摘要
目的:检测初治肺结核患者血浆和痰液IFN-γ、IL-17、TNF-α、IL-8的含量及其mRNA的表达,观察初治肺结核患者血浆和痰液中上述细胞因子的变化及特点、分析相关影响因素、了解宿主抗结核分枝杆菌的免疫机制、探讨其临床应用价值,为揭示结核病的免疫学机制、辅助肺结核的诊断、评估抗结核治疗的疗效提供依据。
方法:受试者为初治继发性肺结核患者44例,正常对照者43例,肺癌患者18例。用ELISA法分别检测三组研究对象的血浆和痰液IFN-γ、TNF-α、IL-8、IL-17的含量;用RT-PCR法分别检测三组研究对象PBMC和痰细胞中IFN-γ、TNF-α、IL-8、IL-17的mRNA表达;正常对照组内用酶联免疫斑点法试验(ELISPOT)判断结核分枝杆菌潜伏感染;用荧光定量PCR法检测肺结核患者痰液中的菌量负荷;对上述检测结果及临床相关因素进行统计分析,对四种细胞因子的诊断价值进行分析。
结果:
1.正常对照组血浆和痰液IFN-γ含量相接近(P>0.05),而血浆IL-17、TNF-α、IL-8含量均明显高于痰液,有统计学差异(P<0.01)。此外,其PBMC、痰细胞中IFN-γ、IL-17、IL-8的mRNA表达水平相接近(P>0.05),而PBMC中TNF-α的mRNA表达水平明显高于痰细胞,有统计学差异(P<0.05)。
2.与正常对照相比,肺结核患者血浆IFN-γ、IL-8含量增高,IL-17、TNF-α的含量降低;痰液IFN-γ含量降低,IL-17、TNF-α、IL-8含量增高;此外,肺结核患者痰液中IL-17、TNF-α含量高于血浆,而IFN-γ、IL-8含量则低于血浆,均有统计学差异(P<0.05或0.01)。
3.影响因素分析:(1)在正常对照组中,潜伏感染组和健康组血浆和痰液中IFN-γ、IL-17、TNF-α、IL-8四种细胞因子含量均相接近(P>0.05)。(2)肺结核患者PBMC中仅IFN-γ、IL-17的mRNA表达高于正常对照组(P<0.05),TNF-α、IL-8的mRNA表达与正常对照组相接近(P>0.05);肺结核患者痰细胞中四种细胞因子的mRNA表达与正常对照组相接近(P>0.05)。肺结核患者痰细胞和PBMC中四种细胞因子的mRNA表达相接近,无统计学差异(P>0.05)。(3)血浆IFN-γ(r=0.843)和IL-8(r=0.861)与菌量负荷呈正相关,血浆中IL-17(r=-0.816)、TNF-α(r=-0.788)与菌量负荷呈负相关(P<0.01);痰液IFN-γ(r=-0.893)与菌量负荷呈负相关(P<0.01),痰液IL-17、TNF-α、IL-8含量与菌量负荷呈正相关(r分别为0.756,0.631,0.889)(P<0.01)。(4)具有空洞病变的患者血浆和痰液四种细胞因子含量与无空洞的肺结核患者相接近(P >0.05)。(5)外周血淋巴细胞降低的患者痰液中IFN-γ、IL-8含量低于淋巴细胞正常的患者(P<0.01或0.05),而痰液中IL-17、TNF-α以及血浆中四种细胞因子则与淋巴细胞正常的患者相接近(P>0.05)。(6)抗结核治疗两周后,肺结核患者血浆IL-17、TNF-α含量增高,IL-8含量降低,有统计学意义(P<0.05);但血浆IFN-γ和痰液四种细胞因子含量无明显变化(P>0.05)。4.与肺癌患者相比,肺结核患者血浆IFN-γ、IL-8含量增高,IL-17、TNF-α的含量降低(P<0.01或P<0.05),痰液IFN-γ含量降低,IL-17、TNF-α含量增高(P<0.01或P<0.05);IL-8含量在两组间无统计学差异(P>0.05)。ROC曲线分析显示血浆和痰液IFN-γ、IL-17、TNF-α、IL-8含量的曲线下面积(AUC)在0.778~0.958之间(P<0.01),均为有效的诊断指标,其诊断的敏感度均大于68%,特异性均大于66%,诊断正确率均大于76%,其中,痰液TNF-α的敏感度最高,为90%;痰液IL-17的特异度最高,为97%;痰液IL-17的诊断正确率最高,为93%。各细胞因子血浆、痰液指标联合诊断可提高诊断的敏感度和特异性。
结论:
1.正常对照者代表全身免疫状态的血浆中IFN-γ和代表局部免疫状态的痰液中IFN-γ保持一致。然而,正常对照者血浆和痰液IL-17、TNF-α、IL-8含量的差异显示及其所参与的局部免疫水平低于全身免疫水平。
2.IFN-γ、IL-17、TNF-α和IL-8与结核病的发生、发展密切相关。其中,肺结核患者血浆IFN-γ含量增高所介导的全身特异性免疫应答增强很难弥补其血浆TNF-α和IL-17降低所导致的相关特异性免疫应答降低,也很难拮抗IL-8增高所导致的免疫损伤。肺结核患者痰液IL-17、TNF-α和IL-8的增高、IFN-γ的降低可能既参与对巨噬细胞活化的抑制也参与免疫损伤的介导,与感染局部病变的形成密切相关。
3.肺结核患者血浆和痰液IFN-γ、IL-17、TNF-α和IL-8的水平受多种因素的影响。其中,血浆中IFN-γ和IL-8 mRNA的高表达与其血浆含量增高相关;菌量负荷对血浆IFN-γ、IL-8的升高以及IL-17、TNF-α的降低有影响,菌量负荷对痰液IFN-γ的降低以及IL-17、IL-8、TNF-α的升高有影响;低水平的淋巴细胞对痰液中IL-8的降低和IFN-γ的增高有一定的影响;抗结核治疗可使患者血浆细胞因子水平趋于正常。而结核分枝杆菌潜伏感染对血浆和痰液中四种细胞因子无明显影响,在空洞的形成中也未见四种细胞因子的显著作用。
4.肺结核患者血浆和痰液IFN-γ、IL-17、TNF-α和IL-8的检测具有一定的临床意义。其治疗前后血浆含量的改变提示动态监测或观察血浆中四种细胞因子的含量可早期评估抗结核治疗的疗效。应用ROC曲线所得到的四种细胞因子的界限值可作为肺结核、特别是菌阴肺结核的辅助诊断指标。
Object: to assess the contents of interferon-gamma(IFN-γ), Tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), interleukin-17 (IL-17) in the plasma and sputum of pulmonary tuberculosis patients with initial treatment, and the messenger RNA (mRNA) expression of these cytokines in patients with pulmonary tuberculosis(PTB); to observe the variations and features of these cytokines; to analyze the relevant influencing factors; to understand the immunologic mechanism of the anti-tuberculosis process; to estimate the value of the cytokines in clinical application; finally to provide the basis of the prehension of the immunological mechanisms of PTB, the auxiliary tuberculosis diagnosis, and the evaluation for the efficacy of anti-TB treatment.
Method: The subjects were 44 patients with secondary pulmonary tuberculosis initially treated, and there were 43 normal controls and 18 lung cancer patients as control groups. To detect the levels of IFN-γ, IL-17, TNF-αand IL-8 in plasma and sputum of the three target groups with ELISA; to check out the expression of the mRNA in PBMC and cells in the sputum of the three groups by RT-PCR; in the normal control group, to distinguish the latent tuberculosis infection(LTBI) by Enzyme-Linked Immune spot (ELISPOT)assay; to check out the mycobacterial load in sputum of the patients with Fluorescent Quantitation Polymerase Chain Reaction(FQ-PCR); Statistical analysis was performed to analyze the results and the relevant factors, and the diagnostic value of the four cytokines were also analyzed.
Result:
1. In the normal control group, IFN-γlevels in Plasma and sputum was similar (P>0.05), while plasma IL-17, TNF-α, IL-8 levels were significantly higher than those in sputum (P<0.01). In addition, the expression of the mRNA in PBMC and in sputum cells of IFN-γ, IL-17, IL-8 were close (P>0.05), the mRNA expression of TNF-αin PBMC was significantly higher than that of sputum cells (P<0.05).
2. Comparing with the normal control group, levels of IFN-γ、IL-8 in plasma of pulmonary tuberculosis patients were higher and levels of IL-17, TNF-αin plasma were lower; levels of IFN-γin sputum were lower and levels of IL-17、TNF-α、IL-8 in sputum of pulmonary tuberculosis patients were higher. In the pulmonary tuberculosis group, comparing with the levels in plasma, levels of IL-17 and TNF-αin sputum were higher and levels of IFN-γand IL-8 in sputum were lower(P<0.01 or P<0.05).
3. Influencing factors: (1) In the normal control group, The contents of the four cytokines IFN-γ, IL-17, TNF-α, IL-8 in plasma and sputum from the LTBI group were closed to that of the healthy groups(P>0.05). (2)only the expression of the mRNA of IFN-γ, IL-17in PBMC from PTB patients were higher than those in the normal control group (P <0.05), the expression of the mRNA of TNF-α, IL-8 in PTB patients were similar to those in the normal control group (P> 0.05).(3) The contents of IFN-γ(r=0.843)and IL-8(r=0.861) in plasma had a positive correlation with the mycobacteria level, the plasma contents of TNF-α(r=-0.788) and IL-17(r=-0.816) had a negative correlation with the mycobacteria level (P<0.01); The contents of IFN-γ(r=-0.893) in sputum had a negative correlation with the mycobacteria level, the sputum TNF-α、IL-8、IL-17 contents had a positive correlation with the mycobacterial level, (r values was 0.631,0.889,0.756, respectively)(P<0.01).(4) The levels of the four cytokines in plasma and sputum from the PTB group with cavitation were close to those without it(P>0.05).(5) The contents of IFN-γand IL-8 in the sputum of those patients whose peripheral blood lymphocyte counts were lower, were lower than the group whose peripheral blood lymphocyte counts was normal(P<0.01 and P<0.05 respectively), while the contents of TNF-α、IL-17 in sputum carried no difference between the two groups(P>0.05).(6) For the PTB patients, two weeks after the treatment, the contents of the TNF-αand IL-17 in plasma were higher and the contents of the IL-8 in plasma were lower than before, which carried a statistical difference(P<0.05). The contents of the IFN-γin the plasma and the four cytokines in sputum were similar before and after the treatment(P>0.05).
4. Comparing with the lung cancer group, the levels of IFN-γ, IL-8 in the plasma of PTB patients were higher, and those of IL-17 and TNF-αwere lower(P<0.01 or P<0.05); the level of IFN-αin their sputum was lower, while levels of IL-17 and TNF-αin their sputum were higher(P<0.01 or P<0.05); the contents of IL-8 in sputum carried no statistical difference between these two groups(P>0.05). Receiver operating characteristic curve (ROC curve) analysis suggested that when the contents of IFN-γ, TNF-α, IL-8 and IL-17 in plasma and sputum were transformed into the area under the curve (AUC) which were 0.778~0.958, it could be an operative diagnosis index(P<0.01). The sensitivities were all above 68%, specificities were all above 66% and accuracies were all above 76%. Among them, the sensitivity of sputum TNF-αwas the highest, 90%; IL-17 in sputum carried the highest specificity, 97%; IL-17 in sputum also carried the highest diagnostic accuracy, which was 93%. The combination indexes of the cytokines in plasma and sputum could improve the sensitivity and specificity of a diagnosis.
Conclusion:
1. In the normal control group, The level of IFN-γin plasma which represents the general immunity status is consistent with that in sputum that represents the local immunity status. However, differences between the levels of IL-17, TNF-α, IL-8 in plasma and in sputum suggested that their participation in the local immunity is lower than that in the systemic immunity.
2. IFN-γ, IL-17,TNF-αand IL-8 were closely related to the incidence and the development of tuberculosis. Among them, the increase of specific immunity which resulted from the increasing level of IFN-γin the plasma of PTB patients can hardly compensate for the reducing level of some specific immunity resulting from the lessening level of TNF-αand IL-17. And it is also difficult to antagonize the immune damage caused by the increasing level of IL-8.The increasing levels of IL-17、TNF-αand IL-8 in the sputum of PTB patients, the reducing level of IFN-γare closely related to the local lesion formation in an infection site caused by Both inhibition of the activation of macrophages and mediation of the immune injury.
3. The levels of IFN-γ、IL-17、TNF-αand IL-8 in plasma and in sputum of the patients with PTB were affected by many factors. Among them, IFN-γand IL-8’s high expressions of the mRNA in plasma was in correlation with the increasing level of plasma. Bacterial counts carried an influence on the increasing levels of IFN-γ、IL-8 in plasma and the reducing levels of IL-17、TNF-αin plasma, bacterial counts affected the reduction of IFN-γand the increase of IL-17,IL-8, TNF-αin sputum. Low levels of lymphocytes had a certain extent to the reducing level of IL-8 and the increase of IFN-γin sputum. Anti-tuberculosis treatment in patients can make the plasma cytokine levels to be nearly normal. The latent Mycobacterium tuberculosis infection had no significant effect on the four cytokines in plasma and sputum, and the prominent role of cytokines had not been seen on cavity formation.
4. Detection of the levels of IFN-γ, IL-17, TNF-αand IL-8 in plasma and sputum in Patients with pulmonary tuberculosis carries some certain clinical significance. The changes of the cytokines levels in plasma before and after treatment indicate that dynamic monitoring or observation the four cytokines levels in plasma may serve as early assessment markers for the efficacy of anti-TB treatment. The cutoff values which we can get from the application of ROC curve can be used as diagnosis indicators for tuberculosis, especially for culture negative pulmonary tuberculosis.
引文
1 Lin Y, Zhang M, Hofman FM, et al. Absence of a prominent Th2 cytokine response in human tuberculosis. Infect Immun, 1996;64 :1351-1356
2 Enarson DE, Rieder HL, Arnadottir T, et al. Management of tuberculosis a guide for low income countries. 5th edn Paris, IUATLD, 2000
3 Ribeiro-Rodrigues R, Resende CT, Johnson JL, Ribeiro F, Palaci M, Sa RT, et al. Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance. Clin Diagn Lab Immun, 2002;9(4):818-823
4 Serbina N, Flynn. Early emergence of CD8+ T cells primed for production of type 1 cytokines in the lungs of Mycobacterium tuberculosis-infected mice. Infect Immun, 1999;67:3980-3988
5 Caruso AM, Serbina N, Kiein E, et al. Mice deficient in CD4+ T cells have only transiently diminished levels of IFN-γ, yet succumb to tuberculosis. J Immunol,1999;162:5407-5416
6 Canaday DH, Ziebold C, Noss EH, et al. Activation of human CD8+αβTCR+ cells by Mycobacterium tuberculosis via an alternate class I MHC antigen-processing pathway. J Immunol, 1999;162:372-379
7 Wang J, Wakeham J, Harkness R, et al. Macrophages are a significant source of type 1 cytokines during mycobacterial infection. J Clin Invest,1999;103:1023-1029
8 Kasahara T, Hooks J J, Dougherty S F, et al. Interleukin-2 mediated immune interferon(IFN-γ) production by human T cells and T cell subsets. J Immunol,1983;130(4):1784-1789
9 Ribera E, Ocana I, Martinez-Vazquez J M, et al. High level of interferon gamma in tuberculous pleural effusion. Chest, 1988;93(2):309-311
10 Hiraki A, Aoe K, Eda R, et al. Comparison of six biological markers for the diagnosis of tuberculous pleuritis. Chest, 2004;125: 987–989
11 Villegas MV, Labrada LA, Saravia NG. Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-γin pleural fluid for the differential diagnosis of pleural tuberculosis. Chest, 2000; 118:1355–1364
12 Shimokata K, Saka H, Musate T, et al. Cytokine content in pleural effusion. Chest,1991;99:1103–1107
13 Aoki Y, Katoh O, Nakanishi Y, et al. A comparison study of IFN-γ, ADA and CA-125 as the diagnostic parameters in tuberculous pleuritis. Respir Med, 1994;88:139–143
14 Villena V, Lopez A, Pozo F, et al. Interferon-γlevels in pleural fluid for diagnosis of tuberculous. Am J Med, 2003;115:365–370
15 Wong CF, Yew WW, Leung SK, et al. Assay of pleural fluid interleukin-6, tumour necrosis factor-αand interferon-γin the diagnosis and outcome correlation of tuberculous effusion. Respir Med, 2003 ;97:1289–1295
16 Sharma SK, Banga A. Diagnostic utility of pleural fluid IFN-γin tuberculosis pleural effusion. J Interferon Cytokine Res, 2004; 24:213–217
17 Gao ZC, Tian RX. Clinical investigation on diagnostic value of interferon-γ, interleukin-12 and adenosine deaminase isoenzyme for tuberculous pleurisy. Chin Med J, 2005;118:234–237
18 Turner J, Corrah T, Sabbally S, et al. A longitudinal study of in vitro IFN-γproduction and cytotoxic T cell responses of tuberculosis patients in the Gambia. Tuberc Lung Dis, 2000;80:161-169
19冯永红,章怿。结核分枝杆菌CE抗原复合物对人单核-巨噬细胞TNF-a产生的影响。同济大学学报(医学版) , 2007;28(2):10-13
20 Zganiacz A, Santosuosso M, Wang J, et al. TNF-alpha is a critical negative regulator of type 1immune activation during intracellular bacterial infect ion. J C l in Invest, 2004;113(3):401-413
21 Mohan VP,Scanga CA,Yu K, et al . Effects of tumor necrosis factor-alphaon host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect Immun, 2001;69:1847-1855
22 Thacker TC,Palmer MV,Waters WR, et a1 . Associations between cytokine gene expression and pathology in Mycobacterium bovis infected cattle. Vet Immunol Immunopathol,2007;119(3-4):204-213
23唐神结,肖和平,范以虎,等。肺结核患者血清前炎细胞因子及其受体的变化。中华结核和呼吸杂志,2002;25:325-329
24 Baggiolini M, Walz A, Kunkel L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest,1989;84:1045-1049
25 Larsen C A, Anderson A O, Appells E, et al. The neutrophil-activating protein(NAP-1) is also chemotactic for T lymphocytes. Science, 1989;243:1464-1466
26 Yoshimura T, Matsushima K, Tanaka EA, et al. Puridication of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci,1987;84:9233-9237
27 Strieter R M, Kunkel S L, Showell H J, et al. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF alpha, LPS, and IL-1 beta. Science, 1989;243:1467-1469
28 Brennan P J, Hunter S W, Mcneil M, et al. Reappraisal of the chemistry of mycobacterial cell walls, with a view to understanding the roles of individual entities in disease processes In Microbial determinants of virulence and host response. American Society for Microbiology, 1990; 55-75
29 Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol, 2007;8:967-974
30 Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med, 2006;203:2271-2279
31 Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature, 2007;448:484-487
32 Burgler S, Ouaked N, Bassin C, Differentiation and functional analysis of human T(H)17 cells. J Allergy Clin Immunol, 2009;123:588-595
33 Dragon S, Saffar AS, Shan L, et al. IL-17 attenuates the anti-apoptotic effects of GM-CSF in human neutrophils. Mol Immunol, 2008;45:160-168
34 Van der Vliet GM, Schepers P , Schukkink RA , et al. Assessment of mycobacterial viability by RNA amplification. Antimicrob Angents Chemother, 1994;38(9):1959-1965
35盛学岐,刘欣,林存智,等。初治肺结核病人强化治疗前后血清IFN-γ和IL-12变化。青岛大学医学院学报,2005;41(2):161-162
36沈云飞,殷凯生,王新宁。肺结核与肺癌患者血IL-12、IFN-γ和IL-4的联合检测及意义。江苏医药,2006;32(12):1110-1111
37项杰,章晓联,席淑红,等。结核病人血清IL-17、TNF-α、IFN-γ的检测及其免疫学意义。数理医药学杂志,2009;22(2):149-151
38 Morosini M, Meloni F, Marone Bianco A, et al. The assessment of IFN-gamma and its regulatory cytokines in the plasma and bronchoalveolar lavage fluid of patients with active pulmonary tuberculosis. Int J Tuberc Lung Dis, 2003;7(10):994-1000
39 Vankayalapati R, Wizel B, Weis SE, et al. Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced cytokine production in patients with tuberculosis. Clin Infect Dis, 2003;36(1):24-28
40 Wang X, Barnes PF, Dobos-Elder KM, et al. ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells. J Immunol, 2009;182(6):3668-77
41 Nagabhushanam V, Solache A, Ting L M, et al. Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol,2003;171:4750-4757
42 Marin ND, París SC, Vélez VM, et al. Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis (Edinb), 2010;90(4):252-261
43 Pasquinelli V, Townsend JC, Jurado JO, et al. IFN-gamma production during active tuberculosis is regulated by mechanisms that involve IL-17, SLAM, and CREB. J Infect Dis,2009;199(5):661-665
44 Mustafa T, Phyu S, Nlsen R, et al. Increase expression of FAS ligand on Mycobacterium tuberculosis infected macrophages: a potential novel mechanism of immune evasion by Mycobacterium tuberculosis. Inflammation, 1999; 23:507-520
45 Hirsch CS, Toossi Z, Vanham G, et al. Apoptosis and T cell hyporesponsiveness in pulmonary tuberculosis. J Infect Dis, 1999; 179(4):945-953
46 Scriba TJ,Kalsdorf B, Abrahams DA,et a1. Distinct,Specific lL-l7- and IL-22-Producing CD4+T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response.J lmmunol, 2008;180:1962-1970
47 Cruz A, Khader SA, Torrado E, et al. Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol, 2006;177:1416-1420
48 Khadet S,Pearl J,Sakamoto K,et al.IL-23 compensates for the absence 0f IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. J Immunol, 2005;175:788-795
49叶一秀,王巍。老年矽肺结核患者血清肿瘤坏死因子水平的临床观察。标记免疫分析与临床, 2001;8( 4) : 200-201
50王安平,庞玉瑛。肺结核患者纤支镜灌洗液IL-6及IL-8测定的临床意义。安徽医科大学学报,2002;37(2):137-138
51 Takabatake N, Nakamura H, Abe S, et al. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease. Am JRespir Crit Care Med, 2000;161:1179-1184
52李红,唐神结。肺结核患者外周血Sil-2R、TNF-α、IFN-γ、IL-6的检测及意义。中国防痨杂志,2011;33(1):57-60
53叶锦辉,郑勤伟,林琦,等。老年性肺结核患者血浆及支气管灌洗液细胞因子的变化及其临床意义。中山大学学报,2004;25:156-158
54张贤兰,吕江青,林兆原,等。肺结核患者CD4+T淋巴细胞凋亡及相关细胞因子水平的变化。广东医学,2008;29(10):1664-1666
55李志惠,杨永辉。肺结核患者体内细胞因子水平的动态变化与耐药关系的研究。河北医药,2008;30(3):332-333
56王成勇,李翠萍。三种检测方法在菌阴肺结核病诊断中的价值。临床肺科杂志,2007;12(9):933-934
1 Bean AG, Roach DR, Briscoe H, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol,1999;162(6): 3504-3511
2 Song CH, Lee JS, Nam HH, et al. IL-18 production in human pulmonary and pleural tuberculosis. Scand J Immunol, 2002;56(6): 611-618
3 Millington KA, Innes JA, Hackforth S, et a1. Dynamic relationship between IFN-gamma and IL-2 profile of Mycobacterium tuberculosis- specific T cells and antigen load. J Immunol, 2007;178(8): 5217-5226
4 Mansouri D, Adimi P, Mirsaeidi M, et a1. Inherited disorders of the IL-12-IFN-gamma axis in patients with disseminated BCG infection. Eur J Pediatr, 2005;164 (12):753-7571
5 Flgnn JL, Chun J, Triebold K , et al. An essential role for interferon in resistance to mycobacterium tuberculosis infection. J Exp Med, 1993;178(6): 2249-2254
6谈介凡,沈燕雅,范惠娟。结核病患者细胞因子检测及其保护性免疫机制研究。中华检验医学杂志,2006;29(7):612-614
7 Laing KJ, Secombes CJ. Chemokines. Dev Com Immunol,2004;28:443-460
8 Ribeiro-Rodrigues R, Resende CT, Johnson JL, et al. Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance. Clin Diagn Lab Immun, 2002;9(4):818-823
9 Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol, 2007;8:967-974
10 Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med, 2006;203:2271-2279
11 Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature, 2007;448:484-487
12 Khader S,Bell G, Pearl J,et a1.IL-23 and IL-17 in establishment of protective pulmonary CD4+T cell responses upon vaccination and during Mycobacterium tuberculosis challenge.Nat Immunol, 2007;8:369-377
13 Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature, 2007;445:648-651
14 Umemura M,Yahagi A,Hamada S,et a1.IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection.J Immunol,2007;178:3786-3796
15 Scriba TJ,Kalsdorf B, Abrahams DA,et a1. Distinct,Specific lL-l7- and IL-22-Producing CD4+T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response.J lmmunol, 2008;180:1962-1970
16 Okamoto Yoshida Y, Umemura M, Yahagi A,et al. Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol,2010;184:4414-4422
17 Dragon S, Saffar AS, Shan L, et al. IL-17 attenuates the anti-apoptotic effects of GM-CSF in human neutrophils. Mol Immunol, 2008;45:160-168
18 Lasco TM , Yamamoto T , Yoshimura T. Effect of Mycobacterium bovis BCG vaccination on Mycobacterium2specific cellular proliferation and tumor necrosis factor alpha production from distinct guinea pig leukocyte populations. Infect Immun , 2003; 71(12):7035-7042
19 Botha T, Rffel B. Reactivation of latent tuberculosis infection in TNF-deficient mice. J Immunol, 2003;171:3110-3118
20 Algood HM, Lin PL, Yankura D, et al. TNF-influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during mycobacterium tuberculosis infection. J Immunol, 2004 ;172:6846-6858
21 Lee JS, Song GH, Lim JH, et al. The production of tumor necrosis factor-alpha is decreased in peripheral blood mononuclear cells from multidrug-resistant tuberculosis patients following stimulation with the 30-KDa antigen of mycobacterium tuberculosis. Clin Exp Immunol, 2003;132:443-449
22唐神结,肖和平,范以虎,等。肺结核患者血清前炎细胞因子及其受体的变化。中华结核和呼吸杂志,2002;25:325-329
23 Thacker TC, Palmer MV, Waters WR. Associations between cytokine gene expression and pathology in Mycobacterium bovis infected cattle. Vet Immunol Immunopathol, 2007;119(3-4):204-213
24 Price NM, Gilman RH, Uddin J, et al. Unopposed matrix metalloproteinase-9 expression in human tuberculous granuloma and the role of TNF-alpha-dependent monocyte networks. J Immunol, 2003;171(10):5579-5586
25 Sharma SK, Banga A. Diagnostic utility of pleural fluid IFN-γin tuberculosis pleural effusion. J Interferon Cytokine Res,2004;24:213-217
26 Gao ZC, Tian RX. Clinical investigation on diagnostic value of interferon-γ, interleukin-12 and adenosine deaminase isoenzyme for tuberculous pleurisy. Chin Med J, 2005;118:234-237
27 Lockhart E, Green AM, Flynn JL. IL-17 production is dominated byγδT cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol, 2006; 177: 4662-4669
28 Peng MY, Wang ZH, Yao CY, et al. Interleukin 17-producing gamma delta T cells increased in patients with active pulmonary tuberculosis. Cell Mol Immunol,2008; 5:203-208
29 Cruz A, Khader SA, Torrado E, et al. Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol, 2006; 177:1416–1420
30 Cruz A, Fraga A, Fountain J, et al. Pathological role of interleukin17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J Exp Med, 2010;207: 1609-1616
31 Wozniak TM, Saunders BM, Ryan AA,et al. Mycobacterium bovis BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of gamma interferon. Infect Immun, 2010;78:4187-4194