Peripheral Multiple Cytokine Profiles Identified CD39 as a Novel Biomarker for Diagnosis and Reflecting Disease Severity in Allergic Rhinitis Patients.

Background: Allergic rhinitis (AR) is a common clinical problem, and immune cells and cytokines were proven to be pivotal in its pathogenesis. Our aim is to measure the peripheral concentrations of multiple cytokines in AR patients and identify novel biomarkers for diagnosis and disease severity. Methods: Peripheral blood samples were collected from 50 AR patients, including 25 mild AR (MAR) patients and 25 moderate-severe AR patients (MSAR), and 22 healthy controls (HCs), and multiple cytokine profiling was outlined by Luminex assay. Cytokine levels were compared among the three groups, and their correlations with disease severity were evaluated. The candidate cytokines were further verified by enzyme-linked immunosorbent assay (ELISA) in a validation cohort. Results: Multiple cytokine profiling revealed that CD39 and interferon (IFN)-γ levels were reduced, and interleukin (IL)-13, IL-5, IL-33, and thymic stromal lymphopoietin (TSLP) levels were elevated in the AR group than the HC group (P < 0.05). Receiver operating characteristic (ROC) curves presented that serum CD39 and IL-33 exhibited strong diagnostic abilities, and serum CD39 and IL-10 presented capacities in distinguishing disease severity (AUC > 0.8, P < 0.05). Moreover, CD39 concentrations were decreased, and IL-10, IL-5, and TSLP concentrations were enhanced in the MSAR group more than in the MAR group. Correlation analysis results showed that serum CD39, IL-5, and TSLP levels were associated with total nasal symptom score (TNSS) and visual analogue score (VAS) (P < 0.05). Further data in the validation cohort suggested that serum CD39 levels were reduced, and IL-5 and TSLP levels were increased in AR patients, especially in MSAR patients (P < 0.05). ROC results revealed potential values of serum CD39 in diagnosis and disease severity evaluation in AR patients (P < 0.05). Conclusion: This study highlighted that peripheral multiple cytokine profiles were significantly varied in AR patients and associated with disease severity. The results in discover-validation cohorts implied that serum CD39 might serve as a novel biomarker for diagnosing AR and reflecting its disease severity.

[Diagnostic value of a novel test paper detection of ECP in nasal secretion for allergic rhinitis].

Objective:To explore the diagnostic value of a novel test paper, which detect eosinophil cationic protein（ECP） of nasal secretion in allergic rhinitis（AR）. Methods:Nasal secretion and serum samples from 107 patients with allergic rhinitis（AR group） and 40 healthy volunteers（control group） were selected. The nasal symptoms were also evaluated in AR group. The degree of ECP coloration was evaluated by nasal secretion eosinophil cationic protein-myeloperoxid（ECP-MPO） test paper, and the concentration of ECP in nasal secretion and the concentration of cytokines in serum were detected at the same time. The difference and correlation among these indexes were analyzed. The best cutoff value and test efficiency of ECP chromogenic grade and concentration of nasal secretion were calculated by receiver operating characteristic curve（ROC）. Results:The concentration of ECP in nasal secretion of AR patients was significantly higher than that of healthy controls（P<0.05）. The color grade of nasal secretion detected by the test paper was positively correlated with the concentration of ECP in nasal secretion（P<0.05）, and there was significant difference among different grades（P<0.05）. There was a satisfying symmetry between the ECP color grade of nasal secretion and the serum specific IgE（sIgE） level as well as a high diagnostic consistency between them（P<0.05）. The area under the curve（AUC） of ECP concentration ROC in nasal secretion was 0.807 2, corresponding to 64% sensitivity and 85% specificity when the cutoff value was set at 0.980 5; when the cutoff value was set at 1, the AUC of nasal secretion ECP color grading was 0.941 9, corresponding to 92% sensitivity and 94% specificity. No clear correlation between the concentration of ECP in nasal secretion and serum cytokines was found（P>0.05）. Conclusion:The results of this novel test paper is in good agreement with those of serological allergens. It could serve as a preliminary test to evaluate the severity of allergy with satisfactory sensitivity and specificity, and is especially suitable in clinical practice for primary hospital.

Successful Elosulfase Alfa Desensitization Protocol in a Patient With Morquio A Syndrome.

Patients with lysosomal storage diseases may require modifications to standard drug desensitization protocols; personalized medicine as well as development of new treatment options are needed.

An Evaluation of Oxidative Stress With Thiol/Disulfide Homeostasis in Patients With Persistent Allergic Rhinitis.

BACKGROUND: We evaluated the efficacy of medical treatment on thiol-disulfide balance despite ongoing allergic stimulation. METHODS: The research design was a prospective observational study that included 35 persistent allergic rhinitis (AR) patients. All patients who were diagnosed with persistent AR were included. A skin prick test was applied to all patients, and the Sino-nasal Outcome Test-22 was used to evaluate sinonasal symptoms. Thiol/disulfide homeostasis balance parameters were measured using a novel automatic and spectrophotometric method and compared statistically. Serum total thiol (TT), native thiol (SH), disulphide (SS), disulphide/native thiol (SS/SH), disulphide/total thiol (SS/TT), and native thiol/total thiol (SH/TT) ratios were measured after the second month of the treatment. RESULTS: The 35 patients included 20 (58%) females and 15 (42%) males. The mean age of the patients was 33.17 ± 9.9 years. Disulphide, SS/SH, and SS/TT ratios decreased significantly after the treatment (P < .05), while SH and SH/TT increased significantly (P < .05). The mean SH measurement increased significantly in the second month (P = .001), but TT mean measurements showed no difference after the treatment (P = .058). The mean SS measurements, on the other hand, decreased significantly in the second month (P = .003). CONCLUSION: Thiol/disulfide homeostasis may be used as a marker to evaluate the efficacy of persistent AR treatments. After the treatment, the increase in SH levels suggested the decrease in oxidative stress, even though allergen exposure continued.

Short-Chain Fatty Acids Promote Immunotherapy by Modulating Immune Regulatory Property in B Cells.

The dysfunction of regulatory B cells (Breg) may result in immune inflammation such as allergic rhinitis (AR); the underlying mechanism is not fully understood yet. Short-chain fatty acids, such as propionic acid (PA), have immune regulatory functions. This study is aimed at testing a hypothesis that modulates PA production alleviating airway allergy through maintaining Breg functions. B cells were isolated from the blood obtained from AR patients and healthy control (HC) subjects. The stabilization of IL-10 mRNA in B cells was tested with RT-qPCR. An AR mouse model was developed to test the role of PA in stabilizing the IL-10 expression in B cells. We found that the serum PA levels were negatively correlated with the serum Th2 cytokine levels in AR patients. Serum PA levels were positively associated with peripheral CD5+ B cell frequency in AR patients; the CD5+ B cells were also IL-10+. The spontaneous IL-10 mRNA decay was observed in B cells, which was prevented by the presence of PA through activating GPR43. PA counteracted the effects of Tristetraprolin (TTP) on inducing IL-10 mRNA decay in B cells through the AKT/T-bet/granzyme B pathway. Administration of Yupinfeng San, a Chinese traditional medical formula, or indole-3-PA, induced PA production by intestinal bacteria to stabilize the IL-10 expression in B cells, which promoted the allergen specific immunotherapy, and efficiently alleviated experimental AR. In summary, the data show that CD5+ B cells produce IL-10. The serum lower PA levels are associated with the lower frequency of CD5+ B cells in AR patients. Administration with Yupinfeng San or indole-3-PA can improve Breg functions and alleviate experimental AR.

The role and correlation of IL-35 and type II intrinsic lymphocytes in children with allergic rhinitis.

To investigate the role and correlation of IL-35 and ILC2 in children with allergic rhinitis. 50 cases of children with allergic rhinitis admitted to our hospital from February 2018 to March 2020 were selected as the research subjects and set as the study group. During the same period, 50 cases of normal children admitted to our hospital for physical examination were selected as the control group. The differences in the expression of IL-35 and ILC2 between the two groups and the correlation with the severity of allergic rhinitis were compared. In BMI, the study group was significantly lower than the control group, and the difference was statistically significant (P<0.05). IL-35 in the study group was significantly lower than that in the control group, while ILC2, IL4+ILC2, IL-5+ILC2, IL-13+ILC2, IgE and ECP in the study group were significantly higher than those in the control group, the difference was statistically significant (P<0.05). Pearson correlation analysis showed a moderate negative correlation between TNSS score and IL-35 (r =-0.642, P<0.05), was positively correlated with ILC2, IL4+ILC2, IL-5+ILC2, IL-13+ILC2, ECP (r =0.745, 0.713, 0.725, 0.769, 0.746, P<0.05), and was strongly correlated with IgE (r =0.952, P<0.05). Also, It was positively correlated with TGF-?1 (r =0.513, P<0.05). IL-35 was strongly negatively correlated with ILC2, IL4+ILC2, IL-5+ILC2, IL-13+ILC2 (r =-0.845, -0.812, -0.805, 0.823, -0.854, P<0.05). Was negatively correlated with ECP and TGF-?1 (r =-0.795, -0.543, P<0.05). ILC2 was strongly correlated with IgE (r =0.812, P<0.05), and moderately positively correlated with ECP and TGF-?1 (r =0.642, 0.541, P<0.05). ROC curve was used to evaluate the diagnostic value. The results showed that among the five indicators, IgE had the highest sensitivity of 92.23%, while IL-35 had the highest specificity of 92.56%. However, the combined area, sensitivity and specificity of the five indicators were the highest, 0.962, 95.18% and 94.25%, respectively (P<0.05). Both IL-35 and type II intrinsic lymphocytes are highly correlated with the severity of allergic rhinitis in children, the former is negatively correlated with the latter is positively correlated. The detection of these indexes in clinical practice can be helpful for clinical diagnosis.

Notch2 suppresses the development of allergic rhinitis by promoting FOXP3 expression and Treg cell differentiation.

AIMS: Notch signaling is closely related to a variety of diseases, but the role of Notch2 in allergic rhinitis (AR) remain unclear. This study was performed to investigate the effects of Notch2 on the differentiation of Treg cells and on the inflammatory response of AR. MATERIALS AND METHODS: Peripheral blood (including 101 AR patients and 66 Controls) and nasal mucosa (including 19 AR patients and 17 Controls) were collected to detect the expression levels of Notch2, NICD2 and FOXP3. CD4+ T cells of human origin were selected to detect the effects of Notch2 on the differentiation of Treg cells and FOXP3. An AR mouse model was established, and lentiviruses overexpressing Notch2 were administered. Then, allergic symptoms, OVA-sIgE titers, nasal mucosal inflammation, Th1/Th2/Th17 cytokines and splenic Treg cells were assessed. KEY FINDINGS: Compared with that in the Control group, the expression of Notch2 in the AR group was decreased, and Notch2 expression was negatively correlated with the degree of allergy (P < 0.01). The expression levels of Notch2, NICD2 and FOXP3 were decreased in the nasal mucosa of AR patients. Notch2 can promote the differentiation of human Treg cells in vitro (P < 0.05), and Notch2 can directly promote FOXP3 transcription. Animal experiments showed after the upregulation of Notch2 expression, the allergic inflammatory of mice with AR was reduced, the differentiation of Treg cells was increased, and the imbalance of T cells was reversed (P < 0.05). SIGNIFICANCE: Notch2 promotes the differentiation of Treg cells by upregulating FOXP3 expression, thus significantly inhibiting the inflammatory response of AR.

sCD48 is elevated in non-allergic but not in allergic persistent rhinitis.

BACKGROUND: CD48 is a costimulatory receptor of the immune response. Interactions between CD48 and CD244 (2B4) on mast cells and eosinophils suggest that these cells can act synergistically in the 'allergic effector unit' to promote inflammation. This report explores the role of CD48 in persistent allergic (PAR) and non-allergic rhinitis (NAR). METHODS: In this study, serum was obtained from 70 subjects (45 female, 64%; mean age, 36; range 18-70 years) to estimate the levels of sCD48 and two eosinophils-related parameters, ECP and eotaxin-1/CCL11. Twenty patients with PAR, 15 patients with NAR, and 35 healthy controls were included. The intensity of rhinitis symptoms was estimated by the Total Nasal Symptom Score. We also assessed the fractional exhaled nitric oxide bronchial and nasal fractions (FeNO) and neutrophil to lymphocyte (NLR) and eosinophil to lymphocyte (ELR) ratios. RESULTS: Significantly higher sCD48 serum levels were observed in the NAR group than in the PAR and control groups, and significant correlations were found between the serum level of sCD48 and the number and percentage of eosinophils. ECP and eotaxin-1/CCL11 serum levels were also found to be significantly higher in the NAR group. CONCLUSIONS: CD48 may be involved in eosinophilic pathophysiological reactions in non-allergic rhinitis.

Role of MicroRNA-155 as a Potential Biomarker for Allergic Rhinitis in Children.

Background: Allergic rhinitis (AR) is an inflammatory state categorized by a disturbance of immunoregulatory mechanisms. MicroRNA-155 (miRNA-155) has an essential role in regulating gene expression and can mediate the allergic TH2 process. Objective: In this study, we aimed to evaluate the role of miR-155 as a biomarker in AR and correlate its level with the total nasal symptom score (TNSS) and the levels of serum interleukin-4 (IL-4). Methods: This study included 90 children: 45 with pollen-induced AR and 45 healthy controls. Serum miR-155 expression levels were measured using quantitative real-time PCR. Human IL-4 ELIZA kits were used for the semiquantitative detection of the serum levels of IL-4. Receiver operating characteristic (ROC) curves were used to determine the best cutoff values for the studied parameters for the diagnosis of AR. Results: The demographic characteristics of the two groups were matched with respect to age and sex. The AR case group included 23 (51.1%) males and 22 (48.9%) females, while the control group included 24 (53.3%) males and 21 (46.7%) females. The miR-155 level was increased in the serum of children with pollen-induced AR compared with controls (mean difference = 2.8, p < 0.001). A significant positive correlation between the serum expression level of miR-155 and TNSS in children with AR was detected (r = 0.494, p < 0.001). However, no significant correlation was identified between the expression of miR-155 and that of IL-4. At a cutoff value of 1.09, the sensitivity of miR-155 as a biomarker for AR was 100%, and the specificity was 71.1%. Conclusion: MiR-155 expression levels were elevated in the serum of AR children. Therefore, miR-155 could be used as a biomarker in AR diagnosis.

Serum Soluble ST2 Correlated with Symptom Severity and Clinical Response of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis Patients.

BACKGROUND: Suppressor of tumorigenicity 2 (ST2) is a key biomarker in inflammation and cardiovascular diseases, but limited data is available on its role in allergic rhinitis (AR). OBJECTIVE: The aim of this study is to explore the role of serum soluble ST2 (sST2) in evaluating disease severity and predicting the efficacy of sublingual immunotherapy (SLIT) in house dust mite- (HDM-) induced AR patients. METHODS: Eighty healthy controls (HC group) and 160 HDM-induced AR patients, including 40 mild patients (MAR group) and 120 moderate-severe patients (MSAR group), were recruited in this study. Serum was collected from all participants and levels of sST2 were determined by ELISA and the relationship between sST2 levels and disease severity was assessed. In the MSAR group, 109 patients received 3 years of SLIT, and the relationship between serum levels of sST2 and efficacy of SLIT was exampled. RESULTS: Serum sST2 levels were increased in HDM-induced AR patients compared to the HC group (P < 0.001), and the concentrations were higher in the MSAR group than in the MAR group and HC group (all P < 0.05). Moreover, sST2 levels positively correlated with the total nasal symptom score (TNSS), visual analogue scale (VAS), and specific IgE levels (P < 0.05). Seventy-eight MSAR patients accomplished SLIT, and they were divided into an effective group (n = 40) and an ineffective group (n = 38). The serum sST2 levels in the effective group were lower than those in the ineffective group (P < 0.001). In addition, patients in the effective group levels exhibited significantly lower sST2 levels post-SLIT than pre-SLIT (P < 0.001), but no statistic difference was observed in the ineffective group (P > 0.05). Receiver operating characteristic (ROC) curve showed promising accuracy for predicting clinical efficacy of SLIT in AR patients (area under the curve = 0.839, P < 0.001). CONCLUSION: Serum sST2 is a potential biomarker for assessing disease severity and may serve as a sensitive biomarker for predicting the therapeutic response of SLIT in HDM-induced AR patients.

Clinical Relevance of Shrimp Sensitization in Patients with Allergic Rhinitis: Anti-Der p 10 IgE as Predictor.

INTRODUCTION: Cross-reactivity between shrimp and house dust mite (HDM) proteins has been widely documented. In tropical region, shrimp (5-15%) and mite sensitization (80-95%) is prevalent in allergic patients. However, the clinical relevance of shrimp sensitization in patients with allergic rhinitis (AR) has been poorly studied. The aim of this study was to determine the prevalence and the clinical relevance shrimp IgE sensitization in AR patients sensitized to Dermatophagoides pteronyssinus. METHODS: The study was conducted in Medellin (Colombia). A cross-sectional study in patients with AR sensitized to HDM was performed in 3 steps: (i) assessment of IgE sensitization frequency to shrimp Penaeus azteca, Litopenaeus vannamei, and tropomyosin homologous allergens rDer p 10, rPen a 1, and rLit v 1, (ii) evaluation of the clinical relevance of shrimp sensitization using oral challenge test (OCT) and (iii) identification of possible risk factors for positive-OCT results. Ethical committee approval was obtained. RESULTS: From 443 patients with AR, 86 (19.4%) were sensitized to shrimp and 23 of them (26.7%) had shrimp allergy diagnosis. Thirty-six of the patients sensitized to shrimp (41.2%) reported not previously consumed this food and eleven of them had a positive-OCT (30.5%). There was not statistically significant difference in total IgE or sIgE (D. pteronyssinus, P. azteca, L. vannamei, rPen a 1, and rLit v 1) between OCT groups (positive vs. negative results). Anti-Der p 10 IgE was associated with risk for a positive-OCT in different multivariable scenarios. DISCUSSION/CONCLUSION: Our results suggest that in patients with HDM-associated AR and shrimp IgE sensitization is necessary to evaluate the clinical relevance of shrimp IgE even if the patient has never consumed shrimp because of cross-reactivity. Anti-Der p 10 could be a possible biomarker of clinical relevance to shrimp sensitization and could reduce the need for OCTs.

Therapeutic effects of SKF-96365 on murine allergic rhinitis induced by OVA.

INTRODUCTION: SKF-96365 is regarded as an inhibitor of receptor-mediated calcium ion (Ca2+) entry. The current study aimed to explore the effects of SKF-96365 on murine allergic rhinitis (AR). METHODS: Intranasal SKF-96365 administration was performed on OVA induced murine AR. Serum and nasal lavage fluid (NLF) from mice were harvested to assay IgE and inflammatory cytokines using ELISA method. Inflammatory cells were counted and analyzed in NLF. Nasal mucosa tissues were collected from mice and used for HE staining, immunohistochemistry (IHC) staining, and real-time PCR detection. RESULTS: SKF-96365 had therapeutic effects on murine AR manifesting attenuation of sneezing, nasal rubbing, IgE, inflammatory cytokines, inflammatory cells, TRPC6 immunolabeling, and TRPC6, STIM1 and Orai1 mRNA levels in AR mice. CONCLUSION: SKF-96365 could effectively alleviate the symptoms of murine AR. SKF-96365 could suppress TRPC6, STIM1, and Orai1 activities, leading to the downregulation of inflammatory cytokines and inflammatory cells in murine AR.

1α,25-Dihydroxyvitamin D3 Supplementation during Pregnancy Is Associated with Allergic Rhinitis in the Offspring by Modulating Immunity.

BACKGROUND: Maternal supplementation with 1α,25-dihydroxyvitamin D3 (VD3) has immunologic effects on the developing fetus through multiple pathways. This study was aimed at investigating the effects of VD3 supplementation on immune dysregulation in the offspring during allergic rhinitis. METHODS: Different doses of VD3 as well as control were given to pregnant female mice. Ovalbumin (OVA) challenge and aluminum hydroxide gel in sterile saline were used to induce allergic rhinitis in offspring mice. Nasal lavage fluids (NLF) were collected, and eosinophils were counted in NLF 24 hours after the OVA challenge. Th1, Th2, Th17, and Treg subtype-relevant cytokines, including IFN-γ, IL-4, IL-10, IL-17, TGF-ß, and OVA-IgE levels from the blood and NLF of offspring mice, were detected by the enzyme-linked immunosorbent assay (ELISA) method. The Treg subtype was analyzed by flow cytometry. Treg cells were purified from offspring and were adoptively transferred to OVA-sensitized allogenic offspring mice. The outcomes were assessed in allogenic offspring. RESULTS: Our data showed that VD3 supplementation significantly decreased the number of eosinophils, basophils, and lymphocytes in the peripheral blood and NLF. The proportion of CD4+CD25+FoxP3+Tregs had a positive correlation with VD3 in a dose-dependent manner. The levels of serum IgE, IL-4, and IL-17 were decreased while the expressions of IFN-γ, IL-10, and TGF-ß were significantly enhanced in VD3 supplementation groups. Adoptive transfer CD4+CD25+FoxP3+Tregs of VD3 supplementation groups promoted Th1 and suppressed Th2 responses in the offspring during allergic rhinitis. CONCLUSION: Our findings indicated that low dose VD3 supply in pregnant mice's diet suppressed Th2 and Th17 responses in allergic rhinitis by elevating the Th1 subtype and the proportion of CD4+CD25+FoxP3+Tregs in offspring. It suggested that low dose VD3 supply may have the potential to act as a new therapeutic strategy for allergic rhinitis.

Therapeutic effects of melatonin on an ovalbumin-induced allergic rhinitis model in rats.

OBJECTIVE: We aimed to investigate the therapeutic effects of melatonin in an experimental AR model. METHODS: Thirty-two Wistar rats were randomised into four groups (n = 8 each). The experimental AR model was established in the saline (SF), ethanol, and melatonin groups via intraperitoneal (i.p.) injections and intranasal application of ovalbumin. The SF, ethanol, and melatonin groups received daily i.p. saline, 2% ethanol dissolved in saline, and 10 mg/kg melatonin dissolved in 2% ethanol and saline. The control group received the same amount of i.p. and intranasal saline. Total nasal symptom scores were recorded in all rats on days 1 (baseline), 15, 20, 25, and 30. Serum ovalbumin-specific IgE, IL-13, and melatonin levels were measured on days 1 (baseline), 15, and 30. The nasal mucosa of all rats was scored histopathologically. RESULTS: The total nasal symptom scores and serum ovalbumin-specific IgE values of the SF, ethanol, and melatonin groups were significantly higher on day 15 than those of the control group. On day 30, the scores and serum ovalbumin-specific IgE values of the melatonin group were similar to those of the control, whereas the SF and ethanol groups had statistically higher scores. The histological scores of the SF and ethanol groups were significantly higher than those of the control and melatonin groups, but no significant difference was found between the melatonin and control groups. CONCLUSION: Melatonin reduced total nasal symptom scores and serum ovalbumin-specific IgE levels and improved histological inflammation parameters in the ovalbumin-induced rat experimental AR model.

Targeting a novel hsa_circ_0000520/miR-556-5p/NLRP3 pathway-mediated cell pyroptosis and inflammation attenuates ovalbumin (OVA)-induced allergic rhinitis (AR) in mice models.

OBJECTIVES: The circRNAs-miRNAs-mRNAs competing endogenous RNA (ceRNA) networks involve in regulating the development of various inflammation-associated diseases, including allergic rhinitis (AR), and the present study aimed to identify novel AR-associated ceRNA networks. METHODS: The mRNA and protein levels of the associated genes were, respectively, examined by real-time qPCR and western blot analysis. The targeting sites in miR-556-5p and NLRP3 were validated by performing dual-luciferase reporter gene system assay. ELISA was used to measure inflammatory cytokines secretion, and CCK-8 assay was conducted to determine cell proliferation. RESULTS: Here, we first identified a hsa_circ_0000520/miR-556-5p/NLRP3 signaling cascade triggered epithelium pyroptosis and inflammation to regulate the development of AR in cellular and mice models. Specifically, the pyroptosis-associated biomarkers (NLRP3, ASC, IL-1ß and IL-18) and pro-inflammatory cytokines (OVA-specific IgE, TNF-α, IL-4 and IL-5) were upregulated in the nasal subjects collected from AR patients and ovalbumin (OVA)-induced AR mice models, compared to their normal counterparts. Next, using the ceRNA networks analysis software, we screened out a hsa_circ_0000520/miR-556-5p axis that potentially regulated NLRP3 in the human nasal epithelial cell line. Mechanistically, miR-556-5p targeted both hsa_circ_0000520 and 3' untranslated region (3'UTR) of NLRP3, and knock-down of hsa_circ_0000520 inactivated NLRP3-mediated epithelium pyroptosis through miR-556-5p in a ceRNA-dependent manner. Furthermore, we proved that both hsa_circ_0000520 ablation and miR-556-5p overexpression suppressed NLRP3-mediated cell pyroptosis to attenuate AR in mice models. CONCLUSIONS: Taken together, we evidenced that targeting the hsa_circ_0000520/miR-556-5p/NLRP3 signaling pathway was a novel AQ1strategy to ameliorate AR progression; however, future clinical data are still required to validate our preliminary results.

Increased Thrombin-Activatable Fibrinolysis Inhibitor in Response to Sublingual Immunotherapy for Allergic Rhinitis.

OBJECTIVES/HYPOTHESIS: The objective of this study was to determine the role of thrombin-activatable fibrinolysis inhibitor (TAFI) as a candidate biomarker for therapeutic efficacy of sublingual immunotherapy (SLIT) and to identify the role of TAFI in the pathogenesis of allergic rhinitis (AR). STUDY DESIGN: Retrospective cohort study and laboratory study. METHODS: Serum was collected from patients with allergies to Japanese cedar pollen before, during, and after treatment with SLIT. We measured the levels of immunoreactive TAFI, C3a, and C5a in serum by enzyme-linked immunosorbent assay (ELISA) and assessed their relative impact on a combined symptom-medication score. We also examined the impact of TAFI on mast cells and fibroblasts in experiments performed in vitro. RESULTS: Serum levels of TAFI increased significantly in response to SLIT. By contrast, serum C3a levels decreased significantly over time; we observed a significant negative correlation between serum levels of TAFI versus C3a and symptom-medication score. Mast cell degranulation was inhibited in response to TAFI, as it was the expression of both CCL11 and CCL5 in cultured fibroblasts. CONCLUSIONS: High serum levels of TAFI may be induced by SLIT. TAFI may play a critical protective role in pathogenesis of AR by inactivating C3a and by inhibiting mast cell degranulation and chemokines expression in fibroblasts. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2413-2420, 2021.

Obesity Can Contribute to Severe Persistent Allergic Rhinitis in Children through Leptin and Interleukin-1ß.

BACKGROUND: Obesity/overweight is associated with a higher risk of allergic rhinitis (AR) in children. OBJECTIVE: This study aimed at exploring the mechanisms by which obesity affects the severity of AR through leptin and interleukin (IL)-1ß were investigated. METHODS: In all, 210 subjects with AR and 82 subjects without AR were included in this study. The levels of leptin and inflammatory biomarkers were measured in the serum to investigate the correlation with the severity of AR. Additionally, we analyzed whether changes in BMI regulate the severity of AR through serial follow-up of obese children. RESULTS: IL-1ß, which is a biomarker of active inflammation in AR, was significantly higher in individuals with AR than in those without and higher in subjects in the obesity group than in those in the normal weight group. A regression analysis showed that the leptin level was associated with increased IL-1ß expression in children with AR. In the multivariate analysis, only parental AR (9.2-fold increase in risk), elevated leptin (11.3-fold increase in risk), and high expression of IL-1ß (5.8-fold increase in risk) emerged as significant risk factors of moderate to severe persistent allergic rhinitis. We also found that children with an increase or decrease in BMI showed changes in IL-1ß and AR symptoms, which these changes were dependent on leptin and BMI. CONCLUSIONS: These results suggest that obesity is an important risk factor for the exacerbation of symptoms and leptin can exacerbate inflammation as well as severe and persistent symptoms through IL-1ß in AR.

Expression of proteins associated with airway fibrosis differs between children with allergic asthma and allergic rhinitis.

Allergic rhinitis (AR) and allergic asthma (AA) exhibit similar inflammatory response in the airways. However, the remodelling is more extensive in the lower airways, suggesting that the inflammation itself is not sufficient for allergic phenotype. We aimed to analyse whether the expression of selected 27 inflammatory and fibrosis-related proteins may be altered in AR and AA in the paediatric population and whether the expression pattern is either similar (due to the inflammation) or disease-specific (due to the remodelling). We analysed 80 paediatric subjects: 39 with AA, 21 with AR and 20 healthy children. The diagnosis of AR and AA was based on clinical manifestation, lung function, positive skin prick tests and increased immunoglobulin E levels. Serum levels of selected inflammatory proteins were measured with custom Magnetic Luminex Assay. Statistical analysis was performed in Statistica v.13. CCL2/MCP1, GM-CSF, gp130 and periostin concentrations were significantly lower, whereas IL-5 levels were higher in AA compared to the control group. CD-40L, CHI3L1/YKL-40, EGF, GM-CSF and periostin levels were significantly decreased in patients with AR than in the control group. Comparison of AA and AR patients revealed significant changes in CHI3L1/YKL-40 (P = 0.021), IL-5 (P = 0.036), periostin (P = 0.013) and VEGFα (P = 0.046). Significantly altered proteins were good predictors to distinguish between AA and AR (P < 0.001, OR 46.00, accuracy 88.57%). Our results suggest that the expression of four fibrotic proteins was significantly altered between AA and AR, suggesting possible differences in airway remodelling between upper and lower airways.