Th17/IL-17在儿童哮喘发病中的作用研究
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摘要
第一部分哮喘儿童外周血Th17水平及其表达IL-17功能研究
第一节流式细胞术检测人Th17细胞方法探讨
目的:探讨流式细胞术检测人Th17细胞方法。
方法:收集健康儿童外周血,分离外周血单个核细胞(PBMC),使用不同剂量PMA、不同刺激培养时间处理后用流式细胞仪检测Th17细胞百分率,检测早期活化标记细胞膜CD69以及表达IFN-γ的Th1细胞作为细胞活化的参照,获得最佳刺激剂量和培养时间。
结果:Th17与Th1的活化条件不相同,PMA 10-100μg/L加上Ionomycin和高尔基体阻断剂,培养4-12 h以内可获得Th17较好检测结果,过高的刺激剂量以及培养时间不能提高检测水平反而影响Th17的检测。
结论:本研究探讨的流式细胞术检测人Th17的方法指导临床和科学研究。
第二节哮喘儿童外周血Th17水平及表达IL-17功能研究
目的:观察哮喘急性发作期患儿外周血Th17水平和功能状态,初步探讨Th17在儿童哮喘发病中的作用。
方法:以正常儿童(对照组,n=20)为对照,流式细胞术(FCM)检测哮喘急性发作期患儿(哮喘组,n=30)外周血Th17以及Th1,Th2细胞百分率,Q-PCR方法检测外周血单个核细胞(PBMC)IL-17 mRNA的表达,ELISA方法检测体外培养上清IL-17,IFN-γ以及血浆IL-17,IL-23,IgE水平。
结果:(1)哮喘组和对照组外周血CD4+T中CD4+IL-17+T百分率([1.25±0.66)% vs (1.27±0.66)%(P>0.05)];CD4+IL-4+T比例([2.40±2.55)% vs (2.52±1.26)% (P>0.05)];两组比较无统计学意义。哮喘组CD4+IFN-γ+T比例显著低于对照组[15.79±7.48 vs 24.10±12.70(P<0.05)]。(2)哮喘组PBMC表达IL-17 mRNA显著低于对照组(8.26(4.40-49.43) vs 4.78(1.0-35.49) Z=1.93 P=0.05);PHA刺激PBMC体外培养72 h上清中,哮喘组IL-17水平显著低于对照组[17.53(0~245.57)ng/L vs 101.74(25.12~500.60)ng/L(P<0.01)];IL-17 mRNA与蛋白水平呈正相关(r=0.76 P=0.01)。IFN-γ水平与对照组比较无统计学意义[3507±2788 ng/L vs 3027±2737 ng/L];两组血浆中IL-17均<2 ng/L,IL-23均<15 ng/L。(3)哮喘组血浆总IgE 499.26(2.3~945.1)IU/mL,显著高于对照组54.57(1.7~318.26)IU/mL(P<0.001);IgE阳性(>150 IU/mL)和阴性(<150 IU/mL)哮喘患儿体外PBMC培养上清中IL-17,IFN-γ水平比较无统计学意义。
结论:哮喘急性发作期患儿外周血Th1细胞以及PHA活化的IL-17表达水平降低,Th1水平和Th17功能异常的机制及其在儿童哮喘发病中的作用值得进一步研究。
第二部分IL-17 G-152A基因多态性与儿童哮喘发病相关性研究
目的:分析中国西南地区汉族人群IL-17 G-152A多态性(rs2275913)与儿童哮喘发病的相关性。
方法:采用PCR-限制性片断长度多态性(Restricion Fragment Length Polymorphism,RFLP)法分析88例哮喘患儿(哮喘组,其中51例为变应性哮喘),89例毛细支气管炎患儿(毛细支气管炎组)和184例健康对照(对照组)IL-17 G-152A位点基因型。ELISA法检测PHA诱导不同基因型PBMC表达IL-17水平。比较不同基因型哮喘患儿血清总IgE、肺功能及毛细支气管炎患儿临床特点。
结果:(1)IL-17 G-152A位点在中国西南地区存在多态性,各组基因型频率符合Hardy-Weinberg平衡。健康人群A、G等位基因频率分别41.6%、58.4%;AA、AG和GG基因型频率分别14.7%、53.8%、31.5%(2)哮喘组G-152A位点等位基因以及基因型频率与正常组比较有统计学差异,OR值及95%CI在A等位基因为1.44(1.00-2.06),P=0.048;在AA基因型为2.44(1.32-4.50),P=0.004。相对于变应性哮喘,A等位基因和AA基因型显示更高的OR值。(3)基础肺功能,血清总IgE平均水平在各基因型组间比较差异无统计学意义;但AA基因型中血清总IgE增高(>150 IU/mL)个体及肺功能FVC、FEV1降低(<80%个人预测值)个体的比例显著高于AG和GG基因型(P<0.05)。(4)PHA诱导的PBMC表达IL-17水平在各基因型组无显著差异(5)毛细支气管炎组基因型和等位基因频率与正常组或哮喘组比较无统计学差异;结合临床资料分析显示AA基因型患儿鼻咽部肺炎链球菌检出率较高(37.5% vs 2.5%,P=0.001);AA基因型患儿住院时间较长(8.89±1.76 vs 7.15±2.05, P=0.02),GG基因型喘息病程较短(9.85±3.36 vs 11.64±2.64,P=0.03)。
结论:本研究在基因水平提示IL-17与哮喘发病有关。IL-17 G-152A多态性(rs2275913)是中国西南地区儿童变应性哮喘发病的危险因素,AA基因型与哮喘患儿血清总IgE升高以及肺功能FVC、FEV1异常有关。在毛细支气管炎患儿中发现该位点不同基因型间临床表现存在差异,可能与发生哮喘有关。有待增加样本量,以及进一步探讨IL-17 G-152A多态性对IL-17表达调节、IL-17基因其它多态性位点的作用,以进一步揭示IL-17在儿童哮喘发病中的作用和机制。
PARTⅠPercentages and function status of circulating T help cell 17(Th17) in asthmatic children
SectionⅠ. Evaluating the protocol of analysing human Th17 cell by Flow Cytometry
Objective: Many studies in animal model indicated the key role of T help cell(Th)-17 in the pathology of autoimmune diseases and allergic diseases. The study is to evaluate the protocol for analysing human Th17 cell by flow cytometry.
Methods: The mononuclure cells were separated from peripheral blood of healthy donors and cultured with different concentration of PMA plus Ionomycin and Golgistop. Th17 was analyzed by flow cytometry at different time points. The expression of membrane CD69 and IFN-γproducing Th1 were detected as positive control for T lymphocyte activtion.
Results: The condition for activation of Th17 and Th1 was not identical. Culturing peripheral blood mononuclure cells(PBMC) in the present of PMA with a concentration from 10-100μg/L plus Ionomycin and Golgistop, for 4-12 hours was the appropriate protocol for both Th17 and Th1 detection. Too much more stimulus or culturing time influenced the detection of Th17 rather than improved it.
Conclusion: The protocol for analysing human Th17 by flow cytometry presented here can be referenced.
SectionⅡ. Percentage and function status of circulating T help cell 17(Th17) in asthmatic children
Objective: Th17 is a recently identified subset of Th cell characterized by production of interleukin (IL)-17, which mediate neutrophils accumulation. Neutrophils accumulation in the airway is a feature of asthmatic children.The study observing the percentage and function status of Th17 in peripheral blood of asthmatic children,was to explore the role of Th17 on the pathogenesis of childhood asthma .
Methods: Thirty children with acute asthma exacerbation and twenty healthy individual as control were recruited. The percentages of Th17, Th1 and Th2 were deceted by flow cytometry; the levels of IL-17 and IFN-γin peripheral blood mononuclear cell (PBMC) cultureed supernatant and IL-17, IL-23, total IgE in serum were detected by enzyme linked immunosorbent assy (ELISA),mRNA expression was detected by real-time RT-PCR.
Results: (1) In asthmatic and healthy children, there was no significantly difference of the percentages of CD4+IL-17+T [(1.25±0.66)% vs (1.27±0.66)% ,P>0.05] and CD4+IL-4+T [2.398±2.548 vs 2.517±1.257(P>0.05)] in CD4+T cell population;the percentages of CD4+IFN-γ+T in asthmatic children was significantly lower than that in control [15.79±7.479 vs 24.10±12.70(P<0.05)] (2) The levels of IL-17 in PBMC culture supernatant of asthmatic children was significantly lower than that in control [17.53(0-245.57)pg/mL vs 101.74(25.12-500.60)pg/mL , P<0.01); So was the IL-17 mRNA expression in PBMC(4.78(1.0-35.49 vs 8.26(4.40-49.43)P=0.05),and it was positively correlated with protein production(r=0.76 P=0.01). There was no significantly difference of IFN-γproduction in both group[3507±2788 pg/mL vs 3027±2737 pg/mL(P>0.05)]. IL-17 in serum was less than 2 pg/mL and the IL-23 was less than 15pg/mL in both groups. (3) Total serum IgE in asthmatic children was significantly higher than that in control [499.26(2.3-945.1) vs 54.57(1.7-318.26)IU/mL, P<0.001]; there was no significantly difference of IL-17 or IFN-γproduction in PBMC cultured supernatant between IgE positive(>150 IU/ml) and negative asthmatic children.
Conclusion: The results demonstrated that the percentages of Th1 and the function of Th17 in asthmatic children were impaired in peripheral blood, while the mechanism remains to be further studied . The change of Th1 percentage and Th17 function may be associated with the pathogenesis of childhood asthma.
PARTⅡThe polymorphisms of IL-17 G-152A and its association with pediatric asthma in Southwestern Han Chinese population
Objective: The interleukin(IL)-17 is linked to the pathology of asthma ; IL-17 gene located on chromosome 6p,the genomic region of which has been reported to be linked to asthma and asthma-related phenotypes. The study was to investigate the association between single nucleotide polymorphism (SNP) of IL-17 G-152A with childhood asthma in Southwestern Han Chinese population.
Methods: Eighty-nine hospitalized children with bronchiolitis, 88 children with asthma and 184 healthy controls were recruited. Polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was used to analyse the IL-17 G-152A polymorphisms (rs2275913).
Results: (1)IL-17 G-152A polymorphisms were present in all groups and in Hardy-Weinberg equilibrium. The frequencies of allele was 41.6% (A) and 58.4% (G) in the healthy children, with a genotype AA frequency of 14.7%, AG frequency of 53.8%,and GG frequency of 31.5%.(2)The frequencies of allele A and genotype AA in asthma group(P=0.048, P=0.013, respectively) , particularly in allergic asthma(P=0.002, P=0.001, respectively) were significantly higher than those of that in control group. Carriers of the A allele had a 1.44-fold (95% confidence interval: 1.00-2.06) risk of developing asthma than those homozygous for the G allele. AA genotype had a 2.44-fold (95% confidence interval: 1.32-4.50) risk of developing asthma than other genotypes. The strength of associations was moderately higher by allergy comorbidity. (3)There was no significantly difference of average level of lung function、PC20 and serum total IgE among the different genotype groups,but the proportions of subjects with abnormal total serum IgE and FVC、F EV1 values were significantly higher in subjects with the genotype AA than in those with AG and GG genotypes. (4)IL-17 production in PHA-induced PBMC was not different among individuals with different genotypes .(5)When patients with bronchiolitis were typed for IL-17 G-152A polymorphism, no difference was observed compared with control. But a significantly higher Streptococcus pneumoniae detection rate was shown in subjects with homozygous A allele compared with subjects with AG and GG genotype (37.5% vs 4.5%; P<0.001). The length of hospital stay was significantly higher in subjects with homozygous A allele than in subjects with AG and GG genotype(8.2 vs 6.3 days; P=0.02). Course of wheezing in subjects with homozygous G allele was significantly shorter than in subjects with AA and AG genotype ( 9.9 vs 11.3 days; P=0.03).
Conclusion: These preliminary results suggested that IL-17 is a candidate gene that confers the genetic susceptibility for childhood asthma in Southwestern Han Chinese population. The homozygous -152A allele of IL-17 was associated with abnormal lung function and serum total IgE in asthmatic patients and with the clinical features of bronchiolitis, even though it seemed to have little influence on IL-17 production in PHA-induced PBMC. It demands further investigations to understand the function and mechanism of IL-17 G-152A polymorphisms in regulating IL-17 expression,as well as increasing samples and association of other SNPs of IL-17 with asthma.
第一节流式细胞术检测人Th17细胞方法探讨
目的:探讨流式细胞术检测人Th17细胞方法。
方法:收集健康儿童外周血,分离外周血单个核细胞(PBMC),使用不同剂量PMA、不同刺激培养时间处理后用流式细胞仪检测Th17细胞百分率,检测早期活化标记细胞膜CD69以及表达IFN-γ的Th1细胞作为细胞活化的参照,获得最佳刺激剂量和培养时间。
结果:Th17与Th1的活化条件不相同,PMA 10-100μg/L加上Ionomycin和高尔基体阻断剂,培养4-12 h以内可获得Th17较好检测结果,过高的刺激剂量以及培养时间不能提高检测水平反而影响Th17的检测。
结论:本研究探讨的流式细胞术检测人Th17的方法指导临床和科学研究。
第二节哮喘儿童外周血Th17水平及表达IL-17功能研究
目的:观察哮喘急性发作期患儿外周血Th17水平和功能状态,初步探讨Th17在儿童哮喘发病中的作用。
方法:以正常儿童(对照组,n=20)为对照,流式细胞术(FCM)检测哮喘急性发作期患儿(哮喘组,n=30)外周血Th17以及Th1,Th2细胞百分率,Q-PCR方法检测外周血单个核细胞(PBMC)IL-17 mRNA的表达,ELISA方法检测体外培养上清IL-17,IFN-γ以及血浆IL-17,IL-23,IgE水平。
结果:(1)哮喘组和对照组外周血CD4+T中CD4+IL-17+T百分率([1.25±0.66)% vs (1.27±0.66)%(P>0.05)];CD4+IL-4+T比例([2.40±2.55)% vs (2.52±1.26)% (P>0.05)];两组比较无统计学意义。哮喘组CD4+IFN-γ+T比例显著低于对照组[15.79±7.48 vs 24.10±12.70(P<0.05)]。(2)哮喘组PBMC表达IL-17 mRNA显著低于对照组(8.26(4.40-49.43) vs 4.78(1.0-35.49) Z=1.93 P=0.05);PHA刺激PBMC体外培养72 h上清中,哮喘组IL-17水平显著低于对照组[17.53(0~245.57)ng/L vs 101.74(25.12~500.60)ng/L(P<0.01)];IL-17 mRNA与蛋白水平呈正相关(r=0.76 P=0.01)。IFN-γ水平与对照组比较无统计学意义[3507±2788 ng/L vs 3027±2737 ng/L];两组血浆中IL-17均<2 ng/L,IL-23均<15 ng/L。(3)哮喘组血浆总IgE 499.26(2.3~945.1)IU/mL,显著高于对照组54.57(1.7~318.26)IU/mL(P<0.001);IgE阳性(>150 IU/mL)和阴性(<150 IU/mL)哮喘患儿体外PBMC培养上清中IL-17,IFN-γ水平比较无统计学意义。
结论:哮喘急性发作期患儿外周血Th1细胞以及PHA活化的IL-17表达水平降低,Th1水平和Th17功能异常的机制及其在儿童哮喘发病中的作用值得进一步研究。
第二部分IL-17 G-152A基因多态性与儿童哮喘发病相关性研究
目的:分析中国西南地区汉族人群IL-17 G-152A多态性(rs2275913)与儿童哮喘发病的相关性。
方法:采用PCR-限制性片断长度多态性(Restricion Fragment Length Polymorphism,RFLP)法分析88例哮喘患儿(哮喘组,其中51例为变应性哮喘),89例毛细支气管炎患儿(毛细支气管炎组)和184例健康对照(对照组)IL-17 G-152A位点基因型。ELISA法检测PHA诱导不同基因型PBMC表达IL-17水平。比较不同基因型哮喘患儿血清总IgE、肺功能及毛细支气管炎患儿临床特点。
结果:(1)IL-17 G-152A位点在中国西南地区存在多态性,各组基因型频率符合Hardy-Weinberg平衡。健康人群A、G等位基因频率分别41.6%、58.4%;AA、AG和GG基因型频率分别14.7%、53.8%、31.5%(2)哮喘组G-152A位点等位基因以及基因型频率与正常组比较有统计学差异,OR值及95%CI在A等位基因为1.44(1.00-2.06),P=0.048;在AA基因型为2.44(1.32-4.50),P=0.004。相对于变应性哮喘,A等位基因和AA基因型显示更高的OR值。(3)基础肺功能,血清总IgE平均水平在各基因型组间比较差异无统计学意义;但AA基因型中血清总IgE增高(>150 IU/mL)个体及肺功能FVC、FEV1降低(<80%个人预测值)个体的比例显著高于AG和GG基因型(P<0.05)。(4)PHA诱导的PBMC表达IL-17水平在各基因型组无显著差异(5)毛细支气管炎组基因型和等位基因频率与正常组或哮喘组比较无统计学差异;结合临床资料分析显示AA基因型患儿鼻咽部肺炎链球菌检出率较高(37.5% vs 2.5%,P=0.001);AA基因型患儿住院时间较长(8.89±1.76 vs 7.15±2.05, P=0.02),GG基因型喘息病程较短(9.85±3.36 vs 11.64±2.64,P=0.03)。
结论:本研究在基因水平提示IL-17与哮喘发病有关。IL-17 G-152A多态性(rs2275913)是中国西南地区儿童变应性哮喘发病的危险因素,AA基因型与哮喘患儿血清总IgE升高以及肺功能FVC、FEV1异常有关。在毛细支气管炎患儿中发现该位点不同基因型间临床表现存在差异,可能与发生哮喘有关。有待增加样本量,以及进一步探讨IL-17 G-152A多态性对IL-17表达调节、IL-17基因其它多态性位点的作用,以进一步揭示IL-17在儿童哮喘发病中的作用和机制。
PARTⅠPercentages and function status of circulating T help cell 17(Th17) in asthmatic children
SectionⅠ. Evaluating the protocol of analysing human Th17 cell by Flow Cytometry
Objective: Many studies in animal model indicated the key role of T help cell(Th)-17 in the pathology of autoimmune diseases and allergic diseases. The study is to evaluate the protocol for analysing human Th17 cell by flow cytometry.
Methods: The mononuclure cells were separated from peripheral blood of healthy donors and cultured with different concentration of PMA plus Ionomycin and Golgistop. Th17 was analyzed by flow cytometry at different time points. The expression of membrane CD69 and IFN-γproducing Th1 were detected as positive control for T lymphocyte activtion.
Results: The condition for activation of Th17 and Th1 was not identical. Culturing peripheral blood mononuclure cells(PBMC) in the present of PMA with a concentration from 10-100μg/L plus Ionomycin and Golgistop, for 4-12 hours was the appropriate protocol for both Th17 and Th1 detection. Too much more stimulus or culturing time influenced the detection of Th17 rather than improved it.
Conclusion: The protocol for analysing human Th17 by flow cytometry presented here can be referenced.
SectionⅡ. Percentage and function status of circulating T help cell 17(Th17) in asthmatic children
Objective: Th17 is a recently identified subset of Th cell characterized by production of interleukin (IL)-17, which mediate neutrophils accumulation. Neutrophils accumulation in the airway is a feature of asthmatic children.The study observing the percentage and function status of Th17 in peripheral blood of asthmatic children,was to explore the role of Th17 on the pathogenesis of childhood asthma .
Methods: Thirty children with acute asthma exacerbation and twenty healthy individual as control were recruited. The percentages of Th17, Th1 and Th2 were deceted by flow cytometry; the levels of IL-17 and IFN-γin peripheral blood mononuclear cell (PBMC) cultureed supernatant and IL-17, IL-23, total IgE in serum were detected by enzyme linked immunosorbent assy (ELISA),mRNA expression was detected by real-time RT-PCR.
Results: (1) In asthmatic and healthy children, there was no significantly difference of the percentages of CD4+IL-17+T [(1.25±0.66)% vs (1.27±0.66)% ,P>0.05] and CD4+IL-4+T [2.398±2.548 vs 2.517±1.257(P>0.05)] in CD4+T cell population;the percentages of CD4+IFN-γ+T in asthmatic children was significantly lower than that in control [15.79±7.479 vs 24.10±12.70(P<0.05)] (2) The levels of IL-17 in PBMC culture supernatant of asthmatic children was significantly lower than that in control [17.53(0-245.57)pg/mL vs 101.74(25.12-500.60)pg/mL , P<0.01); So was the IL-17 mRNA expression in PBMC(4.78(1.0-35.49 vs 8.26(4.40-49.43)P=0.05),and it was positively correlated with protein production(r=0.76 P=0.01). There was no significantly difference of IFN-γproduction in both group[3507±2788 pg/mL vs 3027±2737 pg/mL(P>0.05)]. IL-17 in serum was less than 2 pg/mL and the IL-23 was less than 15pg/mL in both groups. (3) Total serum IgE in asthmatic children was significantly higher than that in control [499.26(2.3-945.1) vs 54.57(1.7-318.26)IU/mL, P<0.001]; there was no significantly difference of IL-17 or IFN-γproduction in PBMC cultured supernatant between IgE positive(>150 IU/ml) and negative asthmatic children.
Conclusion: The results demonstrated that the percentages of Th1 and the function of Th17 in asthmatic children were impaired in peripheral blood, while the mechanism remains to be further studied . The change of Th1 percentage and Th17 function may be associated with the pathogenesis of childhood asthma.
PARTⅡThe polymorphisms of IL-17 G-152A and its association with pediatric asthma in Southwestern Han Chinese population
Objective: The interleukin(IL)-17 is linked to the pathology of asthma ; IL-17 gene located on chromosome 6p,the genomic region of which has been reported to be linked to asthma and asthma-related phenotypes. The study was to investigate the association between single nucleotide polymorphism (SNP) of IL-17 G-152A with childhood asthma in Southwestern Han Chinese population.
Methods: Eighty-nine hospitalized children with bronchiolitis, 88 children with asthma and 184 healthy controls were recruited. Polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was used to analyse the IL-17 G-152A polymorphisms (rs2275913).
Results: (1)IL-17 G-152A polymorphisms were present in all groups and in Hardy-Weinberg equilibrium. The frequencies of allele was 41.6% (A) and 58.4% (G) in the healthy children, with a genotype AA frequency of 14.7%, AG frequency of 53.8%,and GG frequency of 31.5%.(2)The frequencies of allele A and genotype AA in asthma group(P=0.048, P=0.013, respectively) , particularly in allergic asthma(P=0.002, P=0.001, respectively) were significantly higher than those of that in control group. Carriers of the A allele had a 1.44-fold (95% confidence interval: 1.00-2.06) risk of developing asthma than those homozygous for the G allele. AA genotype had a 2.44-fold (95% confidence interval: 1.32-4.50) risk of developing asthma than other genotypes. The strength of associations was moderately higher by allergy comorbidity. (3)There was no significantly difference of average level of lung function、PC20 and serum total IgE among the different genotype groups,but the proportions of subjects with abnormal total serum IgE and FVC、F EV1 values were significantly higher in subjects with the genotype AA than in those with AG and GG genotypes. (4)IL-17 production in PHA-induced PBMC was not different among individuals with different genotypes .(5)When patients with bronchiolitis were typed for IL-17 G-152A polymorphism, no difference was observed compared with control. But a significantly higher Streptococcus pneumoniae detection rate was shown in subjects with homozygous A allele compared with subjects with AG and GG genotype (37.5% vs 4.5%; P<0.001). The length of hospital stay was significantly higher in subjects with homozygous A allele than in subjects with AG and GG genotype(8.2 vs 6.3 days; P=0.02). Course of wheezing in subjects with homozygous G allele was significantly shorter than in subjects with AA and AG genotype ( 9.9 vs 11.3 days; P=0.03).
Conclusion: These preliminary results suggested that IL-17 is a candidate gene that confers the genetic susceptibility for childhood asthma in Southwestern Han Chinese population. The homozygous -152A allele of IL-17 was associated with abnormal lung function and serum total IgE in asthmatic patients and with the clinical features of bronchiolitis, even though it seemed to have little influence on IL-17 production in PHA-induced PBMC. It demands further investigations to understand the function and mechanism of IL-17 G-152A polymorphisms in regulating IL-17 expression,as well as increasing samples and association of other SNPs of IL-17 with asthma.
引文
[1]陈育智.中国儿童哮喘防治近况[J].中华儿科杂志. 2004;2:81-82.
[2] von Mutius E. The burden of childhood asthma[J]. Arch Dis Child. 2000; 82 Suppl 2:II2-5.
[3] Guilbert TW, Morgan WJ, Zeiger RS,et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma[J]. N Engl J Med. 2006; 354:1985-1997.
[4] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8:337-348.
[5] Oboki K, Ohno T, Saito H, et al. Th17 and allergy[J]. Allergol Int. 2008; 57: 121-134.
[6] Schnyder-Candrian S,Togbe D,Couillin I,et al.Interleukin-17 is a negative regulator of established allergic asthma[J]. J Exp Med. 2006;203:2715-2725.
[7] Nakae S,Komiyama Y,Nambu A,et al.Antigen-specific T cell sensitization is impaired in IL-17-deficient mice,causing suppression of allergic cellular and humoral responses[J].Immunity. 2002;17:375-387.
[8] Molet S, Hamid Q, Davoine F, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-438.
[9] Chakir J, Shannon J, Molet S, et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[10] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[11] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[12]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志. 2005; 23:615-617.
[13] Douwes J,Gibson P, Pekkanen J, et al. Non-eosinophilic asthma:importance and possible mechanisms[J]. Thorax. 2002;57:643-648.
[1] Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol. 1986;136(7):2348-2357.
[2] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8(5):337-348.
[3] Kondo T, Takata H, Matsuki F, et al. Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17[J]. J Immunol. 2009;182(4):1794-1798.
[4] Rostaing L, Tkaczuk J, Durand M, et al. Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells[J] . Cytometry, 1999;35(4):318-328.
[5] Coquet JM, Chakravarti S, Kyparissoudis K, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population[J]. Proc Natl Acad Sci U S A. 2008;105(32):11287-11292.
[6] Roark CL, Simonian PL, Fontenot AP,et al. gammadelta T cells: an important source of IL-17[J]. Curr Opin Immunol. 2008;20(3):353-357.
[1] Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults[J]. Lancet.2006;368(9537):780-793.
[2]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志. 2005;23(09):615-617.
[3] Douwes J,Gibson P, Pekkanen J, et al. Non-eosinophilic asthma:importance and possible mechanisms[J]. Thorax. 2002;57(7):643-648.
[4] Peter W. Hellings, Ahmad Kasran, Zhanju Liu, et al: Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma[J]. Am J Respir Cell Mol Biol. 2003;28:42–50.
[5] Sergejeva S, Ivanov S, Lotvall J,et al. Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation[J]. Am J Respir Cell Mol Biol. 2005;33(3):248-253.
[6] Koichi Hashimoto, Barney S. Graham, Samuel B. Ho,et al.Respiratory Syncytial Virus in Allergic Lung Inflammation Increases Muc5ac and Gob-5[J].Am J Respir Crit Care Med. 2004;170: 306-312.
[7] Susumu Nakae,Yutaka Komiyama,Aya Nambu, et al.Antigen-Specific T Cell Sensitization Is Impaired in IL-17-Deficient Mice, Causing Suppression of Allergic Cellular and Humoral Responses[J]. Immunity.2002;17(3): 375-387.
[8] Silvia Schnyder-Candrian, Dieudonnée Togbe, Isabelle Couillin, et al.Interleukin-17 is a negative regulator of established allergic asthma [J].J E M.2006;203(12):2715-2725.
[9] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8(5):337-348.
[10] Kondo T, Takata H, Matsuki F, et al. Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17[J]. J Immunol. 2009;182(4):1794-1798.
[11] He R, Oyoshi MK, Jin H, et al. Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge[J]. Proc Natl Acad Sci USA.2007;104(40):15817-15822.
[12]吕婷婷,朱平,李晓燕等.类风湿关节炎患者外周血Th细胞亚群的变化及依那西普的调节作用[J].细胞与分子免疫学杂志.2008;24(5):495-497
[13] Maek-A-Nantawat W, Buranapraditkun S, Klaewsongkram J, et al. Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection[J]. ViralImmunol .2007;20(1):66-75.
[14] Zhang C, Zhang J, Yang B et al. Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis[J]. Cytokine. 2008; 42(3):345-352.
[15] Smart JM, Horak E, Kemp AS,et al. Polyclonal and allergen-induced cytokine responses in adults with asthma: resolution of asthma is associated with normalization of IFN-gamma responses[J]. J Allergy Clin Immunol. 2002;110(3):450-456.
[16] Fujiwara M, Hirose K, Kagami S,et al. T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways[J]. J Allergy Clin Immunol. 2007;119(3):662-670.
[17] Oboki K, Ohno T, Saito H et al. Th17 and allergy[J]. Allergol Int. 2008; 57: 121-34.
[18] Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-138.
[19] Chakir J, Shannon J, Molet S et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[20] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[21] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[22] Lu YJ, Gross J, Bogaert D,et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization[J]. PLoS Pathog. 2008;4(9):e1000159.
[23] Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates[J]. N Engl J Med. 2007;357(15):1487-1495.
[1] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[2] Oboki K, Ohno T, Saito H et al. Th17 and allergy[J]. Allergol Int. 2008;57: 121-34.
[3] Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-438.
[4] Chakir J, Shannon J, Molet S et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[5] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[6] Moffatt MF.Genes in asthma: new genes and new ways[J].Curr Opin Allergy Clin Immunol. 2008;8(5):411-417.
[7] Silvia Schnyder-Candrian, Dieudonnée Togbe, Isabelle Couillin, et al.Interleukin-17 is a negative regulator of established allergic asthma [J].J E M. 2006;203(12):2715-2725.
[8] Ke Y, Liu K, Huang GQ, et al. Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol. 2009; 182(5):3183-3190.
[9] Arisawa T, Tahara T, Shibata T et al.The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis[J]. J Clin Immunol. 2008 ;28(1):44-49.
[10] Nordang GB, Viken MK, Hollis-Moffatt JE,et al.Association analysis of the interleukin 17A gene in Caucasian rheumatoid arthritis patients from Norway and New Zealand[J]. Rheumatology (Oxford). 2009;48(4):367-370.
[11] Wang JY, Shyur SD, Wang WH,et al. The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population[J]. Allergy. 2009 Feb 5. [Epub ahead of print]
[12] Singh AM, Moore PE, Gern JE, et al. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation[J]. Am J Respir Crit Care Med. 2007;175(2):108-119
[13] Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates[J]. N Engl J Med. 2007;357(15):1487-1495.
[14] Lu YJ, Gross J, Bogaert D,et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization[J]. PLoS Pathog. 2008;4(9):e1000159.
[1] Linden A,Laan M,Anderson GP.Neutrophils,interleukin-17A and lung disease[J].Eur Respir J,2005,25(1):159-172.
[2] Alphonse MP,Saffar AS,Shan L,et al.Regulation of the high affinity IgE receptor (Fc epsilonRI) in human neutrophils:role of seasonal allergen exposure and Th-2 cytokines[J].PLoS ONE,2008,3(4):e1921.
[3] Holgate ST,Polosa R.The mechanisms,diagnosis,and management of severe asthma in adults[J].Lancet,2006,368(9537):780-793.
[4]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志,2005,23(09):615-617.
[5] Douwes J,Gibson P,Pekkanen J,et al.Non-eosinophilic asthma:importance and possible mechanisms[J].Thorax,2002,57(7):643-648.
[6] Zhou L,Lopes JE,Chong MM,et al.TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function[J].Nature,2008,453(7192):236-240.
[7] Bettelli E,Carrier Y,Gao W,et al.Reciprocal developmental pathways for the generation of pathogenic effect or TH17 and regulatory T cells[J].Nature,2006,441(7090):235-238.
[8] Xu L,Kitani A,Fuss I,et al.Cutting Edge: Regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta[J].J Immunol,2007,178(11):6725-6729.
[9] Harrington LE,Hatton RD,Mangan PR,et al.Interleukin 17-producing CD4+ effectorT cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J].Nat Immunol,2005,6(11):1123-1132.
[10] Peter W.Hellings,Ahmad Kasran,Zhanju Liu,et al.Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma[J].Am J Respir Cell Mol Biol,2003,28(1):42-50.
[11] Pichavant M,Charbonnier AS,Taront S,et al.Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment[J].J Allergy Clin Immunol,2005,115(4):771-778.
[12] He R,Oyoshi MK,Jin H,et al.Epicutaneous antigen exposure induces a Th17response that drives airway inflammation after inhalation challenge[J].Proc Natl Acad Sci U S A,2007,104(40):15817-15822.
[13] Schnyder-Candrian S,Togbe D,Couillin I,et al.Interleukin-17 is a negative regulator of established allergic asthma[J].J Exp Med,2006,203(12):2715-2725.
[14] Cheung PF,Wong CK,Lam CW.Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A,IL-17F,and IL-23:implication for Th17 lymphocytes-mediated allergic inflammation[J].J Immunol,2008,180(8):5625-5635.
[15] Sergejeva S,Ivanov S,Lotvall J,et al.Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation[J].Am J Respir Cell Mol Biol,2005,33(3):248-253.
[16] Nakae S,Komiyama Y,Nambu A,et al.Antigen-specific T cell sensitization is impaired in IL-17-deficient mice,causing suppression of allergic cellular and humoral responses[J].Immunity,2002,17(3):375-387.
[17] Ghilardi N,Kljavin N,Chen Q,et al.Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice[J].J Immunol,2004,172(5):2827-2833.
[18] Hashimoto T,Akiyama K,Kobayashi N,et al.Comparison of IL-17 production by helper T cells among atopic and nonatopic asthmatics and control subjects[J].Int Arch Allergy Immunol,2005,137 Suppl 1:51-54.
[19] McKinley L,Alcorn JF,Peterson A,et al.TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice[J].J Immunol,2008,181(6):4089-4097.
[20] Chen Y,Thai P,Zhao YH,et al.Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop[J].J Biol Chem,2003,78(19):17036-17043.
[21] Hashimoto K,Graham BS,Ho SB,et al.Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5[J].Am J Respir Crit Care Med,2004,170(3):306-312.
[22] Kaneko H,Matsui E,Asano T,et al.Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection[J].Pediatr Allergy Immunol,2006,17(5):370-375. 61
[2] von Mutius E. The burden of childhood asthma[J]. Arch Dis Child. 2000; 82 Suppl 2:II2-5.
[3] Guilbert TW, Morgan WJ, Zeiger RS,et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma[J]. N Engl J Med. 2006; 354:1985-1997.
[4] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8:337-348.
[5] Oboki K, Ohno T, Saito H, et al. Th17 and allergy[J]. Allergol Int. 2008; 57: 121-134.
[6] Schnyder-Candrian S,Togbe D,Couillin I,et al.Interleukin-17 is a negative regulator of established allergic asthma[J]. J Exp Med. 2006;203:2715-2725.
[7] Nakae S,Komiyama Y,Nambu A,et al.Antigen-specific T cell sensitization is impaired in IL-17-deficient mice,causing suppression of allergic cellular and humoral responses[J].Immunity. 2002;17:375-387.
[8] Molet S, Hamid Q, Davoine F, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-438.
[9] Chakir J, Shannon J, Molet S, et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[10] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[11] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[12]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志. 2005; 23:615-617.
[13] Douwes J,Gibson P, Pekkanen J, et al. Non-eosinophilic asthma:importance and possible mechanisms[J]. Thorax. 2002;57:643-648.
[1] Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol. 1986;136(7):2348-2357.
[2] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8(5):337-348.
[3] Kondo T, Takata H, Matsuki F, et al. Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17[J]. J Immunol. 2009;182(4):1794-1798.
[4] Rostaing L, Tkaczuk J, Durand M, et al. Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells[J] . Cytometry, 1999;35(4):318-328.
[5] Coquet JM, Chakravarti S, Kyparissoudis K, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population[J]. Proc Natl Acad Sci U S A. 2008;105(32):11287-11292.
[6] Roark CL, Simonian PL, Fontenot AP,et al. gammadelta T cells: an important source of IL-17[J]. Curr Opin Immunol. 2008;20(3):353-357.
[1] Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults[J]. Lancet.2006;368(9537):780-793.
[2]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志. 2005;23(09):615-617.
[3] Douwes J,Gibson P, Pekkanen J, et al. Non-eosinophilic asthma:importance and possible mechanisms[J]. Thorax. 2002;57(7):643-648.
[4] Peter W. Hellings, Ahmad Kasran, Zhanju Liu, et al: Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma[J]. Am J Respir Cell Mol Biol. 2003;28:42–50.
[5] Sergejeva S, Ivanov S, Lotvall J,et al. Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation[J]. Am J Respir Cell Mol Biol. 2005;33(3):248-253.
[6] Koichi Hashimoto, Barney S. Graham, Samuel B. Ho,et al.Respiratory Syncytial Virus in Allergic Lung Inflammation Increases Muc5ac and Gob-5[J].Am J Respir Crit Care Med. 2004;170: 306-312.
[7] Susumu Nakae,Yutaka Komiyama,Aya Nambu, et al.Antigen-Specific T Cell Sensitization Is Impaired in IL-17-Deficient Mice, Causing Suppression of Allergic Cellular and Humoral Responses[J]. Immunity.2002;17(3): 375-387.
[8] Silvia Schnyder-Candrian, Dieudonnée Togbe, Isabelle Couillin, et al.Interleukin-17 is a negative regulator of established allergic asthma [J].J E M.2006;203(12):2715-2725.
[9] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming[J]. Nat Rev Immunol. 2008;8(5):337-348.
[10] Kondo T, Takata H, Matsuki F, et al. Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17[J]. J Immunol. 2009;182(4):1794-1798.
[11] He R, Oyoshi MK, Jin H, et al. Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge[J]. Proc Natl Acad Sci USA.2007;104(40):15817-15822.
[12]吕婷婷,朱平,李晓燕等.类风湿关节炎患者外周血Th细胞亚群的变化及依那西普的调节作用[J].细胞与分子免疫学杂志.2008;24(5):495-497
[13] Maek-A-Nantawat W, Buranapraditkun S, Klaewsongkram J, et al. Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection[J]. ViralImmunol .2007;20(1):66-75.
[14] Zhang C, Zhang J, Yang B et al. Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis[J]. Cytokine. 2008; 42(3):345-352.
[15] Smart JM, Horak E, Kemp AS,et al. Polyclonal and allergen-induced cytokine responses in adults with asthma: resolution of asthma is associated with normalization of IFN-gamma responses[J]. J Allergy Clin Immunol. 2002;110(3):450-456.
[16] Fujiwara M, Hirose K, Kagami S,et al. T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways[J]. J Allergy Clin Immunol. 2007;119(3):662-670.
[17] Oboki K, Ohno T, Saito H et al. Th17 and allergy[J]. Allergol Int. 2008; 57: 121-34.
[18] Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-138.
[19] Chakir J, Shannon J, Molet S et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[20] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[21] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[22] Lu YJ, Gross J, Bogaert D,et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization[J]. PLoS Pathog. 2008;4(9):e1000159.
[23] Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates[J]. N Engl J Med. 2007;357(15):1487-1495.
[1] Bullens DM, Truyen E, Coteur L,et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?[J].Respir Res. 2006;7:135-143.
[2] Oboki K, Ohno T, Saito H et al. Th17 and allergy[J]. Allergol Int. 2008;57: 121-34.
[3] Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblaststo produce cytokines[J]. J Allergy Clin Immunol. 2001;108:430-438.
[4] Chakir J, Shannon J, Molet S et al. Airway remodelingassociated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression[J]. J Allergy Clin Immunol. 2003;111:1293-1298.
[5] Sun YC, Zhou QT, Yao WZ. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma[J]. Chin Med J. 2005;118:953-956.
[6] Moffatt MF.Genes in asthma: new genes and new ways[J].Curr Opin Allergy Clin Immunol. 2008;8(5):411-417.
[7] Silvia Schnyder-Candrian, Dieudonnée Togbe, Isabelle Couillin, et al.Interleukin-17 is a negative regulator of established allergic asthma [J].J E M. 2006;203(12):2715-2725.
[8] Ke Y, Liu K, Huang GQ, et al. Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol. 2009; 182(5):3183-3190.
[9] Arisawa T, Tahara T, Shibata T et al.The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis[J]. J Clin Immunol. 2008 ;28(1):44-49.
[10] Nordang GB, Viken MK, Hollis-Moffatt JE,et al.Association analysis of the interleukin 17A gene in Caucasian rheumatoid arthritis patients from Norway and New Zealand[J]. Rheumatology (Oxford). 2009;48(4):367-370.
[11] Wang JY, Shyur SD, Wang WH,et al. The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population[J]. Allergy. 2009 Feb 5. [Epub ahead of print]
[12] Singh AM, Moore PE, Gern JE, et al. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation[J]. Am J Respir Crit Care Med. 2007;175(2):108-119
[13] Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates[J]. N Engl J Med. 2007;357(15):1487-1495.
[14] Lu YJ, Gross J, Bogaert D,et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization[J]. PLoS Pathog. 2008;4(9):e1000159.
[1] Linden A,Laan M,Anderson GP.Neutrophils,interleukin-17A and lung disease[J].Eur Respir J,2005,25(1):159-172.
[2] Alphonse MP,Saffar AS,Shan L,et al.Regulation of the high affinity IgE receptor (Fc epsilonRI) in human neutrophils:role of seasonal allergen exposure and Th-2 cytokines[J].PLoS ONE,2008,3(4):e1921.
[3] Holgate ST,Polosa R.The mechanisms,diagnosis,and management of severe asthma in adults[J].Lancet,2006,368(9537):780-793.
[4]罗征秀,肖玲,刘恩梅,等.哮喘儿童不同时期痰液细胞的变化及意义[J].临床儿科杂志,2005,23(09):615-617.
[5] Douwes J,Gibson P,Pekkanen J,et al.Non-eosinophilic asthma:importance and possible mechanisms[J].Thorax,2002,57(7):643-648.
[6] Zhou L,Lopes JE,Chong MM,et al.TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function[J].Nature,2008,453(7192):236-240.
[7] Bettelli E,Carrier Y,Gao W,et al.Reciprocal developmental pathways for the generation of pathogenic effect or TH17 and regulatory T cells[J].Nature,2006,441(7090):235-238.
[8] Xu L,Kitani A,Fuss I,et al.Cutting Edge: Regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta[J].J Immunol,2007,178(11):6725-6729.
[9] Harrington LE,Hatton RD,Mangan PR,et al.Interleukin 17-producing CD4+ effectorT cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J].Nat Immunol,2005,6(11):1123-1132.
[10] Peter W.Hellings,Ahmad Kasran,Zhanju Liu,et al.Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma[J].Am J Respir Cell Mol Biol,2003,28(1):42-50.
[11] Pichavant M,Charbonnier AS,Taront S,et al.Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment[J].J Allergy Clin Immunol,2005,115(4):771-778.
[12] He R,Oyoshi MK,Jin H,et al.Epicutaneous antigen exposure induces a Th17response that drives airway inflammation after inhalation challenge[J].Proc Natl Acad Sci U S A,2007,104(40):15817-15822.
[13] Schnyder-Candrian S,Togbe D,Couillin I,et al.Interleukin-17 is a negative regulator of established allergic asthma[J].J Exp Med,2006,203(12):2715-2725.
[14] Cheung PF,Wong CK,Lam CW.Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A,IL-17F,and IL-23:implication for Th17 lymphocytes-mediated allergic inflammation[J].J Immunol,2008,180(8):5625-5635.
[15] Sergejeva S,Ivanov S,Lotvall J,et al.Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation[J].Am J Respir Cell Mol Biol,2005,33(3):248-253.
[16] Nakae S,Komiyama Y,Nambu A,et al.Antigen-specific T cell sensitization is impaired in IL-17-deficient mice,causing suppression of allergic cellular and humoral responses[J].Immunity,2002,17(3):375-387.
[17] Ghilardi N,Kljavin N,Chen Q,et al.Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice[J].J Immunol,2004,172(5):2827-2833.
[18] Hashimoto T,Akiyama K,Kobayashi N,et al.Comparison of IL-17 production by helper T cells among atopic and nonatopic asthmatics and control subjects[J].Int Arch Allergy Immunol,2005,137 Suppl 1:51-54.
[19] McKinley L,Alcorn JF,Peterson A,et al.TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice[J].J Immunol,2008,181(6):4089-4097.
[20] Chen Y,Thai P,Zhao YH,et al.Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop[J].J Biol Chem,2003,78(19):17036-17043.
[21] Hashimoto K,Graham BS,Ho SB,et al.Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5[J].Am J Respir Crit Care Med,2004,170(3):306-312.
[22] Kaneko H,Matsui E,Asano T,et al.Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection[J].Pediatr Allergy Immunol,2006,17(5):370-375. 61