃo de NaOH (100ml, 0,1N) o volume do estÃmago e dos segmentos do intestino delgado foram determinados. A absorbÃncia da amostra foi lida à 540nm. Resultados: O tratamento com 5-FU foi capaz de induzir uma lesÃo intestinal com um importante comprometimento da barreira epitelial funcional com a presenÃa das seguintes alteraÃÃes: encurtamento acentuado das vilosidades intestinais, necrose parcial de criptas, vacuolizaÃÃo de cÃlulas, presenÃa de infiltrado de polimorfonucleares, produÃÃo de radicais livres com consumo de GSH, aumento dos nÃveis de nitrito, aumento na concentraÃÃo de IL-1β e CXCL1 e alteraÃÃes na motilidade digestiva. O tratamento com SB reduziu significativamente as lesÃes intestinais, com recuperaÃÃo da altura dos vilos, recuperaÃÃo da profundidade das criptas, diminuiÃÃo do infiltrado neutrofÃlico e dos nÃveis de nitrito, aumento dos nÃveis de glutationa e reduÃÃo da concentraÃÃo de IL-1β e CXCL1. Contudo, o tratamento com SB foi capaz de reverter o retarde do esvaziamento gÃstrico e do transito gastrintestinal. ConclusÃo: 5-FU induz mucosite intestinal em camundongos com a participaÃÃo de IL-1β e CXCL1, a qual se associa com retarde no esvaziamento gÃstrico e no transito gastrintestinal. O tratamento com SB foi capaz de reverter os achados inflamatÃrios e as alteraÃÃes na motilidade digestiva associadas à mucosite por 5- FU em camundongos. / Introduction: Intestinal mucositis is a frequent side-effect associated to 5-fluorouracil (5-FU) clinical use and results in inflammatory events. It is characterized by epithelial ulcerations in the mucosa and clinical manifestations of abdominal pain, nauseas and diarrhea. Saccharomyces boulardii is a probiotic yeast which has been shown to protect the gastrointestinal microflora from disequilibrium and from associated gastrointestinal disorders. Aim: To evaluate the effect of treatment with Saccharomyces boulardii in inflammatory response and alterations in the gastrintestinal motility in the course of intestinal mucositis experimental induced by 5-FU. Methods: Swiss male mice (25-30g) were treated with 5-FU (450mg/Kg, ip) or saline (control). Other groups received 3 or 6 days during SB (800mg/Kg, gavage) until the day of sacrifice, every day. A group pretreated received the SB for 3 days before and 3 days after administration of 5-FU (SB 6D) and another group received SB only 3 days after administration of 5-FU (SB 3D). At day 3 after 5-FU, the animals were sacrificed, samples of jejunum and ileum were collected to assess the injury epithelial morphometry, histological scores, the activity of MPO, nitrite levels and the concentration of GSH. For evaluation of cytokine samples of jejunum and ileum were removed and the ELISA was determined concentrations of IL-1β and CXCL1. In the technique of gastric emptying, the animals received the same treatment described above. Later, they were left to fast for 18 hours from d6 to d7. At d7, were administered 0.3 ml of glucose solution (5%) containing phenol red (VF) to 0.75 mg / ml in each animal. After 20 min, the animals were sacrificed and underwent a laparotomy. The small intestine was exposed and divided into 3 equal parts: proximal, medial and distal. With the aid of a beaker containing a solution of NaOH (100ml, 0.1 N) the volume of the stomach and small intestine segments were determined. The sample absorbance was read in a wavelength of 540 nm. Results: Treatment with 5-FU was able to induce intestinal injury with a significant impairment of epithelial barrier function in the presence of the following changes: severe shortening of the villus, crypts of partial necrosis, vacuolization of cells, infiltration and mono polymorphonuclear free radical production with consumption of GSH, increased levels of nitrite, increased concentration of IL-1β and CXCL1 and changes in gastrointestinal motility. Treatment with SB significantly reduced intestinal damage, with recovery of villous height, crypt depth recovery, decreased neutrophil infiltration and nitrite levels, increased levels of glutathione and reduced concentrations of IL-1β and CXCL1. However, treatment with SB was able to reverse the delayed gastric emptying and gastrointestinal transit. Conclusion: 5-FU induces intestinal mucositis in mice involving IL-1β and CXCL1, which is associated with delayed gastric emptying and gastrointestinal transit in. Treatment with SB, both 3D and 6D, were able to reverse the inflammatory changes, and revert the changes in gastrointestinal motility associated with mucositis by 5 - FU in mice.
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Molecular regulation of interleukin-8 in human colonic epithelial cellsYu, Yi, 1965- January 1999 (has links)
No description available.
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Wahrnehmung empfohlener Schutzimpfungen bei Patienten mit Morbus Crohn und Colitis ulcerosa / Adherence to vaccination recommendations in patients with inflammatory bowel diseasesTiedemann, Astrid 29 October 2012 (has links)
Hintergrund: Patienten mit chronischen entzündlichen Erkrankungen sind aufgrund ihrer Grundkrankheit, aber auch durch die häufig notwendige immunsuppressive Therapie gefährdet, an einer impfpräventablen Infektionskrankheit zu erkranken. In einer Stichprobe sollte der Impfstand bei Patienten mit chronisch-entzündlichen Darmerkrankungen (CED) erhoben werden. Besondere Beachtung galt Vorbehalten der Patienten gegen die empfohlenen Schutzimpfungen.
Methoden: Wir baten 203 Patienten mit CED (davon 57% Mb. Crohn, 63% weiblich; medianes Alter 36 Jahre), die im letzten Jahr keine Impfberatung erhalten hatten, einen Fragebogen mit 38 Fragen zu beantworten. Zudem wurden alle Impfnachweise erfasst und mit den aktuellen Empfehlungen der Ständigen Impfkommission abgeglichen. Die Befragung erfolgte vom 1.4. bis 30.9.2009.
Ergebnisse: Nur 83% der Patienten hatten einen Impfausweis. Es fanden sich erhebliche Impfdefizite; so wurden in den letzten zehn Jahren nur 67% der Patienten gegen Tetanus und 21% gegen Pertussis geimpft, 28% nahmen die Impfung gegen die saisonale Grippe 2008 wahr und nur 9% wurden jemals gegen Pneumokokken geimpft. Im Subgruppenvergleich von Patienten mit TNF-Blockern (n=39) mit denjenigen Patienten, die noch nie eine immunsuppressive Dauertherapie erhielten (n=67), zeigten sich keine Unterschiede. 80% der Patienten wären bereit, alle offiziell empfohlenen Schutzimpfungen durchführen zu lassen. 22% aller Patienten gaben an, Schutzimpfungen zu vermeiden, weil sie Nebenwirkungen befürchteten, 15% weil das Immunsystem „nicht intakt“ ist und 9% befürchten eine Verschlimmerung der CED durch eine Impfung.
Schlussfolgerungen: Der Impfstand in der untersuchten Stichprobe war unzureichend. Es fand sich insbesondere eine deutliche Diskrepanz zwischen der hohen Bereitschaft der Patienten, Schutzimpfungen durchführen zu lassen, und dem tatsächlichen Impfstand. Unsere Daten legen die Notwendigkeit einer erhöhten ärztlicher Wachsamkeit für Impflücken bei immunsuppressiv behandelten Patienten nahe. / Background: Patients with chronic inflammatory diseases are at increased risk for vaccine preventable infectious diseases. This is caused by the inflammatory state itself as well as often necessary immunosuppressive therapy. In a random sample, we investigated whether patients with inflammatory bowel disease (IBD) are sufficiently vaccinated. Special attention was spent to arguments for vaccine refusal.
Methods: Between 1.4.2009 and 30.9.2009, we asked 203 consecutive IBD patients (thereof 57% Crohn’s disease, 63% female; median age 36 years), who got no vaccination advise within the last year to answer a questionnaire with 38 questions. As well, the vaccination cards were adjusted with the official recommendations.
Results: Only 83% of patients had a vaccination card. We recognized substantial vaccination deficiencies. Within the past 10 years, only 67% of patients had tetanus and 21% had pertussis vaccination. Only 28% had an influenza vaccination in 2008 and only 9% were ever immunized against pneumococcus. A subgroup analysis of patients with TNF-blockers (n=39) with patients, who never had immunosuppressive therapy (n=67) revealed no difference. 80% of all patients are willing to adhere to all officially recommended vaccinations. 22% and 15% of patients stated that they avoid vaccinations as they afraid side effects or as they assess their immune system as not intact. Nine per cent feared a worsening of IBD after vaccination.
Conclusions: In this random sample, the adherence to vaccination recommendations was low. We observed a marked difference between the willingness of IBD patients for immunizations and the realized vaccinations. Our data suggest that an increased medical awareness for vaccination deficiencies in immunosuppressed patients is mandatory.
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Molecular regulation of interleukin-8 in human colonic epithelial cellsYu, Yi, 1965- January 1999 (has links)
Interleukin-8 is a chemokine which is chemotactic for neutrophils and T-lymphocytes and plays a crucial role in the pathogenesis of inflammatory bowel disease. Intestinal mucosal epithelial cells produce IL-8 in response to pathogens which mediates bidirectional communication between pathogen and host. The objective of this study was to investigate the molecular mechanisms involved in IL-8 gene regulation in T84 human colonic epithelial cells. To determine if IL-8 plays a role in the pathogenesis of intestinal amebiasis, the effect of Entamoeba histolytica on IL-8 gene expression was investigated. E. histolytica secreted components enhanced IL-8 mRNA expression and protein production in the absence of amebae-enterocyte contact. The proinflammatory cytokines IL-1beta and TNF-alpha were not involved in IL-8 protein production. As PGE2 is central in mucosal inflammation, the effect of PGE2 on IL-8 gene expression was determined. Using purified PGE2 and PGE2 receptor agonists, it was shown that PGE2 coupled to the EP4 receptor and triggered cAMP-dependent PKA signaling which upregulated IL-8 mRNA expression at the posttranscriptional level. Elevation of [Ca 2+]i from intracellular Ca2+ stores by A23187 or thapsigargin stimulated IL-8 mRNA transcription and IL-8 protein production through the activation of calcineurin. Moreover, IL-8 3'-UTR had a strong suppressive effect on CAT reporter gene expression in COS7 cells by reducing its mRNA level. A unique fragment (nt 2387-2743) containing AU rich elements was shown to attenuate CAT mRNA expression by destabilizing the transcripts. Secondary structure but not AU rich elements played a major role in CAT mRNA turnover.
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NK, T and NK T-cells in ageing, coeliac disease and inflammatory bowel disease.Grose, Randall Hilton January 2008 (has links)
This thesis investigated the number and function of natural killer T-cells (NK T-cells) as a function of age, in coeliac disease, Crohn’s disease and ulcerative colitis. NK T-cells are a newly appreciated class of immune cells that are able to regulate the activity of the broader T-cell population. NK T-cells have been implicated in animal models of autoimmune disease and in human autoimmune disease. A subset of NK cells express the T-cell receptor (TCR) and are termed NK T-cells. In humans a further small subset of NK T-cells express an invariant TCR α chain (Vα24Jα18) and contain the immunoregulatory cell population that is distinguished from classical T-cells by promptly producing interleukin-4 (IL-4). Invariant NK T-cells (iNK T-cells) have the surface phenotype of Vα24+ Vβ11+ T-cells and express CD161+ NK markers. They are CD4+ (single positive; SP) or CD4- (double negative; DN), CD1d restricted and are α-galactosylceramide (α-GalCer) reactive. NKT cells have been implicated in numerous autoimmune disorders. Early work showed a major deficiency of NKT cell numbers in nonobese diabetic (NOD) mice, a well-established model of spontaneous, autoimmune T-cell mediated insulin-dependent diabetes. Both the number of NKT cells and function, as assessed by IL-4 release following TCR ligation, are dramatically reduced in NOD mice. NK T-cells have been implicated in other models of autoimmunity such as, experimental allergic encephalomyelitis (EAE). They have since been investigated and shown to be deficient in a number of human autoimmune diseases including, systemic sclerosis (SSc), and systemic lupus erythematosus (SLE), multiple sclerosis, atopic asthma, atopic dermatitis, rheumatoid arthritis, type 1 diabetes mellitus and scleroderma. The basis of the work presented within this thesis originated from the deficiency of NK T-cells in models of autoimmune diseases and human autoimmune diseases. The initial aim of this thesis was to investigate the phenotype and function of Vα24+ NK T-cells in normal healthy control subjects and with respect to age. The original aim was to investigate whether NK cells, T-cells, NK T-like cells and invariant NK T-cells (iNK T-cells) are deficient in coeliac disease, Crohn’s disease and/or ulcerative colitis. Blood was collected for flow cytometry from normal control subjects, subjects with coeliac disease, Crohn’s disease and ulcerative colitis. The number of circulating NK cells, T-cells, NK T-like cells and iNK T-cells was assessed by three-colour flow cytometry. Intracellular cytokine production was measured after in vitro anti-CD3/ anti-CD28 antibodies, gluten fraction 3 and PMA:ionomycin stimulation. Vα24+ T-cells were quantified in ileocolonic biopsies by immunofluorescence and as mRNA by relative and real-time PCR (RT-PCR). The number of circulating Vα24+ T-cells and iNK T-cells decrease with age in normal healthy control subjects. Cytokine production was also affected by age. The work of this thesis has identified a subpopulation of otherwise normal healthy individuals whom have normal numbers of circulating Vα24+ T-cells, reduced numbers of circulating Vα24+ Vβ11+ T-cells and consequently iNK Tcells. Circulating CD161+ NK cells, Vα24+ T-cells and the SP subset of Vα24+ Tcells were reduced in coeliac disease. The low numbers of circulating Vα24+ T-cells was independent of diet. The number of circulating Vα24+ Vβ11+ Tcells were reduced in coeliac disease, and as a consequence, the number of circulating Vα24+ Vβ11+ α-GalCer/CD1d tetramer+ and Vα24+ 6B11+ iNK T-cells were reduced. The deficiency of Vα24+ T-cells was not confined to the blood, but observed within the intestinal mucosa. Intestinal Vα24 mRNA expression from subjects with coeliac disease was reduced compared to levels in normal subjects as assessed by relative and RT-PCR. Thus, Vα24+ T-cells were deficient in coeliac disease both systemically and mucosally. Cytokine production by Vα24+ T-cells, 6B11+ and Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells after 4 h in vitro anti-CD3 stimulation was also impaired in subjects with coeliac disease. Circulating CD56+, CD57+, CD94+, CD161+ NK cells were reduced in Crohn’s disease and ulcerative colitis. Vα24+ T-cells and the SP subset of Vα24+ T-cells were reduced in Crohn’s disease but not in ulcerative colitis. Circulating Vα24+ Vβ11+ T-cells, Vα24+ Vβ11+ α-GalCer/CD1d tetramer+ and Vα24+ 6B11+ iNK T-cells were deficient in both Cohn’s disease and ulcerative colitis. The deficiency of Vα24+ T-cells was also observed within the intestinal mucosa. Intestinal Vα24 mRNA expression from Crohn’s disease and ulcerative colitis was reduced compared to levels in normal subjects as assessed by relative and RT-PCR. Cytokine production by Vα24+ T-cells, 6B11+ and Vα24+ α-GalCer/CD1d tetramer+ iNK T-cells after 4 h in vitro anti-CD3 stimulation was impaired for subjects with Crohn’s disease and ulcerative colitis. In summary, Vα24+ T-cell number and function were affected by age. Further investigations are warranted to see if deficiency of this immunoregulatory population is associated with disease. The decrease and dysfunction in immunoregulatory cells, Vα24 T-cells and iNK T-cells could contribute to the pathogenesis of coeliac disease, Crohn’s disease and ulcerative colitis. Coeliac disease, Crohn’s disease and ulcerative colitis are polygenetic diseases in which environmental factors play a significant role in disease development and state. The reduced numbers of iNK T-cell along with their impaired function may only be two factors. Presumably, other factors are involved. Nevertheless, iNK T-cells offer a potential target for the therapeutic intervention of coeliac disease, ulcerative colitis and Crohn’s disease. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345088 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2008
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