Baseline Severity and Disease Duration Can Predict the Response to Allergen-specific Immunotherapy in Allergic Rhinitis.

Allergen-specific immunotherapy (AIT) has confirmed its efficacy in improving the symptoms of allergic rhinitis. However, no reliable biomarkers have been identified to predict the efficacy of AIT were found. We aimed to find clinical and immunological markers to predict efficacy in children after 2 years of sublingual immunotherapy (SLIT). A total of 285 children diagnosed with allergic rhinitis were recruited. The clinical efficacy was evaluated by comparing endpoint and baseline symptom and medication scores (SMS). Baseline clinical and immunological markers (serum total and specific immunoglobulin [Ig]E) and their correlation with clinical efficacy were analyzed. Of the 285 children recruited, 249 completed the 2-year SLIT program. After 2 years of SLIT, 68.3% of the children showed a significant response. Children in the Remarkable Response Group had the highest baseline SMS and most extended disease duration, followed by the Effective Relief and Unresponsive Group. Correlation analysis demonstrated that SMS improvement was positively correlated with baseline SMS (r=0.67) and disease duration (r=0.35). SMS improvement was not correlated with age, body mass index, total or specific IgE levels, or their ratios. Our results show that baseline SMS and disease duration can predict the efficacy of SLIT. Our study can guide the selection of suitable candidates for SLIT.

Overexpression of KCNJ2 enhances maturation of human-induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Although human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising cell resource for cardiovascular research, these cells exhibit an immature phenotype that hampers their potential applications. The inwardly rectifying potassium channel Kir2.1, encoded by the KCNJ2 gene, has been thought as an important target for promoting electrical maturation of iPSC-CMs. However, a comprehensive characterization of morphological and functional changes in iPSC-CMs overexpressing KCNJ2 (KCNJ2 OE) is still lacking. METHODS: iPSC-CMs were generated using a 2D in vitro monolayer differentiation protocol. Human KCNJ2 construct with green fluorescent protein (GFP) tag was created and overexpressed in iPSC-CMs via lentiviral transduction. The mixture of iPSC-CMs and mesenchymal cells was cocultured with decellularized natural heart matrix for generation of 3D human engineered heart tissues (EHTs). RESULTS: We showed that mRNA expression level of KCNJ2 in iPSC-CMs was dramatically lower than that in human left ventricular tissues. KCNJ2 OE iPSC-CMs yielded significantly increased protein expression of Kir2.1 and current density of Kir2.1-encoded IK1. The larger IK1 linked to a quiescent phenotype that required pacing to elicit action potentials in KCNJ2 OE iPSC-CMs, which can be reversed by IK1 blocker BaCl2. KCNJ2 OE also led to significantly hyperpolarized maximal diastolic potential (MDP), shortened action potential duration (APD) and increased maximal upstroke velocity. The enhanced electrophysiological maturation in KCNJ2 OE iPSC-CMs was accompanied by improvements in Ca2+ signaling, mitochondrial energy metabolism and transcriptomic profile. Notably, KCNJ2 OE iPSC-CMs exhibited enlarged cell size and more elongated and stretched shape, indicating a morphological phenotype toward structural maturation. Drug testing using hERG blocker E-4031 revealed that a more stable MDP in KCNJ2 OE iPSC-CMs allowed for obtaining significant drug response of APD prolongation in a concentration-dependent manner. Moreover, KCNJ2 OE iPSC-CMs formed more mature human EHTs with better tissue structure and cell junction. CONCLUSIONS: Overexpression of KCNJ2 can robustly enhance maturation of iPSC-CMs in electrophysiology, Ca2+ signaling, metabolism, transcriptomic profile, cardiomyocyte structure and tissue engineering, thus providing more accurate cellular model for elucidating cellular and molecular mechanisms of cardiovascular diseases, screening drug-induced cardiotoxicity, and developing personalized and precision cardiovascular medicine.

Mild pretreatment with Brønsted acidic deep eutectic solvents for fractionating ß-O-4 linkage-rich lignin with high sunscreen performance and evaluation of enzymatic saccharification synergism.

Herein, a mild fractionation method by employing polyol-based Brønsted acidic DESs (BDESs) was proposed to extract lignin with well-preserved ß-O-4 substructures and to enhance fermentable sugar yields simultaneously. For ethylene glycol-oxalic acid (EG-OA), more than 53 % of lignin was obtained and superb carbohydrate digestibility (i.e., glucose and xylose yields were reached to 94.6 % and 87.7 %, respectively) was achieved after pretreatment. Remarkably, detailed structural studies revealed that the polyol was incorporated into lignin, which stabilized reactive carbocation intermediates formed during BDESs treatment and prevented undesired recondensation reactions. This lignin protection mechanism was shown to play a key role in enzymatic hydrolysis enhancement and lignin valorization. The resultant ß-O-4 linkage-rich lignin fractions were attractive for natural sunscreen applications due to their lighter color and excellent UV-blocking performance. Overall, this work proposed a sustainable and economically practical lignin-first biorefinery approach that is beneficial for achieving comprehensive valorization of lignocellulose.

Screening strategy and time points for newborn hearing re-screening with high risk factors.

Objective: To compare and analyze the pass rate and screening strategy of hearing rescreening for newborns with high risk factors. Methods: Retrospective chart review of high-risk newborns who failed their initial newborn hearing screen and subsequently underwent secondary hearing tests from June 2011 to June 2018 in Guangzhou Women and Children's Medical Center were performed. Results: Eight hundred and sixty-eight newborns with high risk factors were included in the study. The 57-70 days (83.5%) and 71-84 days (83.4%) group had the highest pass rate compared with 42-56 days (75.8%) and < 42 days (68.3%) group. As for different screening strategies, the pass rate of OAE(otoacoustic emissions), AABR (auto auditory brainstem response) and OAE + AABR was the highest in 57-70 days group and 71-84 days group, respectively. The OAE + AABR had the lowest pass rate compared to the other two modalities. When the pass rate was compared as different risk factors, the 57-70 days and 71-84 days group also had the highest pass rate compared with 42-56 days and < 42 days group and the pass rate had no significant differences among various risk factors group. Conclusion: Our results showed that all the pass rate of OAE, AABR and OAE + AABR was the highest in 57-70 days group and 71-84 days group with significant difference, suggesting that the delayed screening time (>57 days) may increase the re-screening pass rate and reduce anxiety of parents, which is of great significance for clinical work.

Distinct roles for two Caenorhabditis elegans acid-sensing ion channels in an ultradian clock.

Biological clocks are fundamental to an organism's health, controlling periodicity of behaviour and metabolism. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematode Caenorhabditis elegans. An ACD-5-containing channel, on the apical membrane of the intestinal epithelium, is essential for maintenance of luminal acidity, and thus the rhythmic oscillations in lumen pH. In contrast, the second channel, composed of FLR-1, ACD-3 and/or DEL-5, located on the basolateral membrane, controls the intracellular Ca2+ wave and forms a core component of the master oscillator that controls the timing and rhythmicity of the DMP. flr-1 and acd-3/del-5 mutants show severe developmental and metabolic defects. We thus directly link the proton-sensing properties of these channels to their physiological roles in pH regulation and Ca2+ signalling, the generation of an ultradian oscillator, and its metabolic consequences.

Biological clocks regulate a myriad of processes that occur periodically, from sleeping and waking to how cells use nutrients and energy. One such clock is the one that controls intestinal movements and defecation in the nematode worm Caenorhabditis elegans, which consists of three muscle contractions occurring every 50 seconds. This rhythm is controlled by calcium and proton signalling in the cells of the intestine. The cells of the nematode intestine form a tube, through which gut contents pass. The inside of the tube is acidic, but acidity also plays a role on the outer face of the intestinal tube. In this area, nutrients are distributed and signals are conveyed to other tissues, such as muscles. In fact, acid ­ in the form of protons ­ secreted from the intestinal cells stimulates the muscles that contract in the biological clock that controls the worms' defecation. However, it is poorly understood how the worms control the release of these protons. Kaulich et al. identified two ion channels on the membranes of intestinal cells that become inhibited when the levels of acid surrounding them are high. These channels play distinct roles in controlling the contractions that move the contents of the roundworms' intestines along. The first channel contains a protein called ACD-5, and it is in the membrane of the intestinal cells that faces the inside of the intestinal tube. The second channel is formed by three proteins: FLR-1, ACD-3 and DEL-5. This channel is found on the other side of the intestinal cells, the region where nutrients are distributed and signals are conveyed to the rest of the body. To determine the role of each channel, Kaulich et al. genetically engineered the worms so they would not make the proteins that make up the channels, and imaged the live nematodes to see the effects of removing each channel. The inside of the intestines of worms lacking the ACD-5 containing channel was less acidic than that of normal worms, and the timing of the contractions that control defecation was also slightly altered. Removing the second channel (the one formed by three different proteins), however, had more dramatic effects: the worms were thin, developed more slowly, had less fat tissue and defecated very irregularly. Kaulich et al. imaged live worms to show that the second channel plays a major role in regulating oscillations in acidity both inside and outside cells, as well as controlling calcium levels. This demonstrates that this channel is responsible for the rhythmicity in the contractions that control defecation in the nematodes. Their findings provide important insights towards better understanding proton signalling and the role of acid-sensing ion channels in cellular contexts and biological clocks.

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.

High density lipoprotein inhibited group II innate lymphoid cells proliferation and function in allergic rhinitis.

BACKGROUND: More and more studies had suggested that dyslipidemia was closely related to allergic diseases. High density lipoprotein (HDL) often plays anti-inflammatory and anti-oxidative roles by suppressing immune cell chemotaxis and activation. We aimed to explore the role of HDL in the regulation of group II innate lymphoid cells (ILC2) in allergic rhinitis (AR). METHODS: The blood lipid levels and their correlation with symptom scores of 20 AR subjects and 20 controls were analyzed. Purified ILC2 were stimulated by HDL and cytokines production were examined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The mRNA levels of GATA binding protein 3(GATA3) and retinoid-related orphan receptor α (RORα) expressed by ILC2 were detected using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: HDL level was significantly lower in AR than controls and correlated with the symptom scores. The serum HDL levels were negatively related to the increased number of ILC2, IL-5+ ILC2, and IL-13+ ILC2 in AR patients. HDL decreased the number of ILC2 and type II cytokines levels significantly by inhibiting expression of GATA3 and RORα. CONCLUSIONS: Our data provide preliminary evidence that HDL may play a negative role in ILC2 inflammation in AR, suggesting that HDL may serve as promising treatment target in AR.

Association between the genetic variants of base excision repair pathway genes and allergic rhinitis susceptibility in Chinese children.

Background: Allergic rhinitis (AR) is a frequent inflammatory disorder of the upper respiratory tract, which has complex patterns of inheritance. Accumulating evidence has shown the key roles of DNA damage in inflammatory diseases, and the base excision repair (BER) is the primary pathway responsible for DNA repair during inflammation. Methods: Here, we performed a case-control study to investigate the associations between 20 potentially functional single nucleotide polymorphisms (SNPs) in 6 BER pathway genes (PARP1, hOGG1, FEN1, APEX1, LIG3, and XRCC1) and AR susceptibility in 508 AR cases and 526 controls which originated in China. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for evaluating the association strength. Results: We found that hOGG1 rs1052133 G > C and XRCC1 rs2682585 G > A polymorphisms were associated with decreased AR risk (adjusted OR = 0.67, 95% CI = 0.47-0.94, P = 0.022; and adjusted OR = 0.21, 95% CI = 0.06-0.79, P = 0.022, respectively). Stratification analysis suggested that: hOGG1 rs1052133 GC/CC genotype reduced AR risk in subjects among following subgroups: age ≤60 months, females, and moderate AR; XRCC1 rs2682585 GG genotype decreased AR risk in subjects age >60 months, and LIG3 rs1052536 TT genotype increased AR risk in subjects of severe AR. Conclusion: Our findings indicated that the genetic variants of hOGG1, XRCC1, and LIG3 genes might affect AR susceptibility in the Chinese population, which will provide novel insight into the genetic underpinnings of AR from the DNA damage level.

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.

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.

Immunopathologic characteristics of Chinese pediatric patients with chronic rhinosinusitis.

BACKGROUND: The histopathology of pediatric chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is rarely reported due to low prevalence or the unavailability of tissue samples. Hence, we aimed to characterize and compare the histologic features and protein expression of Th1/Th2/Th17-related cytokines in pediatric CRSsNP and CRSwNP. METHODS: The histologic characteristics of 15 children with CRSsNP, 52 children with CRSwNP, and 12 control participants were analyzed using hematoxylin and eosin staining. The expression of Th1/Th2/Th17-related cytokines were examined using immunohistochemistry and the enzyme-linked immunosorbent assay. RESULTS: Pediatric subjects with CRSwNP had more intact epithelium and less submucosal mucous glands compared to those with CRSsNP. Tissue eosinophils were more prevalent in the younger CRSwNP group compared to the older CRSwNP or the CRSsNP groups. The protein concentrations of Th2 cytokines were significantly higher in the CRSwNP group than the CRSsNP group or the control group. Moreover, the protein concentrations of Th17 cytokines were significantly higher in the younger CRSwNP group than the older CRSwNP group or the CRSsNP and control groups. The protein concentrations of Th1 and Th17 cytokines were also significantly higher in the CRSsNP group than the control group. Compared with non-eosinophilic CRSwNP, eosinophilic CRSwNP presented with elevated protein concentrations of Th1 and Th17 cytokines. CONCLUSION: For the first time, we showed that pediatric CRSwNP presents as eosinophilic with Th2/Th17 inflammation, whereas CRSsNP presents as Th1/Th17 inflammation. Our study may provide a theoretical basis for the precise treatment of pediatric CRS in the future.

Modulating serine palmitoyltransferase-deoxysphingolipid axis in cancer therapy.

A schematic illustration is given regarding serine restriction on tumor growth. Once the cellular abundance of serine decreased or alanine accumulated, the serine palmitoyltransferase (SPT) alternatively conjugates alanine and palmitoyl-CoA to form 3-keto-intermediates, which is rapidly converted to 1-deoxysphinganine and further metabolized to 1-deoxydihydroceramide (1-DeoxyDHCER) and 1-deoxyceramide (1-DeoxyDHCER), so that to exert cytotoxicity for tumor suppression.

Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization.

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4'-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

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.

Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors.

Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants.

The Caenorhabditis elegans tmc-1 is involved in egg-laying inhibition in response to harsh touch.

The conserved family of Transmembrane channel-like (TMC) proteins has attracted significant interest since two members appear to be key components of the mammalian hair cell mechanotransducer involved in hearing. C. elegans expresses two TMC proteins, TMC-1 and TMC-2. TMC-1 is widely expressed in in both muscles and the nervous system. This wide expression pattern suggests that TMC-1 might serve different functions in the various neurons. TMC-1 has previously been shown to function in neurons, playing a role in chemosensation in the ASH neurons and mechanosensation in OLQ neurons, further supporting this hypothesis. tmc-1 is expressed in the high-threshold mechanosensory neuron, ALA. We show that tmc-1 mutants show defects in the ALA-dependent inhibition of egg-laying in response to a harsh mechanical stimulus.

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.

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.

The Inhibition of Group II Innate Lymphoid Cell Response by IL-27 in Allergic Rhinitis.

OBJECTIVES: Interleukin-27 (IL-27) has been reported to inhibit type 2 T helper cell (Th2) response in allergic rhinitis (AR). However, its effects on group II innate lymphoid cells (ILC2) in AR are not fully understood. METHODS: Nineteen patients with AR and nineteen controls were enrolled in this study. The effects of IL-27 on ILC2 differentiation and function as well as the regulation of the IL-27 receptor (IL-27R) were analyzed by tritiated thymidine incorporation, enzyme-linked immunosorbent assay (ELISA), and real-time polymerase chain reaction (PCR), respectively. AR mice were used to confirm the role of IL-27 in vivo. RESULTS: The serum IL-27 protein expression in AR patients was significantly lower compared with controls. IL-27 decreased the ILC2 proliferation and type II cytokine secretion through the interaction with IL-27R. IL-27 also inhibited systemic and nasal ILC2 response of AR mice. CONCLUSION: IL-27 inhibited the proliferation and function of ILC2 in AR, implying that IL-27 may be used as new treatment target in AR.

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.