Changes and clinical significance of CD4~+CD25~+Foxp3~+ regulatory T cell and IL-10 , TGF-β_1 in steroidresistant asthma patients of peripheral blood
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Objective To investigate the changes of CD4+ CD25+ Foxp3+ regulatory T cell and IL-10,TGF-β1 in steroid-resistant asthma patients of peripheral blood,to study their significance.Methods The CD4+ CD25+ Foxp3+ regulatory T cell in 40 cases steroid-resistant asthma patients were detected by flow cytometry.The levels of serum IL-10 and TGF-β1 were detected by ELISA.The control groups were 30 individuals having general physical examination and 46 patients with steroid-sensitive patients.Results The proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell and the levels of serum IL-10,TGF-β1 in steroid-resistant asthma group of Peripheral Blood were decreased significantly than steroid-sensitive group and healthy control group (P ＜0.01,P ＜0.05).The proportion and number of CD4+CD25+ Foxp3+ regulatory T cell and the levelsof serum TGF--β1 in steroid-sensitive group were decreased significantly than healthy control group,but the levels of serum IL-10 were no statistical difference between them.The proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell were positively correlated with the serum IL-10,TGF-β1 (P ＜0.01).Conclusions Lower proportion and number of CD4+ CD25+ Foxp3+ regulatory T cell and lower IL-10,TGF-β1 were observed in steroid-resistant asthma patients,which might play an important role in occurrence and development of steroid-resistant asthma.
Key words:
Steroid-resistant asthma; Regulatory T cell; Transforming growth factor-β1; Interleukin-10Keywords:
Regulatory T cell
The current study aimed to investigate the changes and regulatory mechanism of cluster of differentiation (CD)4+CD25high forkhead box protein 3 (Foxp3+) regulatory T cells (Tregs) in childhood B-cell acute lymphocytic leukemia (B-ALL). A total of 18 children with B-ALL and 15 age-matched healthy children were included. Reverse-transcription quantitative polymerase chain reaction was used to evaluate the mRNA levels of Foxp3, cytotoxic T-lymphocyte associated protein 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3), interleukin (IL)-2 receptor (R)β/γ, IL-6Rα/β, mothers against decapentaplegic homolog (Smad)3/4 and runt-related transcription factor (RUNX)1/3 in CD4-positive cells. The concentration of cytokines in plasma were measured using a cytometric bead array. Additionally, the proportion of CD4+CD25highFoxp3+ Tregs and levels of associated proteins was analyzed using flow cytometry. The results demonstrated that the proportion of CD4+CD25highFoxp3+ and expression of Foxp3 in children with B-ALL was significantly higher compared with healthy controls (P<0.05) and that transcription levels of CTLA4, GITR and LAG3 were also significantly elevated (P<0.05). Compared with healthy controls, the expression of IL-2Rα/β and its downstream molecule phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in CD4-positive cells significantly increased (P<0.05); however, no significant difference of IL-2Rγ levels was identified between the two groups. Correlation analysis demonstrated a significant positive correlation between the expression of phosphorylated (p) signal transducer and activator of transcription factor (STAT)5 and CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.17; P<0.05). The plasma concentration of TGF-β, the expression of its receptor TGF-βRI/II and downstream molecules Smad3/4 were significantly upregulated in children with B-ALL (P<0.05), whereas the expression of RUNX1/3 was lower compared with healthy controls (P<0.05). Furthermore, the expression of Smad3 and RUNX1 was positively correlated with CD4+CD25highFoxp3+ Tregs in children with B-ALL (r=0.87 and 0.60, respectively; P<0.05). Additionally, the expression of pSTAT3 in CD4-positive cells decreased significantly in pediatric patients with B-ALL when compared with healthy controls; however, plasma concentrations of IL-6 was significantly higher (P<0.05). Furthermore, a negative correlation was identified between pSTAT3 and CD4+CD25highFoxp3+ Tregs in pediatric patients with B-ALL (r=-0.39; P<0.05). However, no significant differences in IL-6Rα/β expression were identified between the two groups. The results demonstrated that the excessive activation of IL-2/pSTAT5 and TGF-β/Smad signaling, and insufficiency of pSTAT3 may be correlated with increased CD4+CD25highFoxp3+ Tregs in pediatric B-ALL.
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OBJECTIVE To determine the changes of CD4+CD25+ regulatory T cells and the levels of IL-10 and TGF-beta1 in the mouse model of asthma and the effects of glucocorticoid inhalation on CD4+CD25+ regulatory T cells and IL-10 and TGF-beta1 levels. METHODS Thirty BALB/c mice were randomly divided into three groups: asthma model, glucocorticoid treatment and control. Asthma was induced by OVA administration in the asthma model and the glucocorticoid treatment groups. The glucocorticoid treatment group received budesonide inhalation (0.8 mg/L) before the challenge of asthma. After 24 hrs of the last challenge, the lung tissues of middle lobe of the right lung were obtained for the observation of lung pathological changes. Peripheral anticoagulated blood and lung lymph cells suspension were collected. The percentage of CD4+CD25+ regulatory T cells in CD4+ T cells was detected by flow cytometry, and the levels of IL-10 and TGF-beta1 in plasma were measured using ELISA. RESULTS The percentage of CD4+CD25+ regulatory T cells in peripheral blood and lung lymph cells suspension in the asthma model group was significantly lower than the control group ( P<0.01). The glucocorticoid-treated asthma group showed an increased percentage of CD4+CD25+ regulatory T cells compared with the asthma model group (P<0.01) and a similar percentage of CD4+CD25+ regulatory T cells in peripheral blood and lung lymph cells suspension to the control group. Compared with the control group, plasma levels of IL-10 and TGF-beta1 decreased significantly in the asthma model group (P<0.01). After glucocorticoid treatment plasma IL-10 level increased significantly (P<0.01) and was similar to that in the control group, while plasma TGF-beta1 level remained lower than that in the control group. CONCLUSIONS The percentage of CD4+CD25+ regulatory T cells and the levels of IL-10 and TGF-beta1 decreased in asthmatic mice which might contribute to the pathogenesis of asthma. Glucocorticoid can increase the percentage of CD4+CD25+ regulatory T cells and the levels of IL-10 and thus provides protective effects against asthma. The changes of the percentage of CD4+CD25+ regulatory T cells in peripheral blood were consistent with those in the lung, suggesting that monitoring the changes of CD4+CD25+ regulatory T cells in peripheral blood may be useful to understand the changes of CD4+CD25+ regulatory T cells in the lung.
Regulatory T cell
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Objective To investigate the effects of CD39 and CD73 positive CD4+CD25+Foxp3+regulatory T lymphocytes on airway inflammation and its mechanism in mice with bronchial asthma. Methods 16 adult female BALB/c mice were randomly divided into asthma group and control group. All mice were sacrificed in 24h after the last challenge, and the total IgE in serum was measured by ELISA; the ATP level in the BALF was measured by high-pressure liquid chromatography (HPLC); the left lung was stained by HE staining to observe the inflammation; The upper lobe of the right lung was for CD39, CD73, Foxp3mRNA detection; single cell suspension from the left right lung was used to examine the ratio of CD39+Treg and CD73+Treg cells relative to Treg cells by Flow cytometry. Results The serum total IgE was significantly increased (P<0.01), ATP in BALF was higher (P<0.05), and pathological examination showed that pulmonary inflammatory changes were significantly enhanced in asthma group than that in control group. The difference of CD39, CD73 and Foxp3 mRNA expression between the two groups has statistical significance (P<0.05) FACS test found that the number of CD39+Treg cells and CD73+Treg cells in asthma group decreased compared with the control group. Conclusions The decrease and/or dysfunction of CD39+Treg and CD73+Treg cells in the lung may induce extracellular ATP clearance disorder. It may be one of the important mechanisms of airway inflammation in asthma.
Pathogenesis
Cell counting
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Juvenile idiopathic arthritis (JIA) is a chronic, heterogenous inflammatory disease of unclear pathogenesis. JIA is hypothesized to be linked to a defective immune regulation. Anti-inflammatory cytokines belong to the best known regulatory factors. T-regulatory cells are a crucial cellular component of immune tolerance. One of their functions is synthesis of interleukin 10 (IL-10) and transforming growth factor beta1 (TGF-β1). The aim of this study was to determine the proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood, and serum levels of TGF-β1 and IL-10 in patients with JIA.The study included 25 patients with newly diagnosed JIA: oligoarthritis (n=17) and polyarthritis (n=8). The control group was comprised of 17 healthy children. CD4+CD25highFOXP3+ T cells in peripheral blood were quantified by means of three-color flow cytometry. Serum concentrations of TGF-β1 and IL-10 were estimated with ELISA.The proportion of peripheral CD4+CD25highFOXP3+ cells in patients with JIA was significantly higher than in the controls (p=0.04). The two groups did not differ significantly in terms of their TGF-β1 and IL-10 concentrations.At the time of diagnosis, children with JIA presented with an elevated proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood. Anti-inflammatory cytokines, IL-10 and TGF-β1, are not upregulated in the serum of patients with JIA, and therefore should not be considered as biomarkers of this condition.
Oligoarthritis
Pathogenesis
Proinflammatory cytokine
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Deficiency of Treg cells and hyperactivity of Th17 cells together are involved in the immunological pathogenesis of asthma. The adenosine A2A receptor (A2AR) plays a critical role in the increased Foxp3 expression of Treg cells and the decreased Th17 generation.The study aimed to investigate A2AR expression in peripheral blood and its regulatory effect on balance of Treg/Th17 cells in asthma.Thirty-one patients with chronic persistent asthma were recruited and divided into 18 intermittent to mild asthma patients, 13 moderate to severe asthma patients. A2AR, Foxp3, and ROR-γt mRNA expression levels in peripheral blood mononuclear cells (PBMCs) were measured by quantitative polymerase chain reaction (qPCR). TGF-β, IL-17, and IgE in plasma were detected with enzyme-linked immunosorbent assay (ELISA). Forty-two BALB/c mice were randomly, equally assigned to control group, ovalbumin (OVA) group and OVA + CGS (CGS21680, A2AR agonist) group. The infiltration of lung inflammation cells were evaluated by HE, A2AR, Foxp3, and ROR-γt mRNA in lung tissues measured by qPCR, TGF-β, IL-17, and IgE in plasma measured with ELISA, and IL-17 and TGF-β protein in lung tissues analyzed with immunohistochemical.Our results showed that expression A2AR mRNA in PBMCs was associated with asthma severity. Foxp3 mRNA, TGF-β, and FEV1%pred positively correlated with A2AR mRNA in asthma. ROR-γt mRNA and IL-17 negatively correlated with A2AR mRNA in asthma. CGS could promote Foxp3 mRNA expression, TGF-β, and improve lung function while inhibit ROR-γt mRNA expression, IL-17, and the infiltration of lung inflammation cells.A2AR could regulate the balance of Treg/Th17 cells in asthma.
Pathogenesis
Adenosine A2A receptor
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Objective To study the clinical significance of detecting the level of IL-17,IL-10,TGF-β1 and CD4 +CD25 + Foxp3 + T cell in patients with Multiple sclerosis( MS). Methods Detected the levels of serum IL-17 and IL-10 by ELISA in patients with MS and healthy controls and to detect the levels of peripheral blood CD4 + CD25 + Foxp3+ T cell by flow cytometry in patients with MS and healthy controls. Results The levels of serum IL-17 in patients with MS were significantly higher than that of healthy controls and the levels of IL-10,TGF-β1 and CD4 + CD25 +Foxp3 + T cell were significantly lower in the patients with MS than that of healthy controls. Conclusion IL-17,IL-10,TGF-β1 and CD4 + CD25 + Foxp3 + T cell might play important roles in the induction of MS and be helpful in the diagnosis of MS.
Clinical Significance
Regulatory T cell
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BACKGROUND Anti-inflammatory mediators such as mucin-domain containing-3 (TIM-3) and IL-37 play an important role in the regulation of Th1-mediated immunity. This study was designed to investigate the proportions of various T cell subsets and monocytes in the peripheral blood of rheumatoid arthritis (RA) patients, as well as the level of TIM-3 on these cells and serum cytokine levels. MATERIAL AND METHODS We enrolled 59 RA patients and 46 age- and sex-matched healthy controls in this study. The proportion of T cells and TIM-3 expression on these T cells were determined by flow cytometry. Cytokine levels in serum were determined by ELISA. RESULTS Compared with the healthy controls, the proportions of CD3+CD4+ T cells and CD3+CD4+CD25+CD127low T cells in the peripheral blood were significantly higher in RA patients. However, RA patients had significantly lower proportions of CD3+CD8+ T cells and CD3+CD4-CD8- T cells. TIM-3 was highly expressed on CD3+CD4+, CD3+CD8+, CD3+CD4+CD25+CD127low, and CD3+CD4-CD8- T cells, as well as CD14+ monocytes, in RA patients. Nevertheless, no correlation between TIM-3 level and an RA disease activity score of 28 was found. The elevated serum levels of IL-6 and IL-37 were positively correlated with tumor necrosis factor-α (TNF-α). CONCLUSIONS Both pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory mediators (TIM-3 and IL-37) simultaneously contribute to the pathogenesis of RA. TIM-3 and IL-37 may be used as potential biomarkers of active RA.
Interleukin 15
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Objective To investigate the quantity of peripheral blood CD4~+CD25~+ regulatory T cell,related cytokines and the expression of Foxp3 gene in ulcerative colitis(UC)patients,and to analyze the role of them in the pathogenesis of UC.Methods Anti-coagulated venous blood by heparin was collected from UC patients and healthy people.T cells were collected by Human CD3~+ T cell enrichment column.The quantity of peripheral blood CD4~+CD25~+ regulatory T cell was detected by immunofluorescence staining and bicolor flow cytometry by CD25/CD4 gating.The levels of related cytokines IL-10、TGF-β_1 were assayed by ELISA,the expressions of Foxp3 mRNA on T cell were analyzed by RT-PCR.Results Compared with healthy people,in UC patients,the expression of CD4~+CD25~+T cell and the level of Foxp3 mRNA both decrease significantly(P0.05).The levels of related cytokines IL-10、TGF-β_1 were lower than those of control group.Conclusion There is peripheral blood celluar immunological function disorder in UC patients,and the abnormal expression of CD4~+CD25~+T cell,the related cytokines and Foxp3 mRNA on T cell may involve in UC immunopathogenesis.
Regulatory T cell
Pathogenesis
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The ecto-enzyme CD39 can hydrolyze extracellular ATP which has pro-inflammatory effects. But the role of CD39 in patients with allergic asthma remains unknown. Eighteen patients with persistent asthma allergic to house dust mites and nineteen healthy volunteers were enrolled.The expression of CD39, GATA3, ROR-γt and Foxp3 mRNA in PBMC were determined by SYRB Green Real-time PCR.The cytokines IL-4, IL-17A, TGF-β and DP.sIgE were detected by ELISA. Our data showed that the expression of CD39 mRNA in PBMC from asthmatics was significantly lower than that in normal controls (1.49±0.59×10 -3 vs 2.17±0.77×10 -3 , P P P P P P P =0.122). These data suggest that CD39 mRNA expression was down-regulated in peripheral blood of asthmatics, which was positively relevant to serum IL-4, IL-17A and GATA3 and negatively relevant to serum TGF-β and Foxp3, and was not relevant to ROR-γt. We speculated that CD39 may participate in the occurrence and progress of allergic asthma.
GATA3
Allergic asthma
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