Search

Introduction: This study clarified the expression changes and clinical significance of CD44+CD62L− Treg and CD44−CD62L+ Treg subsets in the peripheral blood of patients with allergic rhinitis (AR). Methods: The peripheral blood of 39 patients with AR and 42 healthy controls was collected. Clinical data, such as sex, age, IgE titer, allergen screening information and visual analogue scale (VAS) score, were recorded. Changes in serum IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ were detected using the cytometric bead array method. Flow cytometry was used to detect the proportions of Th1, Th2, Th17, TFH, and Th9 cells and the proportions of CD44+CD62L− Treg and CD44−CD62L+ Treg subsets. Correlation analysis was performed between the CD44+CD62L− Treg subsets and the CD44−CD62L+ Treg subsets with clinical indicators (VAS score, total IgE titer), cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ), and Th1/Th2/Th17/TFH/Th9 cell proportions. Results: Compared to the control group, the proportion of total Treg cells and CD44+CD62L− Treg cells in the AR group decreased, and the proportion of CD44−CD62L+ Treg cells increased (p < 0.05). The proportions of CD44+CD62L− Treg cells significantly negatively correlated with Th2 cells (R = −0.5270, p < 0.05) and positively correlated with Treg cytokine IL-10 (R = 0.6447, p < 0.05). In addition, CD44+CD62L− Treg cells negatively correlated with the VAS score (R = −0.4956, p < 0.05), total IgE level (R = −0.4177, p < 0.05) and Th2 cytokine IL-6 level (R = −0.3034, p < 0.05) but positively correlated with the Th1 cytokine IL-2 (R = 0.4331, p < 0.05). In contrast, the proportion of CD44+CD62L− Treg cells significantly positively correlated with the Th2 cells (R = 0.6187, p < 0.05). Moreover, the proportion of CD44−CD62L+ Treg cells positively correlated with the VAS score (R = 0.4060, p < 0.05), total IgE level (R = 0.5224, p < 0.05) and Th2 cytokine IL-4 (R = 0.2647, p < 0.05) and IL-6 levels (R = 0.3824, p < 0.05) but negatively correlated with Th1 cytokine IL-2 (R = −0.3451, p < 0.05) and IL-10 (R = −0.3277, p < 0.05). Conclusion: A greater proportion of CD44+CD62L− Tregs correlated with better reversal of the Th1/Th2 imbalance and milder clinical symptoms in AR patients. The presence of more CD44−CD62L+ Tregs correlated with a weaker immunosuppressive effect on Th2 cells and more severe clinical symptoms in AR patients. These findings provide new perspectives for the treatment and disease monitoring of AR. [ABSTRACT FROM AUTHOR]

• Treg cell frequency is positively associated with the effects of AIT. • AIT can reduce the proportions of PU-1+ Treg subtypes in AR patients. • PU-1+ Treg cell numbers can potentially be used as an indicator to monitor the therapeutic effect of AIT on AR. To investigate the role of Tregs and their subtypes in the treatment of allergic rhinitis with allergen immunotherapy (AIT) as well as the underlying mechanism. 1. Thirty-one healthy controls, 29 Allergic rhinitis (AR) patients and 16 AR patients treated with AIT were recruited. The total nasal symptom scores (TNSSs) were calculated. The serum levels of IgE, IL-2, TNF-α, IFN-γ, IL-4, IL-5, IL-6, IL-10 and IL-17 were measured. 2. Changes in the proportions of CD4+ T cells, Treg cells, Treg subtypes and Th1/Th2/Th9/Th17/Tfh cells in the peripheral blood of the subjects in the three groups were measured. 3. The correlations of Treg cells, Treg subtypes and TNSS with the levels of various cytokines in the AR group and AIT group were analysed. 1. Compared with the control group, the TNSS and IgE, IL-5 and IL-6 levels in the AR group were significantly increased, while the IL-2, IFN-γ and IL-10 levels were significantly decreased (P < 0.05). Compared with the AR group, the TNSS and IgE, IL-5 and IL-6 levels in the AIT group were significantly decreased, while the IL-2, IFN-γ and IL-10 levels were significantly increased (P < 0.05). 2. Compared with the control group, the proportions of Tregs, GATA3+ Tregs and Th1 cells in the AR group were significantly reduced, while the proportions of PU-1+ Tregs, T-bet+ Tregs and Th2 cells were significantly increased (P < 0.05). Compared with the AR group, the proportions of Tregs and Th1 cells in the AIT group were significantly increased, while the proportions of PU-1+ Tregs and Th2 cells were decreased (P < 0.05). 3. Correlation analysis showed that Treg cell proportions were negatively correlated with the TNSS, sIgE levels, IL-5 levels and IL-6 levels but positively correlated with the IL-2 and IL-10 levels (P < 0.05). PU-1+ Treg cell proportions were positively correlated with the TNSS, sIgE levels, IL-5 levels and IL-6 levels but negatively correlated with the Treg cell proportions, IL-2 levels and IL-10 levels (P < 0.05). AIT can reduce the proportions of PU-1+ Treg subtypes in AR patients. PU-1+ Treg cell numbers can potentially be used as an indicator to monitor the therapeutic effect of AIT on AR. [ABSTRACT FROM AUTHOR]

• The nasal mucosa of mice in the AR group showed significantly increased LC3II expression, and co-expressed with DCs markers. • The degree of autophagy in DCs increased with the increase of allergen concentration in a dose-dependent manner. • Allergen-induced DCs autophagy aggravated AR by increasing antigen-presenting function and promoting the immune imbalance. The level of autophagy in CD11c+ dendritic cell (DC) and its contribution to the subsequent immune imbalance are still unclear. The aim of this study was to investigate the role and mechanism of them in promoting the allergic inflammatory response. Nasal mucosa tissues were collected from allergic rhinitis (AR) mice and their control group to detect the expression of LC3II, P62 and ATG5 and CD11c+DC autophagy. Different concentration of OVA or the combination of OVA and autophagy inhibitor (3-MA) were used to induce the differentiation of mouse bone marrow-derived DCs (CD11c+BMDCs). Differences in LC3II, P62 and ATG5 expression and autophagosome formation were detected. BMDCs in the above groups were cocultured with spleen lymphocytes to detect the proportions of effector T cells and changes in cytokines. OVA-loaded BMDCs were injected intravenously into C57BL/6 mice to develop allergic model. The nasal mucosa of mice in the AR group showed significantly increased LC3II and ATG5 protein expression, whereas showed significantly decreased P62 protein expression. Moreover, LC3II was mainly co-expressed with CD11c+ DC markers. In vitro, OVA stimulation induced the increase of autophagosomes and the expression of autophagy-related proteins in BMDCs in a dose-dependent manner, and inhibition of autophagy showed significantly decreased LC3II and ATG5 expression and autophagosome abundance. In addition, OVA-induced BMDC autophagy can affect CD4+T cell differentiation and related cytokine levels, however, the Th1/Th2/Th9/Th17/Treg/Tfh cell immune imbalances were significantly reversed after the addition of 3-MA. Adoptive transfer of OVA-loaded BMDCs could promote the allergic inflammation, while the administration of 3-MA on OVA-loaded BMDCs could significantly reduce the AR inflammation. Overall, our findings demonstrate that allergen can induce CD11c+DC autophagy in a dose-dependent manner and promote the immune imbalance of downstream T cells towards a proinflammatory phenotype. [ABSTRACT FROM AUTHOR]

[Display omitted] • GATA3+ Treg cell numbers were significantly decreased in subjects with AR. • Notch2 promoted the immunosuppressive function of GATA3+ Treg cells. • The adoptive transfer of Treg cells overexpressing Notch2 alleviated AR. • The number of GATA3+ Treg cells was decreased in Notch2ΔTreg mice. • After AR modeling, the GATA3+ Treg cells in Notch2ΔTreg mice was further reduced. The aim of this study was to investigate the role and mechanism of Notch2-dependent GATA3+ Treg cells in allergic rhinitis (AR). Samples were collected from patients in the control and AR groups to detect differences in the numbers of GATA3+ Treg cells and their intracellular Notch2 levels. The effects of Notch2 on GATA3+ Treg cell differentiation and function in vitro were detected. AR mice were subjected to adoptive transfer of GATA3+ Treg cells to detect changes in the allergic inflammatory response and Th2 cells. Mice with Treg cell-specific knockout of Notch2 were constructed, and an AR model was established to detect the changes. The number of GATA3+ Treg cells and intracellular Notch2 expression in peripheral blood of the AR group were decreased compared with the controls (P < 0.05), and the number of GATA3+ Treg cells was significantly negatively correlated with the level of allergen-specific IgE (sIgE; P < 0.01). In vitro experiments showed that Notch2 promoted the differentiation and immunosuppressive function of GATA3+ Treg cells, and Notch2 directly promoted GATA3 transcription in Treg cells (P < 0.05). Animal experiments indicated that adoptive transfer of GATA3+ Treg cells reduced the allergic inflammatory response in AR mice (P < 0.05). The number of GATA3+ Treg cells was decreased in gene knockout mice (P < 0.05), and autoimmune inflammation was observed. After modeling, the allergic inflammatory response was further aggravated (P < 0.05). Overall, our findings indicate that Notch2 alleviates AR by specifically increasing GATA3+ Treg cell differentiation. Notch2 expressed in Treg cells is expected to be a new therapeutic target for AR. [ABSTRACT FROM AUTHOR]

Tangeretin demonstrates broad anti-inflammatory effects. The present study aimed to assess whether tangeretin functions in regulating T-regulatory cells (Tregs) and alleviating allergic rhinitis (AR). An ovalbumin (OVA)-induced AR animal model was constructed to monitor the changes in the allergic symptom score, OVA-specific IgE titers, histopathological characteristics and T-helper cell (Th1, Th2, and Th17)-related cytokine levels under tangeretin or dexamethasone (DXM) administration. The expression levels of Notch1/Jagged1 and FOXP3, and the proportion of Tregs in the spleens of these animals, were also detected. Furthermore, purified naive CD4 + T cells were utilized to assess the effects of tangeretin on Notch1 expression and their differentiation in vitro. Both tangeretin and DXM administration alleviated airway inflammation, decreased the production of serum OVA-induced IgE, but only tangeretin administration restored the balance of cytokine profiles compared with those in the AR group. The abundance of splenic CD4 + CD25 + FOXP3 + Treg cells and the transcription factor FOXP3 were significantly increased under tangeretin treatment, either in AR mice or in naïve CD4 + T-cell differentiation, followed by a concomitant reduction in Notch1/Jagged1 expression. However, as a positive control, the treatment of allergic rhinitis with dexamethasone was not related to the expression of Notch1/Jagged1 or the differentiation of Treg cells. Tangeretin could promote regulatory T cell responses by inhibiting Notch1/Jagged1 expression, followed by promoting FOXP3/Treg cell differentiation and thus could serve as a novel curative therapeutic for AR. Unlabelled Image • Tangeretin showed high efficiency in suppressing OVA-induced allergic inflammation. • Tangeretin can promote regulatory T cell differentiation either in vivo or in vitro. • Tangeretin could inhibit Notch1 expression rather than Notch2. [ABSTRACT FROM AUTHOR]

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. 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. 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). Notch2 promotes the differentiation of Treg cells by upregulating FOXP3 expression, thus significantly inhibiting the inflammatory response of AR. [ABSTRACT FROM AUTHOR]