Interleukin-37b Suppressed ILC2s in Children with Allergic Rhinitis.

Background: Interleukin-37b is a fundamental inhibitor of innate and acquired immunity. Type 2 innate lymphoid cells (ILC2s) can secret type 2 cytokines and regulate allergic rhinitis (AR). However, the role of IL-37b in ILC2s in children with AR was not clear. Methods: We recruited 15 AR children and controls. The serum IL-37b levels and its relation with the frequency and functional phenotype of ILC2s. The regulation of IL-37b on ILC2s proliferation and function was confirmed using flow cytometry and enzyme-linked immunosorbent assay (ELISA). The mRNA expression of IL-1R8, IL-18Rα, and ICOSL was examined using RCR. The change of IL-37b protein level in serum during subcutaneous allergen immunotherapy (SCIT) was determined by ELISA. Results: We have demonstrated that both of the frequencies of blood ILC2s, IL-5+ILC2s, and IL-13+ILC2s in AR children were elevated compared with controls. The serum protein level of IL-37b was downregulated in AR, and it was negatively related to the frequency of ILC2s, IL-5+ILC2s, and IL-13+ILC2s. IL-37b increased the mRNA levels of IL-1R8, IL-18Rα, and ICOSL expressed by ILC2s. IL-37b suppressed the proliferation of ILC2s and the secretion of IL-5 and IL-13 from ILC2s. Finally, we found that IL-37b was increased in AR children after 3 years' SLIT, especially in the good response group. Conclusion: Our findings highlight the role of IL-37b in the suppression of ILC2s and establish a new therapeutic target in AR.

Significant efficacy of short-course, low-concentration betamethasone mouthwash therapy for severe erosive oral lichen planus: a randomized controlled trial.

OBJECTIVES: To evaluate the short-term efficacy of low-concentration betamethasone mouthwash for severe erosive oral lichen planus (EOLP). MATERIALS AND METHOD: In this randomized, investigator-blind, positive-controlled trial, OLP patients with erosive lesions received betamethasone mouthwash (0.137 mg/mL) or dexamethasone mouthwash (0.181 mg/mL) three times daily for 2 or 4 weeks and were followed up for 3 months to observe recurrence. The primary outcome was the week-2 reduction in erosive area. RESULTS: Fifty-seven participants were randomized to betamethasone (n = 29) and dexamethasone (n = 28). At week 2, participants using betamethasone (n = 28) experienced a greater reduction in erosive area than gargling with dexamethasone (n = 26). Similarly, secondary outcomes, including the healing proportion of erosions, reduced pain level, reduction in atrophic area, Thongprasom score, and recurrence interval, showed the superiority of betamethasone. At week 4, betamethasone (n = 7) was not superior to dexamethasone (n = 15) in further reducing lesional area and pain level. No serious adverse events were documented. CONCLUSIONS: The 0.137 mg/mL compound betamethasone mouthwash exhibited significant efficacy in rapidly enhancing erosion healing within 2 weeks and extending the recurrence interval with a good safety profile. CLINICAL RELEVANCE: This study proved the significant efficacy of short-course 0.137 mg/mL betamethasone mouthwash therapy for treating erosion and pain, providing a novel topical agent for patients with severe EOLP. TRIAL REGISTRATION: This study was prospectively registered at the International Clinical Trials Registry Platform ( ChiCTR1800016507 ) on 5 June 2018.

Identification of autophagy-related genes in diabetic foot ulcer based on bioinformatic analysis.

Diabetic foot ulcer (DFU) complications involve autophagy dysregulation. This study aimed to identify autophagy-related bioindicators in DFU. Differentially expressed genes (DEGs) between DFU and healthy samples were analysed from the Gene Expression Omnibus (GEO) datasets, GSE7014 and GSE29221. The roles of autophagy-related DEGs were investigated using protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Gene Ontology (GO) enrichment, and Gene Set Enrichment Analysis (GSEA). Immune cell infiltration's correlation with these DEGs was also assessed. From the Human Autophagy Database (HADB), 232 autophagy-related genes (ARGs) were identified, with an intersection of 17 key DEGs between GSE7014 and GSE29221. These genes are involved in pathways like autophagy-animal, NOD-like receptor signalling, and apoptosis. In the protein network, epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) showed significant interactions with ARGs. Survival analysis indicated the prognostic importance of calpain 2 (CAPN2), integrin subunit beta 1 (ITGB1), and vesicle-associated membrane protein 3 (VAMP3). Lower immune scores were observed in the type 2 diabetes mellitus (DM2) group than in controls. Autophagy and ARGs significantly influence DFU pathophysiology.

Effect of IL-35 on apoptosis, adhesion, migration, and activation of eosinophils in allergic rhinitis.

BACKGROUND: Eosinophils play critical roles in the development of allergic rhinitis (AR) by releasing toxic substance. Interleukin-35 (IL-35), a newly identified anti-inflammatory cytokine, had potent inhibitive role for eosinophil infiltration in allergic disease. However, the direct effect of IL-35 on eosinophil was not clear. METHODS: Twenty AR children and sixteen controls were recruited. The correlation between IL-35 protein expression and blood eosinophil counts and activation was analyzed. The effect of IL-35 on eosinophil apoptosis and adhesion was analyzed by flow cytometry. Transwell system was used for the migration assay. The eosinophil cationic protein (ECP) from supernatant of eosinophils after IL-35 stimulation was detected by enzyme-linked immunosorbent assay kits. RESULTS: The IL-35 protein levels were negatively correlated with eosinophil counts (p < .01) and ECP concentration (p < .01) in AR children. IL-35 promotes apoptosis and inhibits adhesion, migration, and activation of eosinophils. Moreover, the mRNA expression of IL-12 receptor ß2 and glycoprotein 130 were significantly enhanced by eosinophils after IL-35 stimulation. The apoptosis induced by IL-35 was mediated by phosphoinositide 3-kinase (PI3K) pathway. IL-35 inhibits adhesion of eosinophils through extracellular regulated protein kinases (ERK) and PI3K pathways. The eosinophil chemotaxis and activation affected by IL-35 were mediated by PI3K and p38 mitogen-activated protein kinase (MAPK) pathways. CONCLUSION: Our results confirmed that IL-35 played inhibitive roles in apoptosis, adhesion, migration, and activation of eosinophils in AR, implying that IL-35 may be used as treatment target in future.

Genetic Variations in Nucleotide Excision Repair Pathway Genes and Risk of Allergic Rhinitis.

Background: Allergic rhinitis (AR) is the most frequent inflammatory disorder in the nasal mucosa that remains unclear etiology. Mounting studies suggested that genetic instability could trigger and worsen the inflammatory response. The nucleotide excision repair (NER) system is an important pathway in maintaining the stability of the genome. Therefore, the genetic variations in NER pathway genes may have potential effects on AR risk. Methods: We evaluated the correlation between 19 candidate single nucleotide polymorphisms (SNPs) in NER pathway genes and AR susceptibility by a case-control study in a Chinese population, which contains 508 AR cases and 526 controls. Results: Three independent SNPs were identified as significantly associated with AR susceptibility, including ERCC1 rs2298881 C > A (recessive model: adjusted odds ratios (OR) = 0.30, 95%confidence interval (CI) = 0.18-0.50, P < 0.0001), ERCC1 rs11615 G > A (dominant model: adjusted OR = 1.44, 95%CI = 1.04-2.01, P = 0.030), and XPC rs2228001 A > C (dominant model: adjusted OR = 0.68, 95%CI = 0.49-0.95, P = 0.024). Stratified analysis showed that ERCC1 rs2298881 AA genotype was correlated with a lower risk of AR among all the subgroups compared with rs2298881 CC/CA genotype. XPC rs2228001 AC/CC genotype reduced AR risk among the following subgroups: age > 60 months, clinical stage I and III. Conclusion: Our finding showed that genetic variations in NER pathway genes: ERCC1 and XPC may affect the risk of AR, which will provide new insights into the genetics of AR from the perspective of DNA damage repair.

Compliance, efficacy, and safety of subcutaneous and sublingual immunotherapy in children with allergic rhinitis.

BACKGROUND: Although previous studies had confirmed the effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), respectively, direct head-to-head comparison of SCIT vs SLIT is sparse. We aimed to compare the efficacy, safety, and compliance of SCIT and SLIT in allergic rhinitis (AR) children. METHODS: This study is a prospective, open-label, and single-center study performed between June 2017 and June 2018. A total of 325 children were grouped into SLIT, Alutard (SCIT1), and NovoHelisen Depot (NHD) (SCIT2) according to the parents' wishes. The adherence and reasons for dropout were recorded. The efficacy of SLIT and SCIT was evaluated by a combined symptom medication score. Adverse events (AEs) were recorded and graded during the whole treatment. RESULTS: The compliance rate was higher in the SCIT group compared with the SLIT group (P < .05). The total nasal symptom score (TNSS), rescue medication score (RMS), and symptom medication score (SMS) after 6-month, 12-month, and 2-year treatment were lower in the SCIT group compared with the SLIT group (P < .05). But the scores between the Alutard and NHD groups were not significantly different. The occurrence of AEs in the SCIT group was significantly higher compared with the SLIT group (P < .05). CONCLUSION: Our results suggested SCIT is more effective compared with SLIT to a certain degree, whereas SLIT had less AEs compared with SCIT. The AIT routes can be chosen according to personal specific conditions.

Inhibited interleukin 35 expression and interleukin 35-induced regulatory T cells promote type II innate lymphoid cell response in allergic rhinitis.

BACKGROUND: Interleukin (IL)-35 and IL-35-producing regulatory T cells (iTr35) have been reported to inhibit TH2 response in allergic rhinitis (AR). However, its effects on type II innate lymphoid cells (ILC2) are not well characterized. OBJECTIVE: To investigate the effect of IL-35 on ILC2 in AR. METHODS: A total of 25 patients with AR and 20 controls were recruited. The expression and regulation of IL-35 receptor in ILC2 were analyzed by real-time polymerase chain reaction. The effect of IL-35 on ILC2 differentiation and cytokine production was analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, iTr35 were cocultured with ILC2 to explore the effect of iTr35 on ILC2. The AR mice models were also established to confirm the role of IL-35 in vivo. RESULTS: The patients with AR had decreased IL-35 expression and iTr35 proportion and increased ILC2 and type II cytokines compared with the controls. Notably, IL-35 inhibited ILC2 differentiation and type II cytokine production by regulating IL-12Rß2 and gp130. IL-35 promoted the inducible costimulatory molecule expression by iTr35 and the inducible costimulatory molecule ligand expression by ILC2. IL-35-treated mice with AR presented decreased frequency and function of nasal ILC2. CONCLUSION: IL-35 inhibited ILC2 responses directly or through mutual contact between iTr35 and ILC2 in AR, suggesting that IL-35 may be used as a potential treatment target in AR.

The Effect of IL-35 on the Expression of Nasal Epithelial-Derived Proinflammatory Cytokines.

BACKGROUND: Airway epithelium plays an important role during the development of allergic rhinitis (AR), which is characterized by production of thymic stromal lymphopoietin (TSLP), interleukin 33 (IL-33), and interleukin 25 (IL-25). IL-35, mainly expressed by Treg cells, have negative regulation in Th2, Th17, and ILC2 inflammation. However, the effect of IL-35 on human nasal epithelial cells (HNECs) especially the secretion of nasal epithelial-derived proinflammatory cytokines as well as the possible mechanism is still unclear. METHODS: HNECs were cultured and stimulated by various stimulators. The expression of IL-33, IL-25, TSLP, eotaxin-1, eotaxin-2, and eotaxin-3 from supernatant was measured using real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). AR mice were developed to verify the effect of IL-35 on nasal epithelial cells in vivo. RESULTS: After Poly I:C stimulation, IL-35 inhibited the production of IL-25, and TSLP from HNECs increased significantly compared with baseline levels (P < 0.05). After Dermatophagoides pteronyssinus or Aspergillus fumigatus stimulation, IL-35 inhibited the production of IL-25, IL-33, and TSLP from HNECs increased significantly compared with baseline levels (P < 0.05). After Dermatophagoides pteronyssinus, IL-35 inhibited the production of eotaxin-1, eotaxin-2, and eotaxin-3 released from HNECs increased significantly compared with baseline levels (P < 0.05). Similarly, IL-35-treated AR mice presented with decreased expression of IL-33, IL-25, TSLP, eotaxin-1, eotaxin-2, and eotaxin-3 in nasal lavage fluid. CONCLUSION: IL-35 suppressed both type 2 inflammation-inducing cytokines and eosinophil chemotactic factor from HNECs, suggesting the important role of IL-35 during the development of AR.

Efficacy of Sublingual Immunotherapy in Allergic Rhinitis Children during Coronavirus Disease 2019.

BACKGROUND: Sublingual immunotherapy (SLIT) had good effectiveness for children with allergic rhinitis (AR). However, no studies explored the effect of persistent allergen exposure on SLIT treatment. Coronavirus disease 2019 (COVID-19) restricts outdoor activities of children significantly. We aimed to evaluate the effectiveness of SLIT during this special period. METHODS: A total of 335 AR children who sensitize to house dust mite (HDM) undergoing SLIT were recruited in this study. The clinical effectiveness and safety were evaluated at different time points using symptom and medication scores. The serum total IgE and specific IgE (sIgE) at different time points were detected by using the Unicap system. RESULTS: The total nasal symptoms score (TNSS) and total medication score (TMS) during the epidemic of COVID-19 increased significantly compared with the same period last year (p < 0.05), despite that they were still significantly lower than baseline levels (p < 0.05). The occurrence of adverse reactions at different time points had no significant differences. We also found that the family of the good response group had more frequent bedding cleaning. Both the tIgE and sIgE levels had no significant changes during SLIT treatment. CONCLUSION: Our results suggest that continuous HDM exposure reduced the effectiveness of SLIT, whereas effective reduction of HDM levels by frequent bed cleaning will be helpful during the SLIT treatment.

Risk Factors for Safety of Allergen-Specific Sublingual Immunotherapy in Children with Allergic Rhinitis.

A good compliance often attributes to good efficacy and safety of sublingual immunotherapy (SLIT). However, few studies have been conducted on the safety of SLIT treatment in children. We aimed to confirm the pretreatment parameters to predict the safety in children who underwent SLIT. 601 children with allergic rhinitis (AR) treated with SLIT were enrolled in this study. Baseline clinical information and laboratory parameters were collected. The clinical response and adverse events (AEs) were recorded and evaluated. A multivariate logistic regression model was established to confirm the predictors for AEs. The AEs were reported in 75 children (13.8%). The serum-specific IgE (s-IgE) level was significantly correlated with the occurrence of AEs by multivariate logistic regression analysis. Our receiver operating characteristic (ROC) analysis of the serum s-IgE levels >21.6 IU/mL had the best sensitivity (83.7%) and specificity (76.7%) to predict safety. The serum s-IgE level was significantly correlated with safety of SLIT in children, which may be helpful for patient selection before SLIT.

The efficacy and safety of thalidomide on the recurrence interval of continuous recurrent aphthous ulceration: A randomized controlled clinical trial.

BACKGROUND: Recurrent aphthous ulceration (RAU) is the most common oral mucosal disease. Some patients have almost continuous oral ulcers which influence the quality of life. The aim of this study was to observe the efficacy and safety of thalidomide on the recurrence interval of continuous RAU. METHODS: A randomized controlled clinical trial was designed, and 60 continuous RAU patients were randomly assigned to the experimental group (n = 32, taking thalidomide before bed at a dose of 100 mg/d for 10 days, then 50 mg/d for 10 days, and 25 mg/d for 10 days) and the control group (n = 28, taking 0.4 mg/kg/d prednisone every morning for 15 days and then 0.2 mg/kg/d for 15 days). The clinical outcomes consisted of the primary outcome (recurrence interval) and the secondary outcomes (pain level, number of ulcers, and days for ulcer healing), and they were measured at every visit. Adverse reactions were recorded. RESULTS: A total of 54 and 51 patients presented at the first and second return visit, respectively. After 1 month, the increase in the recurrence interval was not shown to differ between the two groups (P = .12). However, the improvement in the recurrence interval was significantly greater in the experimental group (P < .001) at the second return visit. The improvement in the secondary outcomes was identical between two groups at each return visit (P > .05). The incidence of adverse reactions was similar between two groups (P = .50). CONCLUSIONS: Thalidomide had a long-term effect of extending the recurrence interval of continuous RAU.

Long noncoding RNA POU3F3 enhances cancer cell proliferation, migration and invasion in non-small cell lung cancer (adenocarcinoma) by downregulating microRNA-30d-5p.

BACKGROUND: Long noncoding RNA POU class 3 homeobox 3 (POU3F3) is upregulated in esophageal squamous-cell carcinomas. The present study aimed to investigate the role of POU3F3 in non-small cell lung cancer (NSCLC). METHODS: A total of 80 patients with NSCLC (adenocarcinoma) admitted by Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine between May 2016 and May 2018 were enrolled in this study. All patients were diagnosed by histopathological approaches. Expression levels of POU3F3 and microRNA-30d-5p (miR-30d-5p) in cancer and non-tumor tissues from these NSCLC patients were determined by qRT-PCR. Cell transfections were performed to assess interactions between miR-30d-5p and POU3F3. Cell proliferation, Transwell migration and invasion assays were performed to investigate the role of miR-30d-5p and POU3F3 in the regulation of cell proliferation, migration and invasion. RESULTS: POU3F3 was upregulated, while miR-30d-5p was downregulated in cancer tissues than in adjacent healthy tissues of NSCLC patients. Correlation analysis showed that expression levels of POU3F3 and miR-30d-5p were inversely correlated in tumor tissues. Overexpression of miR-30d-5p did not affect the expression of POU3F3, while overexpression of POU3F3 resulted in the suppression of miR-30d-5p in NSCLC cell lines. Overexpression of POU3F3 mediated enhanced proliferation, migration and invasion of NSCLC cells. In addition, overexpression of miR-30d-5p played an opposite role and attenuated the effects of overexpressing POU3F3 on cancer cell proliferation, migration and invasion. CONCLUSIONS: POU3F3 might positively regulate NSCLC cell proliferation, migration and invasion through downregulation of miR-30d-5p.

Predictors for Short-Term Efficacy of Allergen-Specific Sublingual Immunotherapy in Children with Allergic Rhinitis.

BACKGROUND: A good compliance in allergen-specific sublingual immunotherapy (SLIT) often comes from good short-term efficacy. We aimed to evaluate the pretreatment parameters which can predict the short-term clinical efficacy in children that underwent SLIT. METHODS: 517 children with allergic rhinitis (AR) that underwent SLIT were recruited in this study. Baseline clinical characteristics and laboratory parameters were collected, and the clinical efficacy was evaluated using symptom and medication scores. A multivariate logistic regression model and receiver operating characteristic (ROC) curves were established. RESULTS: A total of 303 (65%) in 466 children that underwent SLIT achieved short-term clinical efficacy. The time of using the air conditioner was negatively correlated with clinical efficacy, whereas the serum-specific IgE (s-IgE) levels, the serum IL-10 and IL-35 levels, and the s-IgE/total-IgE ratio were positively correlated with clinical efficacy. CONCLUSION: The time of using the air conditioner, serum-specific IgE (s-IgE) levels, serum IL-10 and IL-35 levels, and s-IgE/total-IgE ratio may be helpful for child selection before SLIT.

Leptin Promoted IL-17 Production from ILC2s in Allergic Rhinitis.

BACKGROUND: Interleukin-17 plays important roles in allergic diseases. Several studies proved that leptin promoted Th17 immune responses by inducing RORγt transcription. ILC2 is an important member of the early stage of immune response. Therefore, we aimed to explore the effect of leptin on the IL-17 production by ILC2 in AR in this study. METHODS: Fifteen AR patients and fifteen healthy controls were enrolled. Serum leptin levels were measured, and their correlation with the frequency of IL-17+ ILC2 cells was analyzed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. ILC2 was stimulated by leptin, and the expression of IL-17, IL-5, and IL-13 was detected by ELISA. The correlated pathways were confirmed by real-time PCR. RESULTS: We found that serum leptin and the frequency of IL-17-producing ILC2s in AR were significantly higher compared with those in controls. After being incubated with leptin, the frequency of IL-17+ ILC2 cells and IL-17 production from ILC2 was upregulated compared with that in controls. We also found that leptin induced RORγt and Ahr expression by ILC2. Moreover, leptin-induced IL-17-producing ILC2 concomitantly expressed IL-5 and IL-13. CONCLUSIONS: Our data provide preliminary evidence that leptin-induced IL-17 production from ILC2 cells is dependent on RORγt and Ahr expression and the blockade of leptin may be a promising target for the treatment of AR.

Leptin Regulated ILC2 Cell through the PI3K/AKT Pathway in Allergic Rhinitis.

BACKGROUND: Recent studies suggest that leptin is involved in Th2 response in allergic rhinitis (AR). However, the effect of leptin on type II innate lymphoid cells (ILC2s) in AR is not well characterized. METHODS: Twenty-six AR patients and 20 healthy controls were enrolled. Serum leptin levels were measured, and their correlation with ILC2 and type II cytokines were analyzed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. ILC2 differentiation and cytokine production stimulated by human recombinant leptin were analyzed by real-time polymerase chain reaction (PCR) and ELISA. AR mouse models were also established to verify the effect of leptin on ILC2 cell regulation. RESULTS: Our results showed that elevated serum leptin in AR patients was correlated with the percentage of ILC2 and the expression of type II cytokines. The recombinant leptin enhanced the expression of ILC2 cell transcription factors and type II cytokine through the PI3K/AKT pathway. The AR mice treated with leptin showed as stronger ILC2 inflammation and symptoms compared with control mice. CONCLUSIONS: Our data provide evidence that upregulation of leptin promotes ILC2 responses in AR and this process was achieved through the PI3K/AKT pathway.

MicroRNA-181a and microRNA-155 are involved in the regulation of the differentiation and function of regulatory T cells in allergic rhinitis children.

BACKGROUND: Regulatory T cells (Tregs) play central roles in limiting airway allergic inflammation and preventing inappropriate Th2 responses to environmental allergens. This study aims to evaluate the role of miR-181a and miR-155 in the regulation of the differentiation and function of Tregs through both in vivo and in vitro studies. METHODS: The CD4+ T cells and Tregs were purified from peripheral blood mononuclear cells (PBMCs) in allergic rhinitis (AR) children, respectively. The miR-155/181a mimics and inhibitors were transfected into CD4+ T cells and Tregs. The differentiation and function of Tregs were evaluated by flow cytometry and enzyme-linked immunosorbent assay. AR mice models were established, and miR-155/181a mimics or inhibitors were injected through tail vein. The Treg percentage and function from mice were compared among different groups. RESULTS: The miR-181a up-regulated the release of interleukin (IL)-10 and TGF-ß, whereas the miR-155 promoted Treg differentiation in CD4+ T cells. Similarly, we also found that miR-155 promoted Treg proliferation directly through suppressor of cytokine signaling 1 (SOCS1) and sirtuin1 (SIRT1) signaling pathway, whereas miR-181a up-regulated mRNA expression of IL-10 and TGF-ß through phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. We also found that miR-155/181a affect Treg percentage and function in mice model. CONCLUSION: Our findings suggest that miR-181a and miR-155 were closely correlated with the proliferation and function of Tregs in AR, providing new potential treatment target.

Decreased Treg-derived miR-181a and miR-155 correlated with reduced number and function of Treg cells in allergic rhinitis children.

BACKGROUND: Regulatory cells (Tregs) have been proved to be deeply involved in allergic airway inflammation. This study aims to evaluate the expression of miRNA in children with AR and their association with Tregs as well as the severity of AR. METHODS: Twenty-five AR children and 20 healthy children were enrolled in this study. The Treg-cell percentage and expression of IL-10 and TGF-ß were detected by flow cytometry and enzyme-linked immunosorbent assay. The microRNA microarray analysis in purified Tregs was performed and differentially expressed microRNAs were confirmed by quantitative polymerase chain reaction (qPCR). RESULTS: Children with AR had lower percentage of Tregs and expression of IL-10 and TGF-beta compared with control children. We found that significantly lower levels of miR-155 and miR-181a in Tregs from AR than healthy controls. Furthermore, intracellular miR-155 and miR-181a level were positively correlated with percentage of Tregs and expression of IL-10 and TGF-beta. Similarly, total nasal severity scores (TNSS) were found to be negatively correlated with miR-155 and miR-181a levels. CONCLUSION: Decreased Treg-derived miR-181a and miR-155 were correlated with reduced number and function of Tregs in AR children. The intracellular miR-155 and miR-181a levels may serve as predictors of disease severity in childhood AR.

Association of leptin with disease severity and inflammation indicators in Chinese obese children with allergic rhinitis.

BACKGROUND: The prevalence of both obesity and allergic diseases in children has increased over the last several decades. However, the direct relationship between diverse allergic diseases and obesity has varied in different studies. Therefore, we aimed to examine the effect of obesity on the incidence and severity of allergic rhinitis (AR) and the possible key inflammation mediators during AR. METHODS: A total of 3126 healthy students (without chronic diseases) were recruited from 14 randomly selected secondary schools in Guangzhou, China. Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHR), and body fat percentage (PBF) were measured and compared. The effect of obesity indicators and leptin level (exposures) on the incidence (primary outcome) and severity of AR (secondary outcomes) was analyzed. Inflammatory markers were detected and compared among groups. RESULTS: The symptom score (9.5 ± 3.1 vs 8.2 ± 3.5, P < .05) and medication score (3.6 ± 1.6 vs 2.9 ± 1.8, P < .05) were significantly higher in obese children with AR than in non-obese children with AR. After adjusting for potential confounders, multiple linear regression analysis showed that the serum leptin concentration was significantly correlated with the levels of T-helper (TH) 2 cytokines (coefficient, 0.48 [95% CI, 0.05-0.91]), TH17 cytokines (coefficient, 0.39 [95% CI, 0.11-0.89]), and regulatory T-cell cytokines (IL-10, coefficient, -0.43 [95% CI, -0.02-0.65]; TGF-ß, coefficient, -0.65 [95% CI, -0.06-1.35]) in patients with AR. CONCLUSIONS: Our study shows that obesity exacerbates inflammation and contributes to disease severity in AR. Our study provides evidence that leptin was involved in enhanced TH inflammation as well as the accumulation and activation of inflammatory cells in obese children with AR.

Leptin/osteopontin axis contributes to enhanced T helper 17 type responses in allergic rhinitis.

BACKGROUND: Recent studies suggest that T helper 17 (Th17) cell subset, a distinct pro-inflammatory CD4 +  T cell lineage, may play an important role in the pathophysiology of allergic rhinitis (AR). However, the regulation of Th17 response in allergic disease is not well characterized. METHODS: Thirty AR and 30 healthy children were enrolled. Serum leptin and OPN levels were measured, and their correlation with IL-17 expression was analyzed using enzyme-linked immunosorbent assay (ELISA). Th17 cell differentiation and cytokine production in peripheral blood mononuclear cell (PBMCs) stimulated by leptin and OPN and related inhibitors were analyzed by ELISA. AR mice models were also established to verify the effect of leptin and OPN on Th17 cell regulation. Immunoprecipitation was performed to explore the interaction between OPN and leptin in Th17 cells. RESULTS: Our results showed that elevated serum leptin and OPN in AR children were correlated with serum IL-17 level (r = .53, P < .01). The recombinant leptin and OPN enhanced Th17 responses from PBMCs synergistically through nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathway and ß3 integrin receptor. The AR mice showed as more severe Th17 responses and symptoms compared with control mice. Immunoprecipitation showed that OPN and leptin may interact with each other directly, and this process may be mediated by ß3 integrin. CONCLUSIONS: Our data provide evidence that upregulation of leptin and OPN promotes Th17 responses in AR, and this process may be achieved through NF-κB, MAPK, and JNK pathway and ß3 integrin.

Role of Leptin/Osteopontin Axis in the Function of Eosinophils in Allergic Rhinitis with Obesity.

BACKGROUND: Allergic rhinitis (AR) is characterized by tissue and blood eosinophilia. Previous studies showed enhanced eosinophilia in allergic rhinitis patients with obesity, suggesting an association between obesity and eosinophilia. However, the interaction and mechanism between obesity and eosinophilia is still unclear. METHODS: We recruited thirty AR children and 30 controls in this study. Expression of leptin and osteopontin (OPN) proteins in serum was detected, and correlation analysis with eosinophilia was performed. The effect of leptin or OPN on eosinophil apoptosis, adhesion, migration, and activation of eosinophil was examined. Ovalbumin-sensitized mice were established to prove the role of obesity on eosinophil regulation by leptin and OPN. RESULTS: We found that upregulated serum and nasal leptin and OPN expression in AR were positively correlated with eosinophilia and eosinophil cationic protein levels. Leptin or OPN inhibited eosinophil apoptosis, demonstrated as inhibited DNA fragmentation and phosphatidylserine (PS) redistribution (P < 0.05). Leptin and OPN promote expression of cluster of differentiation 18 (CD-18) and intercellular adhesion molecule 1 (ICAM-1) and inhibit expression of ICAM-1 and L-selectin by eosinophils, which contribute to the adhesion of eosinophils. Leptin and OPN mediated migration and activation of eosinophil through phosphatidylinositol-3-OH kinase (PI3K) pathway. Obese AR mice presented with more severe eosinophilia and symptoms compared with nonobese AR mice or control mice. Immunochemistry staining of leptin and OPN of nasal turbinate in obese AR mice was also stronger than those in nonobese AR mice or control mice. Anti-OPN, anti-leptin, and anti-α4 treatments reduce nasal eosinophilia inflammation and clinical symptoms in model mice. CONCLUSION: Our results suggested that in an obese state, upregulation of leptin and OPN regulates apoptosis, adhesion, migration, and activation of eosinophils, and this process may be mediated by the PI3K and anti-α4 pathways.