Immune Dysfunction in Cystic Fibrosis

Xu, Yaqin; Worgall, Stefan

doi:10.5772/30274

Cited by 3 publications

(1 citation statement)

References 89 publications

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“…ამ დროს გაზრდილია ანთებითი ციტოკინების და მედიატორების სინთეზი. რამდენიმე კვლევამ დაადასტურა, რომ ნახველსა და ბრონქოალვეოლური ამორეცხვის შედეგად მიღებულ სითხეში (BALF) ანთებითი ციტოკინების, როგორიცაა ინტერლეიკინ-1 (IL-1), ინტერლეიკინ-6 (IL-6), ინტერლეიკინ-8 (IL-8), და სიმსივნის ნეკროზის ფაქტორი-ალფა (TNFα), კონცენტრაცია მომატებულია კისტური ფიბროზით დაავადებულ პაციენტებში [5]. მათ სინთეზს ხელს უწყობს ტრანსკრიფციის ფაქტორი NF-κB, რომელიც მნიშვნელოვან როლს თამაშობს უჯრედშიდა სიგნალების გადაცემაში ანთებითი ციტოკინების წარმოქმნის დროს [6].…”

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Dna Methylation Profile of Selected Cytokines in Cystic Fibrosis

GHUGHUNISHVILI,

KVARATSKHELIA,

TKEMALADZE

et al. 2023

jecm

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Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disorder in Caucasians with an incidence of about 1:3,000 live births. The gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein is found on the human chromosome 7 q31.2. CF is characterized by recurrent pulmonary infections, elevated sweat chloride, pancreatic and hepatic insufficiency, intestinal abnormalities, failure to thrive, diabetes, meconium ileus (MI) and other glandular defects. Chronic airway dysfunction and inflammation are the main cause of morbidity and mortality of patients. This inflammation is characterized by an increased production of pro-inflammatory cytokines in the lung. The aim of the presented study is to identify the methylation status of the promoters of inflammatory and anti-inflammatory cytokines (IL-8, TNFα IL-10) and quantitative analysis of these cytokines in cystic fibrosis patients. DNA methylation analysis of cytokine promoters was performed by the methylationspecific polymerase chain reaction. DNA fragments were amplified using specific primers for methylated or unmethylated DNA. Methylation analysis revealed statistically significant hypomethylation of IL-8 and TNFα gene promoter regions, whereas IL-10 gene promoter CpG sites were hypermethylated in cystic fibrosis patients compared to control individuals. In conclusion, identification of disease-modifying epigenetic factors at early stages of disease crucial for finding new therapeutic solutions and personalized approach in treatment of patients with Cystic Fibrosis.

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Dna Methylation Profile of Selected Cytokines in Cystic Fibrosis

GHUGHUNISHVILI,

KVARATSKHELIA,

TKEMALADZE

et al. 2023

jecm

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Transcriptional consequences of impaired immune cell responses induced by cystic fibrosis plasma characterized via dual RNA sequencing

et al. 2019

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Background In cystic fibrosis (CF), impaired immune cell responses, driven by the dysfunctional CF transmembrane conductance regulator ( CFTR ) gene, may determine the disease severity but clinical heterogeneity remains a major therapeutic challenge. The characterization of molecular mechanisms underlying impaired immune responses in CF may reveal novel targets with therapeutic potential. Therefore, we utilized simultaneous RNA sequencing targeted at identifying differentially expressed genes, transcripts, and miRNAs that characterize impaired immune responses triggered by CF and its phenotypes. Methods Peripheral blood mononuclear cells (PBMCs) extracted from a healthy donor were stimulated with plasma from CF patients ( n = 9) and healthy controls ( n = 3). The PBMCs were cultured (1 × 10 5 cells/well) for 9 h at 37 ° C in 5% CO 2 . After culture, total RNA was extracted from each sample and used for simultaneous total RNA and miRNA sequencing. Results Analysis of expression signatures from peripheral blood mononuclear cells induced by plasma of CF patients and healthy controls identified 151 genes, 154 individual transcripts, and 41 miRNAs differentially expressed in CF compared to HC while the expression signatures of 285 genes, 241 individual transcripts, and seven miRNAs differed due to CF phenotypes. Top immune pathways influenced by CF included agranulocyte adhesion, diapedesis signaling, and IL17 signaling, while those influenced by CF phenotypes included natural killer cell signaling and PI3K signaling in B lymphocytes. Upstream regulator analysis indicated dysregulation of CCL5, NF-κB and IL1A due to CF while dysregulation of TREM1 and TP53 regulators were associated with CF phenotype. Five miRNAs showed inverse expression patterns with three target genes relevant in CF-associated impaired immune pathways while two miRNAs showed inverse expression patterns with two target genes relevant to a dysregulated immune pathway associated with CF phenotypes. Conclusions Our results indicate that miRNAs and individual transcript variants are relevant molecular targets contributing to impaired immune cell responses in CF. Electronic supplementary material The online version of this article (10.1186/s12920-019-0529-0) contains supplementary material, which is available to authorized users.

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Role of Neutrophils in Cystic Fibrosis Lung Disease

Conese¹,

Castellani²,

D’Oria³

et al. 2017

Role of Neutrophils in Disease Pathogenesis

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Cystic fibrosis (CF) is a genetic syndrome caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. In CF patients, chief morbidity and mortality are due to pulmonary manifestations. CFTR lack/dysfunction brings an altered ion flux through the airway epithelium and ablation of mucociliary clearance, which in turn ensues in colonization and infection by opportunistic bacterial pathogens and subsequent neutrophil-dominated inflammation. This response eventually leads to the damage of the lung tissue. A host of inflammatory mediators attract, activate, and reprogramme neutrophils to survive (avoiding apoptosis) and produce a wealth of proteases and radical oxygen species. The protease/antiprotease imbalance and oxidative stress have multiple downstream effects, including impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses, thus facilitating and fostering bacterial infections. On the other hand, CFTR lack or dysfunction is likely responsible for alterations in neutrophils concerning chemotaxis, phagocytosis, oxidative burst, degranulation, and neutrophil extracellular trap (NET) formation. A good opportunity to reveal new and non-invasive biomarkers of CF lung disease is the evaluation of circulating neutrophils. Indeed, neutrophil responses are now investigated as outcomes of the aetiological therapies in CF, such as hypertonic saline, antiproteases, CFTR correctors and potentiators.

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Immune Dysfunction in Cystic Fibrosis

Cited by 3 publications

References 89 publications

Dna Methylation Profile of Selected Cytokines in Cystic Fibrosis

Dna Methylation Profile of Selected Cytokines in Cystic Fibrosis

Transcriptional consequences of impaired immune cell responses induced by cystic fibrosis plasma characterized via dual RNA sequencing

Role of Neutrophils in Cystic Fibrosis Lung Disease

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