Allergic rhinitis (AR) is a common disorder affecting up to 40% of the population worldwide and it usually persists throughout life. Nasal epithelial barrier constitutes the first line of defense against invasion of harmful pathogens or aeroallergens. Cell junctions comprising of tight junctions (TJs), adherens junctions, desmosomes and hemidesmosomes form the nasal epithelial barrier. Impairment of TJ molecules plays causative roles in the pathogenesis of AR. In this review, we describe and discuss the components of TJs and their disruption leading to development of AR, as well as regulation of TJs expression by epigenetic changes, neuro-immune interaction, epithelial-derived cytokines (thymic stromal lymphopoietin, IL-25 and IL-33), T helper 2 (Th2) cytokines (IL-4, IL-5, IL-6 and IL-13) and innate lymphoid cells. These growing evidence support the development of novel therapeutic approaches to restore nasal epithelial TJs expression in AR patients.
Allergic rhinitis (AR) is a common disease affecting 400 million of the population worldwide. Nasal epithelial cells form a barrier against the invasion of environmental pathogens. These nasal epithelial cells are connected together by tight junction (TJ) proteins including zonula occludens-1 (ZO-1), ZO-2 and ZO-3. Impairment of ZO proteins are observed in AR patients whereby dysfunction of ZOs allows allergens to pass the nasal passage into the subepithelium causing AR development. In this review, we discuss ZO proteins and their impairment leading to AR, regulation of their expression by Th1 cytokines (i.e., IL-2, TNF-α and IFN-γ), Th2 cytokines (i.e., IL-4 and IL-13) and histone deacetylases (i.e., HDAC1 and HDAC2). These findings are pivotal for future development of targeted therapies by restoring ZO protein expression and improving nasal epithelial barrier integrity in AR patients.
Keros and Gera classifications are widely used to assess the risk of skull base injury during endoscopic sinus surgery. Although, both classifications are useful preoperatively to stratify risk of patients going for surgery, it is not practical to measure the respective lengths during surgery. In this study, we aimed to propose a new radiological classification (Thailand-Malaysia-Singapore (TMS)) to assess the anatomical risk of anterior skull base injury using the orbital floor (OF) as a reference. A total of 150 computed tomography images of paranasal sinuses (300 sides) were reviewed. The TMS classification was categorized into 3 types by measuring OF to cribriform plate and OF to ethmoid roof. Most patients were classified as TMS type 1, Keros type 2 and Gera class II, followed by patients classified as TMS type 3, Keros type 1 and Gera class 1. TMS has significant correlation with Keros classification (p < 0.05). There was no significant correlation between Keros and Gera classifications (p = 0.33) and between TMS and Gera classifications (p = 0.80). The TMS classification has potential to be used for risk assessment of skull base injury among patients undergoing ESS. It serves as an additional assessment besides the Keros and Gera classifications.
Allergic rhinitis (AR) represents a global health concern where it affects approximately 400 million people worldwide. The prevalence of AR has increased over the years along with increased urbanization and environmental pollutants thought to be some of the leading causes of the disease. Understanding the pathophysiology of AR is crucial in the development of novel therapies to treat this incurable disease that often comorbids with other airway diseases. Hence in this mini review, we summarize the well-established yet vital aspects of AR. These include the epidemiology, clinical and laboratory diagnostic criteria, AR in pediatrics, pathophysiology of AR, Th2 responses in the disease, as well as pharmacological and immunomodulating therapies for AR patients.
The breakdown of nasal epithelial barrier occurs in allergic rhinitis (AR) patients. Impairment of cell junction molecules including tight junctions (TJs) and desmosomes plays causative roles in the pathogenesis of AR. In this study, we investigated the transcript expression levels of TJs including occludin (OCLN), claudin-3 and -7 (CLDN3 and CLDN7), desmoglein 3 (DSG3) and thymic stromal lymphopoietin (TSLP) in AR patients (n = 30) and non-allergic controls (n = 30). Nasal epithelial cells of non-allergic controls and AR patients were collected to examine their mRNA expression levels, and to correlate with clinico-demographical and environmental parameters. We demonstrated that the expression of OCLN (p = 0.009), CLDN3 (p = 0.032) or CLDN7 (p = 0.004) transcript was significantly lower in AR patients compared with non-allergic controls. No significant difference was observed in the expression of DSG3 (p = 0.750) or TSLP (p = 0.991) transcript in AR patients compared with non-allergic controls. A significant association between urban locations and lower OCLN expression (p = 0.010), or exposure to second-hand smoke with lower CLDN7 expression (p = 0.042) was found in AR patients. Interestingly, none of the TJs expression was significantly associated with having pets, frequency of changing bedsheet and housekeeping. These results suggest that defective nasal epithelial barrier in AR patients is attributable to reduced expression of OCLN and CLDN7 associated with urban locations and exposure to second-hand smoke, supporting recent findings that air pollution represents one of the causes of AR.
The IL-4/IL-13 axis is involved in the pathogenesis of allergic rhinitis (AR). In this study, we investigated the serum cytokines levels of IL-4, IL-5, IL-6, and IL-13 in AR patients, and the transcript expression levels of their receptors (i.e. IL4R, IL5RA, IL6R, and IL13RA1) in nasal epithelial cells of AR patients versus non-allergic controls. Nasal epithelial cells and blood samples of non-allergic controls (n = 30) and AR patients (n = 30) were collected to examine mRNA expression and serum cytokines levels, respectively. Bioinformatics analyses of IL-4/IL-13 receptor heterodimer association with tight junction (TJ) and JAK/STAT signaling genes were conducted in a gene expression profiling (GEP) dataset (GSE44037) of AR patients (n = 12) and healthy controls (n = 6). Serum IL-4, IL-5, IL-6 or IL-13 levels, and IL13RA1 transcript expression were significantly higher in AR patients compared with non-allergic controls. IL-4 and IL-13 serum levels were positively correlated with IL13RA1 expression in AR patients but not in non-allergic controls. In the GEP dataset (GSE44037), six TJ (CLDN4, CLDN7, CLDN12, CLDN15, TJP1, and TJP2) genes’ expressions were negatively correlated, respectively, with IL-4Rα/IL-13Rα1 heterodimeric receptor expression in AR patients and not in control samples. These six TJ genes contributed to the significant enrichment of tight junction Gene Ontology (GO ID: 0070160). Lastly, STATs DNA binding motif analysis showed that each of these TJ genes contains STATs binding consensus sequence within intronic and intergenic regions. Our results suggest that increased IL-4/IL-13 serum cytokines levels may contribute to decreased TJs expression via IL-4Rα/IL-13Rα1 heterodimeric receptor in nasal epithelium of AR patients.
Background Chronic rhinosinusitis (CRS) is one of the most common and complex chronic inflammatory disease of sinonasal mucosa. Even though the pathogenesis of CRS is multifactorial and still unclear, the role of cytokines especially interleukin-1 (IL-1) is being investigated worldwide in different population because of varying results obtained. Objective To study the association of IL-1 ( A and B ) gene polymorphisms with chronic rhinosinusitis with nasal polyp (CRSwNP) and without nasal polyp (CRSsNP), and other factors related. Methods This is a case-controlled study which include a total of 138 subjects recruited from Otorhinolaryngology-Head and Neck Surgery clinic in Hospital Universiti Sains Malaysia. Genotyping of the IL-1A (+4845G, +4845T) and IL-1B (−511C, −511T) were performed with restriction fragment length polymorphism analysis. Results There was a statistical significant association between IL-1B (−511C, −511T) polymorphism with CRSwNP and CRSsNP ( p < 0.001). The CT genotype of IL-1B was markedly increased in CRSwNP subjects (52.2%). However, there was no significant association found between IL-1A (+4845G, +4845T) with CRSwNP and CRSsNP ( p = 0.093). No association was found in factors related to CRS, which included asthma, atopy, allergy, aspirin sensitivity, and family history of nasal polyp ( p value of 0.382, 0.382, 0.144, >0.95, and 0.254, respectively). Conclusion This study indicates an association of IL-1B (−511C, −511T) polymorphism with CRSwNP and CRSsNP in our population, hence there is a possibility of IL-1B involvement in modulating pathogenesis of CRS. There was no significant association of IL-1A (+4845G, +4845T) polymorphism with CRSwNP and CRSsNP, and other factors related.
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