Saudi Cultural Missions Theses & Dissertations
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Item Unknown INVESTIGATING LINKS BETWEEN THE IMMUNE RESPONSE AND HELICOBACTER PYLORI-MEDIATED DISEASE OUTCOMES.(University of Nottingham, 2024) Alzahrani, shatha; Karen, RobisonBackground: Helicobacter pylori is the primary cause of chronic gastritis and peptic ulcer disease and a significant risk factor for gastric adenocarcinoma. Numerous studies have reported the role of cytokines in the pathogenesis of gastric inflammation during H. pylori infection and disease outcomes are more likely with virulent strains that carry the Cytotoxin Associated Gene Pathogenicity Island (cag PAI). Interleukin-16 (IL-16) is a multifunctional cytokine implicated in various chronic inflammatory conditions, such as inflammatory bowel disease, asthma, and rheumatoid arthritis. Elevated IL-16 levels have previously been observed in the serum of gastric cancer patients compared to healthy controls. However, the connection between IL-16 production and H. pylori infection remained unclear. A comprehensive study profiling plasma cytokine levels across different stages of gastric cancer prognosis, including non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, and gastric cancer could provide insights into the correlation between cytokines and disease progression and their potential as biomarkers for gastric cancer. Previous research demonstrated H. pylori's ability to induce IL-16 production in gastric epithelial cell lines. Since monocytes and dendritic cells are among the first cells to encounter H. pylori after it breaches the gastric epithelial barrier, the effect of H. pylori and its virulence factors on IL-16 production in these cells has not been explored. Aims; A key objective of this thesis was to measure IL-16 concentrations in plasma samples from H. pylori-positive and negative patients and to investigate potential links between IL-16 and H. pylori-mediated gastro-duodenal disease. The study explored relationships between serum IL-16 and colonization by more virulent cagA-positive H. pylori strains, associations with gender and smoking status, the presence and severity of histopathological changes in the gastric mucosa, oesophageal diseases, and the impact of H. pylori eradication therapy and other co-expressed inflammatory cytokines. Additionally, the thesis aimed to explore the effects of H. pylori infection and its virulence factors, and bile metabolites, on cytokine production by monocytes and dendritic cells. Another significant aim was to understand differential cytokine expression concerning gastric cancer progression and their potential as biomarkers for the disease. Materials and Methods; Gastric biopsy and plasma samples were collected from H. pylori-infected and non-infected patients, including those who had received successful eradication therapy for the infection. IL16 mRNA and plasma IL-16 levels were measured using RT-qPCR and a commercial ELISA kit respectively. cag PAI-negative H. pylori, cag PAI-positive H. pylori, and isogenic virulence factor mutants co-cultured with human peripheral blood monocytes, monocyte-derived dendritic cells, and THP-1 and KG-1 cell lines for 24 hours. IL-6, IL-10 and IL-16 cytokines were measured by ELISA and flow cytometry. 320 plasma samples were collected from H. pylori-infected and uninfected patients with various gastric conditions, including non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, and gastric cancer. Concentrations of cytokines and chemokines (including IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-16, IL-17, IL-18, IL-23, CCL2, CCL3, CXCL10, IFN-γ, and TNF-α) were measured using multiplex assays from Mesoscale Discovery (MSD). Results: IL-16 was detected in all plasma samples, from both H. pylori-infected and uninfected patients, with wide variation in both groups, and there were no significant differences. IL-16 levels were not significantly associated with gender, age, or smoking status, nor did they differ based on whether the colonizing strain was cagA-positive or negative. No link was found between IL-16 concentration and histopathological changes in the gastric mucosa, or oesophageal diseases, and there were no significant differences in plasma IL-16 levels before and after H. pylori eradication. The results showed that H. pylori virulence factors did not alter cytokine production by monocytes and dendritic cells. Interestingly, GC patients exhibited a significant reduction in IL-16 plasma levels compared to individuals with gastritis, peptic ulcer disease, and healthy controls. This outcome contradicts a previous study that reported elevated IL-16 serum concentrations in GC patients relative to healthy controls, likely due to different patient recruitment criteria. This finding's reliability was further substantiated by similar results from another ethnic group, a Mexican patient population, which showcased a reduction in both IL-16 and IL-18 plasma levels in GC patients compared to those with non-atrophic gastritis, atrophic gastritis, and intestinal metaplasia. Conclusion: This comprehensive study analyzed various sample types, including plasma, gastric tissue, cell lines, and peripheral blood monocytes, utilizing techniques such as ELISA, MSD, RT-qPCR, and Flow Cytometry. Participants were categorized as healthy controls, H. pylori-infected and uninfected patients, individuals with different gastric conditions, and those from diverse ethnic backgrounds. The study considered multiple parameters potentially influencing plasma IL-16 levels, including age, gender, smoking status, cagA status, and oesophageal disorders. The study concluded that H. pylori infection does not affect IL-16 cytokine levels. A suggested correlation between IL-16 and IL-18 cytokines in the context of gastric cancer presents a novel research avenue. Both interleukins could be components of a larger immune regulatory network. Disruption in this network might lead to inadequate tumor control. Further research should be conducted to explore how IL-16 and IL-18 interact and influence each other in the context of cancer immunology. Investigating the combined roles of IL-16 and IL-18 can provide deeper insights into their contributions to immune response modulation.15 0Item Unknown The Modulation Effect of Inflammatory Cytokines on T cell Proliferation in Hypertension(University of Glasgow, 2024-05) Alsheikh, Eman; Marta, Czesnikiewicz-Guzik; Tomasz, GuzikHypertension is a common medical condition with very serious target organ consequences, increasing the risk of heart disease, stroke, and severe health complications. Despite the identification of various mechanisms (vascular, renal, and central mechanism) contributing to the pathogenesis of hypertension, the majority of cases lack a clear aetiology. Emerging evidence has established a significant association between hypertension and immune responses, particularly involving adaptive immune cells and inflammatory cytokines. Immunosuppressive drugs and cytokine inhibitors have shown potential in mitigating hypertension, suggesting a crucial role of the immune system in this condition. Given the central role of T lymphocytes in the adaptive immune response, this study hypothesises that, in the context of hypertension, inflammatory cytokines can modulate T cell activation independently of antigen stimulation. To test this hypothesis, total T cells were isolated from the spleens and PBMCs of normotensive and hypertensive mice and exposed to a range of cytokines, including TNF-α, IL-6, IL-15, IFN-γ, IL-7, IL-1β, IL-17A, IL-2, and IL-12, using different stimulation protocols. Aiming to understand the effects of these cytokines on T cell proliferation, differentiation, and the expression of activation markers such as CD69. Our findings highlight the varying abilities of cytokines to sustain T cell viability, with IL 7, IL-15, and IL-6 demonstrating a tendency for greater efficacy compared to other cytokines. In addition, IL-7 and IL-15 significantly impact T cell proliferation, notably affecting the CD8+ T cell population. However, despite these effects, no significant difference was detected between normotensive and hypertensive T cells in response to IL-7 and IL-15. This suggests that while these cytokines are potent in driving T cell proliferation, their influence is not specifically heightened in the context of hypertension. In GSEA and KEGG analyses, the Ca2+ signalling pathway was distinctively activated in response to IL-7 and IL-15 in Ang II induced hypertension. Conclusion: These data imply that most studied cytokines linked to hypertension pathology do not substantially affect normotensive or hypertensive T cells in a murine model. However, T cell proliferation was elevated in both Sham and Ang II mice in response to IL-15 and IL-7. Together, the data presented in this thesis warrant further investigations into the role of cytokines in hypertension and may point to IL-15 or IL-7 as biological targets for antihypertension therapy.43 0Item Unknown Investigating the mechanisms underpinning antipsychotic-mediated pneumonia(Saudi Digital Library, 2023-11-01) Howsawi, Alanood; Caroline, Copeland; Athanasios, SekerisBackground: The mechanisms behind the association between antipsychotics and pneumonia risk remain inadequately understood. Existing studies propose that antipsychotics might attenuate the immune response through cytokine modulation. The present study aimed to explore the impact of olanzapine and quetiapine on surface markers expression and cytokines released by CD4+ lymphocytes. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from four healthy volunteers. Olanzapine doses (6, 20, and 60 ng) and quetiapine doses (15, 50, 150 ng) were employed. The cells were stimulated with Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). Stimulated cells were treated with olanzapine or quetiapine and compared to control cells. Flow cytometry was used to analyse CD25, CD28, CD127 (IL-7R-a), CD152 (CTLA4), CD274 (PD-L1), CD279 (PD-1) markers, and cytokines IL-2, IL-10, and IFN-Y. Statistical analyses were performed with GraphPad Prism 9.0, employing one way- analysis of variance (ANOVA) and Friedman tests (P < 0.05 for significance). Results: Olanzapine and quetiapine increased CD25 expression, with olanzapine 20 ng reached statistical significance in PA-stimulated cells. PD-L1 expression exhibited an upward trend in SA-stimulated cells treated with both drugs, with quetiapine 15 ng being significant. Both drugs significantly increased CD28 expression in the stimulated cells. CD152 decreased slightly with therapeutic doses of both drugs in PA-stimulated cells. CD127 and PD-1 expressions remained unchanged. Regarding cytokines, olanzapine 6 ng significantly reduced IL-2 release in stimulated cells, while quetiapine caused a mild IL-2 release in PA-stimulated cells. IFN-Y release slightly dropped in PA-stimulated cells in both drugs. Quetiapine slightly lowered IFN-Y release in SA-stimulated cells, whereas olanzapine left IFN-Y unchanged. IL-10 release decreased significantly with olanzapine 6 ng and 20 ng in PA and SA-stimulated cells, and quetiapine led to a slight reduction in IL-10 release. Conclusions: This in vitro study revealed how olanzapine and quetiapine affect CD4+ markers and cytokines. It emphasizes immune reduction via elevated CD25 and PD L-1 markers, known to decrease activated T-cells. Reduced immune response is evidenced by lower cytokine levels from activated T-cells, possibly increasing infection susceptibility, including pneumonia. Immune stimulation via CD28 and CD152 modulation might induce immunosuppression over time, exacerbating infection risk. Further studies are warranted to investigate the impact of antipsychotics on immune cells surface markers to better understand their immunomodulatory effects.5 0