Two-stage genome-wide association study of chronic rhinosinusitis and disease subphenotypes highlights mucosal immunity contributing to risk.
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ABSTRACT:
SUBMITTER: Soliai M
PROVIDER: S-EPMC8048969 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundChronic rhinosinusitis is a multifactorial process disease in which bacterial infection or colonization may play an important role in the initiation or persistence of inflammatory response. The association between mucosal bacteria presence and inflammatory patterns has only been partially explored.ObjectiveTo demonstrate specific mucosal microorganisms possible association with inflammatory patterns.MethodsWe collected nasal polyps or sinus tissues from a clinical selection of six patient groups with defined sinus disease using tissue biomarkers. In the tissues, we detected bacteria using peptide nucleic acid fluorescence in situ hybridization (PNA-FISH).ResultsAfter reviewing a total of 115 samples (15-20 samples per group), the mucosal presence of Staphylococcus aureus was correlated with IL-5 and SE-IgE positive chronic rhinosinusitis with nasal polyps and nasal polyps from cystic fibrosis patients. Chronic rhinosinusitis without nasal polyps with TNF? >20 pg/ml was associated with the mucosal presence of Pseudomonas aeruginosa.ConclusionThis study identifies the relationship between intramucosal microbes and inflammatory patterns, suggesting that bacteria may affect the type of inflammation in chronic rhinosinusitis. Additional investigation is needed to further identify the nature of the relationship.
| S-EPMC4537217 | biostudies-literature
Project description:BackgroundPrior research has identified several components of the innate immune system that may play a significant role in chronic rhinosinusitis (CRS), but the role of innate immunity in patients with CRS is poorly understood. The objective of this study was to determine differential expression of innate immunity genes in the mucosa of patients with CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) when compared with controls.MethodsControl patients (n = 9) and patients with CRS (n = 36) who failed medical management were prospectively enrolled. Ethmoid mucosa samples were harvested during surgery and quantitative real-time polymerase chain reaction was used to determine levels of mRNA expression of Toll-like receptor (TLR) 2 and TLR9 and interleukin-22 receptor (IL-22R). The average change in crossover threshold and fold change were calculated and differences between controls, CRSwNP, and CRSsNP were compared. Statistical analysis was performed using the Kruskall-Wallis and adjusted Mann-Whitney U tests.ResultsPatients with CRSwNP (n = 16) and CRSsNP (n = 20) showed lower mean expression of TLR2 (p < 0.05) compared with controls. Patients with CRSsNP showed significantly higher mean expression of IL-22R (p < 0.05) than controls.ConclusionThe sinonasal innate immune system may have a significant role in the development of CRS. We found differential expression of innate immune mediators between patients with and without nasal polyposis. These results provide further evidence of disruption of innate immunity at the mucosal level in CRS and highlight differences between polyp- and non-polyp-forming CRS phenotypes at the molecular level. In addition to our knowledge, this is the first report of altered IL-22R expression in CRSsNP patients. This study was a part of the clinical trial NCT01332136 registered in www.clinicaltrials.gov.
| S-EPMC4151703 | biostudies-literature
Project description:PurposeThe Toll-like receptor 9 (TLR9) signaling pathway is involved in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis. The aim of this study was to assess the therapeutic potential of the TLR9 pathway inhibitor chloroquine in CRS mice.MethodsThe expression of type I interferons (IFNs) in human CRS tissues was evaluated using quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescence. Mice were divided into 4 treatment groups: the control, nasal polyp (NP), chloroquine treatment (NP + Chlq), and dexamethasone treatment (NP + Dexa) groups. The effects of chloroquine on polyp formation and mucosal inflammation were examined by hematoxylin and eosin staining. The expression levels of type I IFN, B-cell activating factor (BAFF), TLR9, high mobility group box 1 (HMGB1), and proinflammatory cytokine expression levels were assessed using qPCR, western blot, or enzyme-linked immunosorbent assay.ResultsIFN-α and IFN-β mRNA levels were significantly higher in patients with eosinophilic NPs (EPs) than in healthy individuals or non-EP patients. The polyp score, epithelial thickness, mucosal thickness, and the number of eosinophils in nasal mucosa were significantly higher in the NP group compared with the control, NP + Chlq, and NP + Dexa groups. NP + Chlq or NP + Dexa significantly suppressed the induction of type I IFN and BAFF expression in the NP group; these treatments also significantly suppressed the induction of TLR9, HMGB1, interferon regulatory factors, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and Th cytokine expression in the NP group. The secreted levels of anti-dsDNA Immunoglobulin G (IgG) were significantly higher in the NP group than in the control, NP + Chlq, and NP + Dexa groups. There were significant positive correlations between BAFF and mRNA levels of IFN-α/β/the protein levels of anti-dsDNA IgG.ConclusionsChloroquine may be used for the treatment of patients with eosinophilic CRS.
| S-EPMC7492509 | biostudies-literature
Project description:Bacterial microbiota of the sinuses in CRS.
| PRJEB20232 | ENA
Project description:Background: Recent studies have implied a role for Th17 cells in CRS with nasal polyps (CRSwNP) patients. However, the capacity of these cells to produce Th17 cytokines is still unknown. Here we sought to quantify IL-17A, IL-17F, IL-21, and IL-22 cytokines produced by Th17 cells in mucosal tissue and peripheral blood of CRSwNP, CRS without nasal polyps (CRSsNP) and control patients. Methods: Samples were prospectively collected from CRS patients and non-CRS controls. We used flow cytometry to characterize the Th17 cells and their cytokines in sinonasal tissue and peripheral blood. Results: A total of 36 patients were recruited to the study. CRSwNP patients had significantly more tissue IL-17A (9.53 ± 2.71 vs. 1.11 ± 0.43 vs. 0.77 ± 0.07), IL-17F (4.96 ± 1.48 vs. 0.88 ± 0.31 vs. 0.56 ± 0.04), IL-21 (5.55 ± 2.01 vs. 1.60 ± 0.71 vs. 1.53 ± 0.55) and IL-22 (4.73 ± 1.58 vs. 0.70 ± 0.28 vs. 0.88 ± 0.26) producing Th17 cells compared to CRSsNP and control mucosa per mg of tissue, respectively. Allergic CRSwNP patients had decreased numbers of IL-21 producing Th17 cells compared to non-Allergic CRSwNP. (1.69 ± 0.57 vs. 9.41 ± 3.23) per mg of tissue, respectively (Kruskal-Wallis p < 0.05). Conclusion: In summary our study identified increased numbers of IL-17A, IL-17F, IL-21 and IL-22 positive Th17 cells in CRSwNP patient polyps and peripheral blood suggesting an altered activation state of those cells both locally and systemically. Atopic CRSwNP had decreased amounts of tissue Th17 cell derived IL-21 implying a potential protective role for IL-21 in CRSwNP allergic inflammation.
| S-EPMC5742278 | biostudies-literature
Project description:The long pentraxin 3 (PTX3) is a prototypic molecule for recognizing pathogens. Liver X receptors (LXRs), belonging to nuclear receptors (NRs) for cholesterol metabolism through heterodimerizing with other NRs, were recently reported to participate in inflammation. However, their roles in chronic rhinosinusitis without nasal polyps (CRSsNP) are unclear. Therefore, this study was sought to explore roles of LXRs in chronic rhinosinusitis (CRS) sinonasal tissues and derived fibroblasts. Immunohistochemistry indicated that LXRα and β expression and lipid/fat deposition were differentially expressed in the control and CRSsNP nasal mucosa. GW7647 (a peroxisome proliferator activated receptor α (PPARα) agonist) and GW3965 (a dual agonist for LXRα and β) significantly caused PTX3 induction in the fibroblast cells. GW3965 induced PTX3 mRNA and protein expression, and the induction substantially led to PTX3 secretion. Meanwhile, an endogenous agonist-cholesterol had a similar enhancing effect on the induction of PTX3 protein. LXR siRNA knockdown to lower LXRα or β expression significantly compromised PTX3 induction. Interestingly, GW3965 also induced phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) activation and its inhibition reduced PTX3 expression. Collectively, we demonstrated here for the first time that CRSsNP nasal mucosa differentially expresses LXRα and β and deposits lipids/fats that may contain cholesterol metabolites to activate LXRs. Activation of LXRs leads to PTX3 production in sinonasal mucosa-derived fibroblasts. Our previous study showed PTX3 overexpression in the nasal cavity of CRSsNP, whereas this study highlights that cholesterol metabolites and LXR activation regulate PTX3 production and may contribute to antimicrobial activity and tissue repair during CRSsNP progression.
| S-EPMC7865759 | biostudies-literature
Project description:Increasing evidence suggests that CRS is a heterogeneous group of sinus disorders involving overlapping but distinct disease entities.The factors leading to different CRS phenotypes remain enigmatic. The role of miRNAs in the regulation of immunological and inflammatory processes is beginning to emerge.Thus, we examined microRNAs expression profiles in eosinophilic CRSwNP adn CRSsNP. Compared with controls, 31 differentially expressed miRNAs (30 downregulated and 1 upregulated miRNAs) in eosinophilic CRSwNP and 4 differentially expressed miRNAs (2 downregulated and 2 upregulated miRNAs) in CRSsNP were indentified. Real time RT-PCR was subsequently performed to verify the miRNA microarray result.
2011-12-08 | GSE32300 | GEO
Project description:Chronic rhinosinusitis (CRS) is a public health problem that has a significant socio-economic impact. Moreover, the complexity of this disease due to its heterogeneous nature based on the underlying pathophysiology - leading to different disease variants - further complicates our understanding and directions for the most appropriate targeted treatment strategies. Several International/national guidelines/position papers and/or consensus documents are available that present the current knowledge and treatment strategies for CRS. Yet there are many challenges to the management of CRS especially in the case of the more severe and refractory forms of disease. Therefore, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), a collaboration between EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus (ICON) on Chronic Rhinosinusitis. The purpose of this ICON on CRS is to highlight the key common messages from the existing guidelines, the differences in recommendations as well as the gaps in our current knowledge of CRS, thus providing a concise reference. In this document we discuss the definition of the disease, its relevance, pharmacoeconomics, pathophysiology, phenotypes and endotypes, genetics and risk factors, natural history and co-morbidities as well as clinical manifestations and treatment options in both adults and children comprising pharmacotherapy, surgical interventions and more recent biological approaches. Finally, we have also highlighted the unmet needs that wait to be addressed through future research.
| S-EPMC4213581 | biostudies-literature
Project description:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a widespread disease causing obstruction of the nasal cavity. Its cause remains unclear. The transforming growth-factor beta (TGF-?) superfamily and their receptors, termed Activin receptor-like kinases (ALKs), have recently been suggested to play a role in local airway inflammation, but have so far not been evaluated in human nasal epithelial cells (HNECs) from CRSwNP patients. We demonstrated that ALK1-7 were expressed in the nasal polyp epithelium, and the expression of ALK1-6 was markedly elevated in polyps compared to nasal mucosa from healthy controls. Stimulation with the ALK ligand TGF-?1 decreased Ki67 expression in HNECs from CRSwNP patients, not evident in controls. Likewise, TGF-?1, Activin A and Activin B, all ALK ligands, decreased IL-8 release and Activin A and Activin B reduced ICAM1 expression on HNECs from CRSwNP patients, not seen in controls. Pre-stimulation with TGF-?1, Activin A, BMP4 and Activin B attenuated a TNF-?-induced ICAM1 upregulation on HNECs of CRSwNP. No effect was evident in controls. In conclusion, an increased expression of ALK1-6 was found on polyp epithelial cells and ligand stimulation appeared to reduce proliferation and local inflammation in polyps.
| S-EPMC5784055 | biostudies-literature
Project description:Objectives/hypothesisTo measure the change in quality-of-life (QoL) after endoscopic sinus surgery (ESS) in patients with medically recalcitrant chronic rhinosinusitis (CRS) and minimally affected computed tomography (CT) scans of the paranasal sinuses.Study designProspective, multicenter cohort study at three academic, tertiary care centers.MethodsA total of 778 patients with CRS were enrolled between January 2001 and April 2009 after electing ESS. For the purposes of this analysis, patients with nasal polyposis, history of prior sinus surgery, or follow-up <6 months were excluded. Final study patients were categorized as low-stage CT CRS (Lund-Mackay ≤3; n = 17) and high-stage CT CRS (Lund-Mackay >3; n = 207). Primary outcome measures included two disease-specific QoL instruments: the Rhinosinusitis Disability Index and the Chronic Sinusitis Survey.ResultsIn patients with low-stage CT CRS, a statistically significant improvement was found across all disease-specific QoL scores (all P ≤ .012), with the exception of the CSS medication usage subscale (P = .073). These QoL improvements were comparable to those in patients with high-stage CT CRS.ConclusionsSome patients will present with CRS that is refractory to medical therapy even though their CT demonstrates relatively minimal disease. Based on the results of this study, ESS is associated with improved QoL in patients with low-stage CT CRS and can provide significant benefit to carefully selected patients with minimally affected CT scans.
| S-EPMC3075849 | biostudies-literature