Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.

Asthma is a widespread airway disorder where GATA3-dependent Type-2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma-associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926-970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma-associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP-qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral T cell subsets. We next generated mice lacking the mG900 region (mG900KO mice) were generated by the CRISPR-Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady-state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady-state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM-induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high-throughput sequencing (4C-seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation.

暂无摘要。

Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/- mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.

Objective:To investigate the mechanism of adipose derived stem cell exosomes（ADSC-exos） regulating Th2/Treg balance in peripheral blood of patients with allergic rhinitis（AR）. Methods:Thirty patients with AR who were treated in Department of Otolaryngology Head and Neck Surgery, the First Affiliated Hospital of Zhengzhou University from March 2022 to October 2022 were selected, and 30 patients with simple deviation of nasal septum who were treated in our department during the same period were selected as the control group. 10 mL peripheral venous blood was collected from all patients. The levels of IL-4 and TGF-β in plasma were analyzed by ELISA. PBMCs were isolated by density gradient centrifugation. Then, protein and RNA were further extracted, and the expression levels of IL-4, TGF-β, GATA3 and Foxp3 genes were detected by qRT-PCR. Western Blotting detected p-PI3K（P85）, p-AKT（Ser473） in PBMCs of AR patients and healthy controls. Protein expression levels of p-mTOR（Ser2448）, p-p70S6K（Thr389）, and the proportion of Th2 and Treg cells were analyzed by flow cytometry. PBMCs of AR patients were stimulated to differentiate and co-cultured with exosomes of adipose stem cells. p-PI3K（P85）, p-AKT（Ser473）, p-mTOR（Ser2448） were detected in exosome treated group and untreated group by Western Blotting. The expression level of p-p70S6K（Thr389） protein, the proportion of Th2 and Treg cells were analyzed by flow cytometry, and the levels of IL-4 and TGF-β in the supernatant of cell culture were detected by ELISA. Results:Compared with the control group, the mTOR pathway in peripheral blood of AR group was significantly activated, the level of IL-4 in plasma was increased, and the level of TGF-β was decreased（P<0.05）. Compared with the control group, the proportion of Th2 cells in peripheral blood was increased, and the proportion of Treg cells was decreased（P<0.01）. Compared with the untreated group, the expression level of mTOR pathway protein decreased, the level of IL-4 decreased, and the level of TGF-β increased. The proportion of Th2 cells decreased, and the proportion of Treg cells increased（P<0.01）. Conclusion:There is an imbalance of Th2 and Treg cells in peripheral blood mononuclear cells of AR patients; the PI3K/AKT/mTOR/p70S6K pathway is activated in peripheral blood mononuclear cells of AR patients Exosomes derived from adipose mesenchymal stem cells may regulate Th2/Treg balance in AR patients through the PI3K/AKT/mTOR/p70S6K pathway.
目的：探讨脂肪间充质干细胞来源外泌体（adipose-derived stem cell exosomes，ADSC-exos）调节变应性鼻炎（allergic rhinitis，AR）患者外周血Th2/Treg平衡的机制。 方法：选取2022年3月-2022年10月于郑州大学第一附属医院耳鼻咽喉头颈外科就诊的AR患者30例，再选择30例同期就诊的单纯鼻中隔偏曲患者作为对照组。期间收集所有患者的外周静脉血10 mL，采用ELISA检测法分析血浆中IL-4、TGF-β细胞因子水平，密度梯度离心法提取外周血单个核细胞（peripheral blood mononuclear cells，PBMCs）后进一步提取蛋白及RNA，行qRT-PCR检测IL-4、TGF-β、GATA3、Foxp3基因的表达水平，Western Blotting检测AR患者与对照者PBMCs中p-PI3K（P85）、p-AKT（Ser473）、p-mTOR（Ser2448）、p-p70S6K（Thr389）的蛋白表达水平，流式细胞术分析Th2和Treg细胞的比例。刺激分化AR患者的PBMCs，并与ADSC-exos共培养。Western Blotting检测外泌体处理组与未处理组p-PI3K（P85）、p-AKT（Ser473）、p-mTOR（Ser2448）及p-p70S6K（Thr389）蛋白的表达水平，流式细胞术分析Th2和Treg细胞的比例，ELISA检测细胞培养上清中IL-4、TGF-β的水平。 结果：AR组患者外周血中mTOR通路较对照组显著激活，血浆中IL-4水平较对照组升高，TGF-β水平较对照组降低，差异均有统计学意义（P<0.05）。AR组患者外周血Th2细胞比例较对照组升高，Treg细胞比例下降，差异有统计学意义（P<0.01）。外泌体处理组与未处理组比较，mTOR通路蛋白表达水平下降，IL-4水平下降，TGF-β水平升高；Th2细胞比例下降，Treg细胞比例升高（P<0.01）。 结论：AR患者外周血单个核细胞中存在Th2、Treg细胞的失衡，其外周血单个核细胞中PI3K/AKT/mTOR/p70S6K通路被激活，ADSC-exos可能通过PI3K/AKT/mTOR/p70S6K通路调节AR患者Th2/Treg的平衡。.

暂无摘要。

In a Japanese chemical factory, lung diseases such as pneumoconiosis have been reported among workers handling cross-linked water-soluble acrylic acid polymers (CWAAP). Our previous study reported that a single intratracheal administration of CWAAP induces acute inflammation and fibrosis. In this study, we investigated the effects of multiple intratracheal administrations of CWAAP on inflammatory responses and pulmonary fibrosis along with inducible bronchus-associated lymphoid tissues (iBALT) formation, which is involved in allergic inflammation. Male F344 rats (190-200 g) received single or multiple intratracheal administrations of phosphate-buffered saline (PBS) or CWAAP. To assess inflammatory responses and pulmonary fibrosis, immunohistochemical and histological staining was performed. CD68, CD163, CD169, TGF-β, and collagen I positive cells/areas in the lungs of the CWAAP-group rats were significantly increased than those in the PBS group. Furthermore, the number of iBALT structures, CD4 + T cells, along with CD19, PAX5, IL-4, GATA-3, T-bet, and IgE-positive cells in the terminal bronchioles and blood vessels of the lungs were significantly increased in the CWAAP group. Moreover, pulmonary fibrosis, iBALT formation, and levels of specific IgG were significantly increased in rats who received multiple intratracheal administrations of CWAAP compared to those with single intratracheal administration. Multiple intratracheal administrations of CWAAP potentiated the classical fibrotic pathway (M2 macrophage-TGF-β-collagen I) more potently than single intratracheal administration. Furthermore, it was possible that iBALT was formed around terminal bronchioles and blood vessels and the number of immune cells was increased, resulting in enhanced allergic inflammation and pulmonary fibrosis.

OBJECTIVE: To elucidate the effect of Jiaweidaochi powder on the Th1/Th2 ratio in rats with recurrent aphthous ulcers (RAU).
METHODS: 40 Sprague-Dawley rats were included in this study, randomly divided into a control group, a model group, and three treatment groups (0.5 g/ ml, 1 g/ml, 2 g/ml Jiaweidaochi powder). The RAU model of rats was established by autoantigen injection. The effects of Jiaweidaochi powder on the expression of INFG, IL-4, TBX21, and GATA3 mRNA were detected by real-time PCR. The expression of IFN-γ, IL-4, and IFN-γ/IL-4 proteins in oral ulcer tissue and serum of rats were analyzed by Western blot and ELISA, respectively. The proportion of Th1 cells and Th2 cells in RAU rats was analyzed by flow cytometry.
RESULTS: Jiaweidaochi powder reduced the number, diameter, and duration of oral ulcers in RAU rats. Real-time PCR showed that middle and high-dose Jiaweidaochi powder decreased the expression of INFG TBX21 mRNA and increased the expression of IL-4 and GATA3 mRNA in the oral tissue of RAU rats. ELISA and western blot confirmed that the expression of IFN-γ protein was significantly decreased, and the level of IL-4 protein was increased both in oral tissue and serum of RAU rats treated with middle or high doses of Jiaweidaochi powder. Flow cytometry found that the Jiaweidaochi powder decreased the proportion of Th1 cells and increased the proportion of Th2 cells in RAU rats.
CONCLUSIONS: This study found that Jiaweidaochi powder promoted the balance of Th1/Th2 in RAU rats, contributing to the healing of RAU.

The PRR11 gene (Proline Rich 11) has been implicated in lung cancer; however, relationship between PRR11 and immune infiltration is not clearly understood. In this study, we used The Cancer Genome Atlas (TCGA) data to analyze the lung adenocarcinoma patients; PRR11 gene expression, clinicopathological findings, enrichment, and immune infiltration were also studied. PRR11 immune response expression assays in lung adenocarcinoma (LUAD) were performed using TIMER, and statistical analysis and visualization were conducted using R software. All data were verified using Gene Expression Profiling Interactive Analysis (GEPIA), and the Human Protein Atlas (HPA). We found that PRR11 was an important prognostic factor in patients with LUAD. PRR11 expression was correlated with tumor stage and progression. Gene Set Enrichment Analysis (GSEA) showed that PRR11 was enriched in the cell cycle regulatory pathways. Immune infiltration analysis revealed that the number of T helper 2 (Th2) cells increased when PRR11 was overexpressed. These results confirm the role of PRR11 as a prognostic marker of lung adenocarcinoma by controlling the cell cycle and influencing the immune system to facilitate lung cancer progression.

Asthma is a common chronic respiratory disease in which epithelial cytokines and airway inflammation play critical pathophysiological roles. Thymic stromal lymphopoietin (TSLP), an epithelial cytokine, is central in the initiation and persistence of airway inflammation in asthma. Tezepelumab is a human immunoglobulin G2λ (IgG2λ) monoclonal antibody developed for treating moderate-to-severe asthma by specifically binding to TSLP and preventing its binding to the TSLP receptor on inflammatory cells. In this narrative review, we describe the results of clinical trials that evaluated the pharmacokinetics, pharmacodynamics, efficacy and safety of tezepelumab in patients with moderate-to-severe asthma. We also introduce the ongoing clinical trials in patients with asthma as well as future trials investigating the use of tezepelumab for other indications.
Asthma is a long-term disease that causes inflammation in the cells of the lung. One of the cytokines (proteins) involved in asthma is called thymic stromal lymphopoietin (TSLP). This cytokine is produced by the airway epithelium, a layer of cells covering the respiratory tract in the lungs, where it activates inflammatory cells. Tezepelumab is a new drug that blocks the activity of TSLP in the lungs and helps reduce asthma symptoms, such as coughing and breathlessness. In this article, we describe the clinical trials that investigated how well tezepelumab works, as well as its safety, in people with moderate or severe asthma. We also describe the trials of tezepelumab that are now underway in people with asthma, allergies or other inflammatory diseases.