Rα97-116(V108A)鼻粘膜耐受对实验性自身免疫性重症肌无力T-bet及GATA-3的影响
|
摘要
目的:
1.验证鼠源乙酰胆碱受体抗体α亚基97-116 (Rα97-116)肽段诱导建立实验性自身免疫性重症肌无力(EAMG)动物模型的可行性,为对重症肌无力(MG)进行进一步研究提供理想的实验动物模型。
2.验证Rα97-116 (V108A)鼻粘膜耐受对EAMG治疗效果,探索鼻粘膜耐受治疗的临床应用价值。
3.研究Th1、Th2细胞关键转录因子T-bet及GATA-3在正常组,模型组,耐受组中的表达变化规律,探究重症肌无力的发病机制及鼻粘膜耐受治疗理论依据。
方法:
将人工合成的鼠源肽段Rα97-116与完全氟氏佐剂(CFA)充分乳化混匀后多点皮下注入6-8周龄雌性Lewis大鼠,并在第30、60天强化注射与不完全氟氏佐剂(IFA)充分混合后的同等量肽段免疫制备EAMG大鼠模型。正常对照组则皮下注入等量的磷酸盐缓冲液(PBS)。通过称量实验大鼠体重,进行Lennon临床评分,低频重复神经电刺激(RNES)观察电衰减反应,ELISA法检测血清中AchR-Ab(IgG)滴度明确EAMG大鼠是否成模。将成模大鼠随机分为EAMG模型组、鼻粘膜耐受组,于第71-80天经双侧鼻腔分别滴注PBS液和含Rα97-116(V108A)肽段。耐受日起每日记录体重变化,隔日记录两组临床评分,至第95天结束观察。取外周血用RT-PCR检测PBMCs中T-betmRNA及GATA-3mRNA表达强度,ELISA测定血浆中IL-4、IFN-γ表达水平,AchR-Ab(IgG)含量。
结果:
1.造模Lewis大鼠中75%Lennon临床评分>1分,3Hz、5 Hz低频重复神经电刺激电衰减反应D5>10%,血浆中AchR-Ab IgG滴度与正常对照组血清比值>2.1。验证EAMG模型成模率达75%。
2.经Rα97-116(V108A)鼻粘膜耐受治疗后第15天,耐受组大鼠体重较模型组鼠明显增加,差异具有统计学意义(P﹤0.05)。
3.耐受治疗后第10天开始,耐受组、模型组两组平均Lennon临床评分分别为2.1±0.32和1.55±0.27(P<0.05)。
4. Rα97-116(V108A)鼻粘膜耐受治疗后第25天,耐受组AchR-Ab IgG(0.98±0.15)含量明显下降,与模型组(1.29±0.18)比较有统计学意义(P﹤0.05)。
5.模型组IL-4、IFN-γ的表达与正常组相比显著性增高(P<0.05);耐受组经Rα97-116(V108A)耐受治疗后,IL-4、IFN-γ表达水平虽与模型组相比显著降低(P<0.05),但仍较正常组略高(P>0.05)。
6.模型组与正常组比较,T-bet和GATA-3 mRNA的表达显著增强(P<0.05);耐受组经Rα97-116(V108A)治疗后,T-bet和GATA-3 mRNA表达水平与EAMG模型组相比显著减弱(P<0.05)而与正常组相比较,差异无显著性(P>0.05)
结论:
1.人工合成鼠源肽段Rα97-116免疫Lewis大鼠可成功诱导EAMG动物模型,成模率约为75%。该实验动物模型为MG的基础研究提供简便易得的研究动物。
2. Rα97-116(V108A)鼻粘膜耐受能明显改善EAMG大鼠的肌无力症状,为MG的治疗提供新途径。
3. T-bet和GATA-3在MG的免疫发病机制中可能具有关键性的调控作用,鼻黏膜耐受治疗作用可能与其下调T-bet和GATA-3的表达,抑制异常Th1和Th2反应从而下调AChR特异性T和B细胞异常的免疫应答反应有关。
Objective:
1. To verify the feasibility of rat-derived 97-116(Rα97-116) peptide of the acetylcholine receptor( AchR) a-subunit inducing experimental autoimmune myasthenia gravis(EAMG) ,in order to provide a simple and available animal models for futher study of myasthenia gravis (MG.).
2. To verify the therapeutic efficacy of nasal tolerance with Rα97-116(V108A) on the EAMG and explore the clinical application value of nasal tolerance in MG.
3. To explore the expression changes of T-bet and GATA-3 during normal control group,EAMG group,nasal tolerance group and the pathogenesis of MG as well as the theoretical basis of nasal tolerance .
Methods:
Female Lewis rats(6-8 weeks) were injected subcutaneously at four spots with the synthetic peptide Rα97-116 in complete Freund's adjuvant(CFA) and boosted on day 30 and 60 with the same peptide in incomplete Freund's adjuvant(IFA) to iduce rat models of EAMG , or only with phosphate buffer saline(PBS) in control group. Clinical manifestation was evaluated by measurement of body weight and Lennon clinical score. Disease was further confirmed by 3、5 Hz repetitive nerve stimulation (RNS) for positive decremental response and ELISA for sera AchR-Ab(IgG) titers. Modeling Lewis rats were divided into EAMG group and nasal tolerance group , and then PBS and Rα97-116(V108A) was respectively droped in bilasteral nasal cavity on days 71 to 80 once daily , Clinial Lennon score and body weight were evaluated for 24 days since nasal administration. All experiment rats were sacrificed on day 95. The expression levels of transcription factor T-bet/GATA-3mRNA in peripheral blood mononuclear cells(PBMCs) were measured by reverse transcription polymerase chain reaction(RT-PCR).IL-4、IFN-γ、AchR-Ab(IgG) in plasma were detected by ELISA.
Results:
1. Signs of EAMG occurred in 75% of Lewis rats ,which was confirmed by the Lennon clinical score>1 grade, the positive decremental response D5 >10% of 3、5 Hz RNS and the ratio >2.1 of the plasma AchR-Ab(IgG) titers to the normal control group. The achievement ratio of EAMG model was 75%.
2. The 15th day after Lewis rats receiving nasal tolerance with Rα97-116(V108A) , the body weight of Lewis rats in the nasal tolerance group were increased significantly compared with the EAMG group(P﹤0.05).
3. The 10th day after Lewis rats received nasal tolerance with Rα97-116(V108A), average clinical score of nasal tolerance group was significant better than EAMG group (P<0.05).
4. Compared with the EAMG group , the amount of anti-AChR IgG in nasal tolerance group decreased (P<0.05) after the 25th day nasal tolerance with Rα97-116(V108A).
5. The expression levels of IL-4 and IFN-γin EAMG group were much higher than those in normal control group (P<0.05);while IL-4 and IFN-γexpression were obviously decreased after nasal tolerance with Rα97-116(V108A) (P<0.05),there were not significant difference between nasal tolerance group and control group(P>0.05).
6. The expression levels of T-bet/GATA-3 mRNA in EAMG group were much higher than those in control group (P<0.05);while T-bet/GATA-3 mRNA expression were obviously decreased after nasal tolerance with Rα97-116(V108A) (P<0.05),there were not significant difference between nasal tolerance group and control group (P>0.05).
Conclusions:
1. Immunization with the synthetic Rα97-116 peptide could induce EAMG in Lewis rats .The achievement ratio of EAMG model was 75% . This animal models provided a simple and available research materials for MG.
2. Nasal tolerance with Rα97-116(V108A) could ameliorate muscular weakness and improve related Lab indexes of EAMG rats, which will provide a new way of treament for MG.
3. T-bet and GATA-3 may play a critical role in pathogenesis of MG, nasal tolerance with Rα97-116(V108A) could surpress ongoing EAMG, which may be related to the decrease of T-bet/GATA-3 expression and downregulation of AChR-specific B-cell responses and AChR-reactive T-cell function.
1.验证鼠源乙酰胆碱受体抗体α亚基97-116 (Rα97-116)肽段诱导建立实验性自身免疫性重症肌无力(EAMG)动物模型的可行性,为对重症肌无力(MG)进行进一步研究提供理想的实验动物模型。
2.验证Rα97-116 (V108A)鼻粘膜耐受对EAMG治疗效果,探索鼻粘膜耐受治疗的临床应用价值。
3.研究Th1、Th2细胞关键转录因子T-bet及GATA-3在正常组,模型组,耐受组中的表达变化规律,探究重症肌无力的发病机制及鼻粘膜耐受治疗理论依据。
方法:
将人工合成的鼠源肽段Rα97-116与完全氟氏佐剂(CFA)充分乳化混匀后多点皮下注入6-8周龄雌性Lewis大鼠,并在第30、60天强化注射与不完全氟氏佐剂(IFA)充分混合后的同等量肽段免疫制备EAMG大鼠模型。正常对照组则皮下注入等量的磷酸盐缓冲液(PBS)。通过称量实验大鼠体重,进行Lennon临床评分,低频重复神经电刺激(RNES)观察电衰减反应,ELISA法检测血清中AchR-Ab(IgG)滴度明确EAMG大鼠是否成模。将成模大鼠随机分为EAMG模型组、鼻粘膜耐受组,于第71-80天经双侧鼻腔分别滴注PBS液和含Rα97-116(V108A)肽段。耐受日起每日记录体重变化,隔日记录两组临床评分,至第95天结束观察。取外周血用RT-PCR检测PBMCs中T-betmRNA及GATA-3mRNA表达强度,ELISA测定血浆中IL-4、IFN-γ表达水平,AchR-Ab(IgG)含量。
结果:
1.造模Lewis大鼠中75%Lennon临床评分>1分,3Hz、5 Hz低频重复神经电刺激电衰减反应D5>10%,血浆中AchR-Ab IgG滴度与正常对照组血清比值>2.1。验证EAMG模型成模率达75%。
2.经Rα97-116(V108A)鼻粘膜耐受治疗后第15天,耐受组大鼠体重较模型组鼠明显增加,差异具有统计学意义(P﹤0.05)。
3.耐受治疗后第10天开始,耐受组、模型组两组平均Lennon临床评分分别为2.1±0.32和1.55±0.27(P<0.05)。
4. Rα97-116(V108A)鼻粘膜耐受治疗后第25天,耐受组AchR-Ab IgG(0.98±0.15)含量明显下降,与模型组(1.29±0.18)比较有统计学意义(P﹤0.05)。
5.模型组IL-4、IFN-γ的表达与正常组相比显著性增高(P<0.05);耐受组经Rα97-116(V108A)耐受治疗后,IL-4、IFN-γ表达水平虽与模型组相比显著降低(P<0.05),但仍较正常组略高(P>0.05)。
6.模型组与正常组比较,T-bet和GATA-3 mRNA的表达显著增强(P<0.05);耐受组经Rα97-116(V108A)治疗后,T-bet和GATA-3 mRNA表达水平与EAMG模型组相比显著减弱(P<0.05)而与正常组相比较,差异无显著性(P>0.05)
结论:
1.人工合成鼠源肽段Rα97-116免疫Lewis大鼠可成功诱导EAMG动物模型,成模率约为75%。该实验动物模型为MG的基础研究提供简便易得的研究动物。
2. Rα97-116(V108A)鼻粘膜耐受能明显改善EAMG大鼠的肌无力症状,为MG的治疗提供新途径。
3. T-bet和GATA-3在MG的免疫发病机制中可能具有关键性的调控作用,鼻黏膜耐受治疗作用可能与其下调T-bet和GATA-3的表达,抑制异常Th1和Th2反应从而下调AChR特异性T和B细胞异常的免疫应答反应有关。
Objective:
1. To verify the feasibility of rat-derived 97-116(Rα97-116) peptide of the acetylcholine receptor( AchR) a-subunit inducing experimental autoimmune myasthenia gravis(EAMG) ,in order to provide a simple and available animal models for futher study of myasthenia gravis (MG.).
2. To verify the therapeutic efficacy of nasal tolerance with Rα97-116(V108A) on the EAMG and explore the clinical application value of nasal tolerance in MG.
3. To explore the expression changes of T-bet and GATA-3 during normal control group,EAMG group,nasal tolerance group and the pathogenesis of MG as well as the theoretical basis of nasal tolerance .
Methods:
Female Lewis rats(6-8 weeks) were injected subcutaneously at four spots with the synthetic peptide Rα97-116 in complete Freund's adjuvant(CFA) and boosted on day 30 and 60 with the same peptide in incomplete Freund's adjuvant(IFA) to iduce rat models of EAMG , or only with phosphate buffer saline(PBS) in control group. Clinical manifestation was evaluated by measurement of body weight and Lennon clinical score. Disease was further confirmed by 3、5 Hz repetitive nerve stimulation (RNS) for positive decremental response and ELISA for sera AchR-Ab(IgG) titers. Modeling Lewis rats were divided into EAMG group and nasal tolerance group , and then PBS and Rα97-116(V108A) was respectively droped in bilasteral nasal cavity on days 71 to 80 once daily , Clinial Lennon score and body weight were evaluated for 24 days since nasal administration. All experiment rats were sacrificed on day 95. The expression levels of transcription factor T-bet/GATA-3mRNA in peripheral blood mononuclear cells(PBMCs) were measured by reverse transcription polymerase chain reaction(RT-PCR).IL-4、IFN-γ、AchR-Ab(IgG) in plasma were detected by ELISA.
Results:
1. Signs of EAMG occurred in 75% of Lewis rats ,which was confirmed by the Lennon clinical score>1 grade, the positive decremental response D5 >10% of 3、5 Hz RNS and the ratio >2.1 of the plasma AchR-Ab(IgG) titers to the normal control group. The achievement ratio of EAMG model was 75%.
2. The 15th day after Lewis rats receiving nasal tolerance with Rα97-116(V108A) , the body weight of Lewis rats in the nasal tolerance group were increased significantly compared with the EAMG group(P﹤0.05).
3. The 10th day after Lewis rats received nasal tolerance with Rα97-116(V108A), average clinical score of nasal tolerance group was significant better than EAMG group (P<0.05).
4. Compared with the EAMG group , the amount of anti-AChR IgG in nasal tolerance group decreased (P<0.05) after the 25th day nasal tolerance with Rα97-116(V108A).
5. The expression levels of IL-4 and IFN-γin EAMG group were much higher than those in normal control group (P<0.05);while IL-4 and IFN-γexpression were obviously decreased after nasal tolerance with Rα97-116(V108A) (P<0.05),there were not significant difference between nasal tolerance group and control group(P>0.05).
6. The expression levels of T-bet/GATA-3 mRNA in EAMG group were much higher than those in control group (P<0.05);while T-bet/GATA-3 mRNA expression were obviously decreased after nasal tolerance with Rα97-116(V108A) (P<0.05),there were not significant difference between nasal tolerance group and control group (P>0.05).
Conclusions:
1. Immunization with the synthetic Rα97-116 peptide could induce EAMG in Lewis rats .The achievement ratio of EAMG model was 75% . This animal models provided a simple and available research materials for MG.
2. Nasal tolerance with Rα97-116(V108A) could ameliorate muscular weakness and improve related Lab indexes of EAMG rats, which will provide a new way of treament for MG.
3. T-bet and GATA-3 may play a critical role in pathogenesis of MG, nasal tolerance with Rα97-116(V108A) could surpress ongoing EAMG, which may be related to the decrease of T-bet/GATA-3 expression and downregulation of AChR-specific B-cell responses and AChR-reactive T-cell function.
引文
1. Tzartos SJ, Barkas T, Cung MT,et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor[J]. Immunol,Rev,1998 ,163:89-120.
2. Penn AS,Chang HW,Loveace RE,et al.Antibodies to acetylcholine receptors in rabbits: immunochemical and electrophysiological studies[J].Ann N Y Acad Sci,1976,274:354-7.
3. Barchan D, Souroujon MC, Im SH,et al. Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha-subunit[J]. Proc Natl Acad Sci U S A, 1999,96(14):8086-91.
4. Maiti PK ,Feferman T,Im SH et al. Immunosuppression of rat myasthenia gravis by oral administration of a syngeneic acetylcholine receptor fragment[J]. J Neuroimmunol ,2004,152(1-2)112-20.
5. Shi FD,Li H,Wang H et al.Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells[J]. J Immunol, 1999 ,162(10):5757-5763.
6. Mosman TR,Coffman RL,Heterogenerty of Cytokine secretion patterns and functions of helper T cells[J] Adv Immunol,1989,46:111-147.
7. Romagnami S,Human Th1 and Th2 subsets:doubt no more[J]. Immunol Today, 1991,12(8):256-257
8. Brown JA, Dorfman DM,Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production[J]. J Immunol, 2003,170:1257-1266.
9. Zheng W,Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells[J] .Cell ,1997 ,89(4):587-596.
10. O’Garra A. Innunology:commit ye heppers[J] Nature 2000,404(6779):719-720.
11. Zhang DH,Yang L,Cohn L,et al ,Inhibition of allergic inflammation in a murine model of asthma by espression of a dominant–negative mutant of GATA-3[J]. Immunity,1999,11:473.
12. Yao D , Zhang X,Wei H,etal Antisense-induced blockage of GATA-3 expression could inhibit Th2 excusion of tumor cells in vitro and vivo[J], Cell Moll Immunol ,2005,2(3):189-196.
13. Avni O, Lee D, Macian F,et al. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes[J].Nat Immunol,2002,3(7): 643-651.
14. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γloci accompany Th1/Th2 differentiation[J]. J Immunol, 2002,169:647-650.
15. Cho JY, Grigura V, Murphy TL,et al.Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-γpromoter[J]. Int Immunol, 2003,15:1149-1160.
16.许文华韩莹莹汪思应,等.鼠源乙酰胆碱受体α亚基97-116肽段免疫Lewis鼠诱导实验性重症肌无力模型[J].中国神经精神疾病杂志,2006,32(2):179-180.
17. Lennon VA, Lindstrom JM, Seybold ME. Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs[J].Exp Med,1975, 141(6): 1365-1375.
18. Juel VC,Massev JM.Myasthenia gravis[J]. Orphanet J Rare Dis,2007 6,2:44.
19. Graus YM,De Baets MH. Myasthenia gravis: an autoimmune response against the acetylcholine receptor[J]. Immunol Res,1993,12(1):78-100.
20. Evmad B.Antibody in myasthenia gravis.Rev Neurol[J].2009,165(2):137-143.
21. Oda K, Korenaga S, Ito Y. Myasthenia gravis: passive transfer to mice of antibody to human and mouse acetylcholine receptor[J]. Neurology,1981,31(3):282-287.
22. Sthoeger Z,Neiman A ,Elbirt D et al. High prevalence of systemic lupus erythematosus in 78 myasthenia gravis patients: a clinical and serologic study[J]. Am J Med Sci,2006,331(1):4-9.
23. Trabelsi L, Charfi N, Triki Ch,et al. Myasthenia gravis and hyperthyroidism: two cases[J]. Ann Endocrinol (Paris),2006,67(3):265-269.
24. Kerkeni S, Marotte H. Miossec P. Improvement with rituximab in a patient with both rheumatoid arthritis and myasthenia gravis[J]. Muscle Nerve, 2008,38(4):1343-1345.
25.杨颖.重症肌无力发病机制的研究现状与展望[J].北京医学,2004,26(5):349-350.
26.唐冰杉.实验性自身免疫性重症肌无力动物模型的研究概况[J].国外医学神经病学神经外科分册[J]. 2002,29(3):265-268.
27. Shenoy M, Goluszko E, Christadoss P. The pathogenic role of acetylcholine receptor alpha chain epitope within alpha 146-162 in the development of experimental autoimmune myasthenia gravis in C57BL6 mice[J]. Clin Immunol Immunopatho,1994,73(3):338-43.
28. Vincent A. Unravelling the pathogenesis of myasthenia gravis[J]. Nat. Rev.Immunol. 2002, 2(10):797-804.
29. Baggi F,Annoni A.Ubiali F et al.immunization with rat,but not Torpedo-derived 97-116 peptide of the AchR alpha-subnuit induces experiment myasthenia gravis in Lewis rat[J] Ann N Y Acad Sci 2003,998:391-394.
30. Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis:Recommendations for clinical research standards[J]. Task Force of the Medical Scientific Advisory Board of theMyasthenia Gravis Foundation of America1[J]. Neurology, 2000,55(1):16-23.
31. Levinson AI, Zheng Y, Gaulton G,et al. Intrathymic expression of neuromuscular acetylcholine receptors and the immunpathogenesis of myasthenia gravis[J]. Immunol Res,2003,27(2-3):399-408.
32. Zheng Y, Wheatley LM, Liu T,et al. Acetylcholine receptor alpha subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-gamma[J]. Clin Immunol,1999,91(2):170-177.
33. Fleury MC,Tranchant C.Myasthenia gravis[J].Rev Prat,2008,58(20):2217-2224.
34.李清芬.特异性免疫应答的特点及机制[M].医学免疫学,2005:241-243.
35. Wang LH,Wang HB,Tian QH.Mechanism of cellular immunity accommodation in prophylactic effects of nasal tolerance with dual analogue on experimental autoimmune myasthenia gravis in Lewis rats[J] Zhonghua Yu Fang Yi Xue Za Zi 2004,38(4):244-247.
36. Dora Barchen, Miriam C.Souroujon,Sin-Hyeog Im,et al. Antigen-specific modulation of. experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor a-subunit[J]. Proc. Natl. Acad. Sci. USA 1999 , 96:8086–8091.
37. Link J.Interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in multiple sclerosis and myasthenia gravis[J]. Acta Neurol Scand Suppl 1994;158:1-58.
38. Wang ZY,Link H,Ljungdahl A et al. Induction of interferon-gamma, interleukin-4, and transforming growth factor-beta in rats orally tolerized against experimental autoimmune myasthenia gravis[J]. Cell Immunol 1994,157(2):353-368.
39. C.-G. MA,G.-X Zhang,B.-G. Xiao.Cellular mRNA expression of interferon-gamma(IFN-γ),IL-4 and transforming growth factor-beta(TGF-β)in rats nasally tolerized against experimental autoimmune myasthenia gravis(EAMG) [J].Cin ExpImmunol 1996,104:509-516.
40. Bian T, Yin K S, Jin S X,et al.Treatment of allergic airway inflammation and hyperresponsiveness by imiquimod modulating transcription factors T-bet and GATA-3[J].Chin Med J (Engl),2006, 119(8):640-648.
41. Szabo SJ, Kim ST, Costa GL, et al, Fathman a novel transcription factor,T-bet, directs Th1 lineage commitment[J] Cell,100:655-669.
42. Dorfman DM, Hwang ES, Shahsafaei A, et al.T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders [J] 2004 Am.J. Clin .Pathol,122:292-297.
43. Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells [J]Science, 2002,295:338-342.
44. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation[J] .Immunity,1998 9: 765-775.
45. Martins GA, Hutchins AS, Reiner SL.. Transcriptional activators of helper T cellfate are required for establishment but not maintenance of signature cytokine expression[J] J.Immunol,2005 ,175:5981-5985.
46. Morrisey EE, IP HS, Lu MM, et al. A zinc finger transcriptionfactor that is expressed in multiple cell lineages derived from lateral mesoderm[J]. Dev Biol 1996,(1770):309-322
47. Yang Z,Lin Gu,Romeo PH,et al. Human GATA- 3 trans-activation,DNA-binding, and nuclear location activities are organized into distinct structural domains[J].Mol Cell Biol,1994 ,14 (3 ):2201-2212.
48. Bettelli E, Sullivan B, Szabo SJ,et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis[J]. J Exp Med. 2004,200:79-87.
49. Nath N,Prasad R,Giri S,et al. T-bet is essential for the progression of experimental autoimmune encephalomyelitis[J].Immunology. 2006,118:384-391.
50. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes[J]. Immunity. 2004,21:719-731.
51. Nath N, Giri S, Prasad R,et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy[J]. J Immunol. 2004,172:1273-1286.
52. Dasgupta S,Roy A,Jana M,et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha[J]. Mol Pharmacol. 2007,72:934-946.
53. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production[J]. Proc Natl Acad Sci U S A. 2002,99: 5545-5550.
54. Chan RW,Lai FM,Li EK,et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis[J].Rheumatology(Oxford) 2006,45:951-957.
55. Nakamura Y,Ghaffar O,Olivenstein R,et al.Gene expression of the GATA-3 transcription factor is increased in atopic asthma[J].J Allergy Clin Immunol, 1999,103: 215-222.
56. Lee CC, Huang HY, Chiang BL. Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness[J]. Mol Ther,2008,16(1): 60-65.
57. Arakawa S,Hatano Y,Katagiri K.Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signalling in peripheral blood mononuclear cells of patients with atopic dermatitis[J].Clin Exp Immunol,2004,135(8):505-510.
58. Kimura J,Takada H,Nomura A,et al. Th1 and Th2 cytokine production is suppression at the level of transcription regulation in Kawasaki diease[J].Clin Exp Immunol,2004,137(2):444-449.
59. Zhou M, Ouyang W. The function role of GATA-3 in Th1 and Th2 differentiation[J]. Immunol Res,2003;28(1):25-37.
60. Yang Y, Ochando JC, Bromberg JS,et al. Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals[J]. Blood, 2007,110(7): 2494-2500.
1. Murphy KM, Reiner SL. The lineage decisions of helper T cells[J]. Nature Rev Immunol.2002,2:933-944.
2. Szabo SJ, Kim ST, Costa GL,et al. A novel transcription factor, T-bet, directs Th1 lineage commitment[J]. Cell.2000,100:655-669.
3. Grogan JL, Mohrs M, Harmon B,et al. Early transcription and silencing of cytokine genesunderlie polarization of T helper cell subsets[J]. Immunity.2001,14:205-215.
4. Mullen AC, High FA, Hutchins AS, et al. Role of T-bet incommitment of TH1 cells before IL-12-dependent selection [J]. Science.2001,292:1907-1910.
5. Afkarian M, Sedy JR, Yang J, et al. T-bet is a STAT1-induced regulator of IL-12R expression in na?ve CD4+ T cells[J]. Nat Immunol.2002,3:549-557.
6. Kikkawa E, Yamashita M, Kimura M, et al. T(h)1/T(h)2 cell differentiation of developing CD4 single-positive thymocytes[J]. Int Immunol.2002,14:943-951.
7. Avni O, Lee D, Macian F,et al. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes[J]. Nat Immunol.2002,3: 643-651.
8. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γloci accompany Th1/Th2 differentiation[J]. J Immunol. 2002,169: 647-650.
9. Chang S, Aune TM. Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells[J]. Proc Natl Acad Sci U S A. 2005,102: 17095-17100.
10. Martins GA, Hutchins AS, Reiner SL. Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression[J]. J Immunol. 2005,175:5981-5985.
11. Cho JY, Grigura V, Murphy TL, Murphy K. Identification of cooperativemonomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-γpromoter[J]. Int Immunol. 2003,15:1149-1160.
12. Shnyreva M, Weaver WM, Blanchette M, et al. Evolutionarily conserved sequence elements that positively regulate IFN-γexpression in T cells[J]. Proc Natl Acad Sci U S A. 2004,101: 12622-12627.
13. Tong Y, Aune T, Boothby M. T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-γpromoter via a conserved T-box half-site[J]. Proc Natl Acad Sci U S A. 2005,102:2034-2039.
14. Mullen AC, Hutchins AS, High FA, et al. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction[J]. Nat Immunol. 2002,3:652-658.
15. Grenningloh R, Kang BY, Ho IC. Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses[J]. J Exp Med. 2005,201:615-626.
16. Hilliard BA, Mason N, Xu L, et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation[J]. J Clin Invest. 2002,110:843-850.
17. Mullen AC, Hutchins AS, Villarino AV, et al. Cell cycle controlling the silencing and functioning of mammalian activators[J]. Curr Biol. 2001,11:1695-1699.
18. Morinobu A, Kanno Y, O'Shea JJ. Discrete roles for histone acetylation in human T helper 1 cell-specific gene expression[J]. J Biol Chem. 2004,279:40640-40646.
19. Smits HH, van Rietschoten JG, Hilkens CM, et al. IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression[J]. Eur J Immunol. 2001,31:1055-1065.
20. Toshiyuki Owaki, Masayuki Asakawa,et al. IL-27 induces Th1 differentiation via p38 MAPK/T-bet-and intercellular adhesion molecule-1/LFA-1 /ERK1/2-dependent pathways[J]. J Immunol.2006,177:7579-7587.
21. Minter LM, Turley DM, Das P, et al. Inhibitors ofγ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21[J].NatImmunol.2005,6:680-688.
22. Quiroga MF, Martinez GJ, Pasquinelli V, et al. Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection[J]. J Immunol. 2004,173:4120-4129.
23. Kumanogoh A, Shikina T, Suzuki K, et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A- deficient mice[J]. Immunity. 2005,22:305-316.
24. Strengell M, Sareneva T, Foster D, et al.IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response[J]. J Immunol. 2002,169: 3600-3605.
25. Patel M, Xu D, Kewin P, et al. Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis[J]. Eur J Immunol. 2005,35: 3581-3590.
26. Chen CH, Seguin-Devaux C, Burke NA, et al. Transforming growth factorβblocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation[J]. J Exp Med. 2003,197:1689-1699.
27. Park IK, Shultz LD, Letterio JJ,et al. TGF-β1 inhibits T-bet induction by IFN-γin murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2domain-containing phosphatase-1[J]. J Immunol. 2005,175:5666-5674.
28. Lin JT, Martin SL, Xia L,et al. TGF-β1 uses distinct mechanisms to inhibit IFN-γexpression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet[J]. J Immunol. 2005,174:5950-5958.
29. Smeltz RB, Chen J, Shevach EM. Transforming growth factor-β1 enhances the interferon-γ-dependent, interleukin-12-independent pathway of T helper 1 cell differentiation. Immunology[J]. 2005,114:484-492.
30. Jones DC, Ding X, Zhang TY, et al. Peroxisome proliferator-activated receptorαnegatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation[J]. J Immunol. 2003,171:196-203.
31. Tanaka Y, So T, Lebedeva S,et al. Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice[J]. Blood. 2005,106: 1286-1295.
32. Szabo SJ, Sullivan BM, Stemmann C,et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γproduction in CD4 and CD8 T cells[J]. Science. 2002,295:338-342.
33. Yin Z, Chen C, Szabo SJ,et al. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γbyγδT cells[J]. J Immunol. 2002,168: 1566-1571.
34. Finotto S, Hausding M, Doganci A, et al. Asthmatic changes in mice lacking T-bet are mediated by IL-13[J]. Int Immunol. 2005,17:993-1007.
35. Sullivan BM, Juedes A, Szabo SJ,et al. Antigen-driven effector CD8 T cell function regulated by T-bet[J]. Proc Natl Acad Sci U S A. 2003,100:15818-15823.
36. Intlekofer AM, Takemoto N, Wherry EJ, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin[J]. Nat Immunol. 2005,6:1236-1244.
37. Hohler T, Reuss E, Adams P, et al. A genetic basis for IFN-γproduction and T-bet expression in humans. J Immunol. 2005; 175:5457-5462.
38. Sundrud MS, Grill SM, Ni D, et al. Genetic reprogramming of primary human T cells reveals functional plasticity in Th cell differentiation[J]. J Immunol. 2003,171:3542-3549.
39. Dorfman DM, Hwang ES, Shahsafaei A,et al. T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders[J]. Am J Clin Pathol. 2004,122:292-297.
40. Harashima A, Matsuo Y, Drexler HG, et al. Transcription factor expression in B-cell precursor-leukemia cell lines: preferential expression of T-bet[J]. Leuk Res. 2005,29:841-848.
41. Durali D, de Goer de Herve MG, Giron-Michel J,et al. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment[J]. Blood. 2003,102:4084-4089.
42. Liu N, Ohnishi N, Ni L,et al. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells[J]. Nat Immunol. 2003,4:687-693.
43. Peng SL, Li J, Lin L,et al. The role of T-bet in B cells[J]. Nat Immunol. 2003,4:1041.
44. Fre′de′rique Larousserie, Pascaline Charlot, Emilie Bardel,et al. Differential effects of IL-27 on human B cell subsets[J]. J Immunol. 2006, 176:5890-5897.
45. Harris DP, Goodrich S, Gerth AJ,et al. Regulation of IFN-γproduction by B effector 1 cells: essential roles for T-bet and the IFN-γreceptor[J]. J Immunol. 2005,1746781-6790.
46. Xu W, Zhang JJ. Stat1-dependent synergistic activation of T-bet for IgG2a production during early stage of B cell activation[J]. J Immunol. 2005,175:7419-7424.
47. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production[J]. Proc Natl Acad Sci U S A. 2002,99: 5545-5550.
48. Yoshimoto T, Okada K, Morishima N, et al. Induction of IgG2a class switching in B cells by IL-27[J]. J Immunol. 2004,173:2479-2485.
49. Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon-γin lymphoid and myeloid cells[J]. Proc Natl Acad Sci U S A. 2001,98: 15137-15142.
50. Lugo-Villarino G, Maldonado-Lopez R, Possemato R,et al.T-bet is required for optimal production of IFN-γand antigen-specific T cell activation by dendritic cells[J]. Proc Natl Acad Sci U S A. 2003,100:7749-7754.
51. Lugo-Villarino G, Ito S, Klinman DM, et al. The adjuvant activity of CpG DNArequires T-bet expression in dendritic cells[J]. Proc Natl Acad Sci U S A. 2005,102: 13248-13253.
52. Townsend MJ, Weinmann AS, Matsuda JL, et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells[J]. Immunity. 2004,20: 477-494.
53. Robbins SH, Tessmer MS, Van Kaer L,et al. Direct effects of T-bet and MHC class I expression, but not STAT1, on peripheral NK cell maturation[J]. Eur J Immunol. 2005,35:757-765.
54. Xiao L,Tan WP,Xiao X,et al. Effect of T-bet on biological functions of mouse macrophage Raw264.7[J].Ai Zheng.2006 ,25:1069-1075.
55. Bettelli E, Sullivan B, Szabo SJ,et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis[J]. J Exp Med. 2004,200:79-87.
56. Nath N,Prasad R,Giri S,et al. T-bet is essential for the progression of experimental autoimmune encephalomyelitis[J].Immunology. 2006,118:384-391.
57. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes[J]. Immunity. 2004,21:719-731.
58. Weaver A, Goncalves da Silva A, Nuttall RK, et al. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization[J]. FASEB J. 2005,19:1668-1670.
59. Nath N, Giri S, Prasad R,et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy[J]. J Immunol. 2004,172:1273-1286.
60. Dasgupta S,Roy A,Jana M,et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha[J]. Mol Pharmacol. 2007,72:934-946.
61. Neurath MF, Weigmann B, Finotto S, et al. The transcription factor T-bet regulatesmucosal T cell activation in experimental colitis and Crohn's disease[J]. J Exp Med. 2002,195:1129-1143.
62. Weigmann B, Nemetz A, Becker C, et al. A critical regulatory role of leucin zipper transcription factor c-Maf in Th1-mediated experimental colitis[J]. J Immunol. 2004,173:3446-3455.
63. Iijima H, Neurath MF, Nagaishi T, et al. Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1[J]. J Exp Med. 2004,199:471-482.
64. Honda K, Nakamura K, Matsui N, et al. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis[J]. Inflamm Bowel Dis. 2005,11:1044-1052.
65. Monteleone G, Monteleone I, Fina D, et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-γproduction in Crohn's disease[J]. Gastroenterology. 2005,128:687-694.
66. Melanitou E, Liu E, Miao D,et al. Absence of the T-bet gene coding for the Th1-related transcription factor does not affect diabetes-associated phenotypes in Balb/c mice[J]. Ann N Y Acad Sci. 2003,1005: 187-191.
67. Juedes AE, Rodrigo E, Togher L,et al.T-bet controls auto-aggressive CD8 lymphocyte responses in type 1 diabetes[J]. J Exp Med. 2004,199:1153-1162.
68. Sasaki Y, Ihara K, Matsuura N, et al. Identification of a novel type 1 diabetes susceptibility gene, T-bet[J]. Hum Genet. 2004,115: 177-184.
69. Wang J, Fathman JW, Lugo-Villarino G, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells[J]. J Clin Invest. 2006,116:414-421.
70. Hultgren OH, Verdrengh M, Tarkowski A. T-box transcriptionfactor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis[J]. Microbes Infect. 2004,6:529-535.
71. Kawashima M, Miossec P. mRNA quantification of T-bet, GATA-3, IFN-γ, andIL-4 shows a defective Th1 immune response in the peripheral blood from rheumatoid arthritis patients: link with disease activity[J]. J Clin Immunol. 2005,25: 209-214.
72. Li B, Yang P, Zhou H, et al. T-bet expression is upregulated in active Behcet's disease[J]. Br J Ophthalmol. 2003,87:1264-1267.
73. Li B, Yang P, Zhou H, et al. Upregulation of T-bet expression in peripheral blood mononuclear cells during Vogt-Koyanagi-Harada diseas[J]e. Br J Ophthalmol. 2005,89:1410-1412.
74. Chan RW,Lai FM,Li EK,et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis[J].Rheumatology(Oxford) 2006,45:951-7.
75. Kimura J, Takada H, Nomura A, et al. Th1 and Th2 cytokine production is suppressed at the level of transcriptional regulation in Kawasaki disease[J]. Clin Exp Immunol. 2004,137: 444-449.
76. Shirota H, Gursel M, Klinman DM. Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-γ-and IL-12-mediated signaling[J].J Immunol. 2004,173:5002-5007.
77. Hwang ES, Szabo SJ, Schwartzberg PL,et al. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science[J]. 2005,307:430-433.
78. Hwang ES, Hong JH, Glimcher LH. IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508[J]. J Exp Med. 2005,202:1289-1300.
79. Mehta DS, Wurster AL, Weinmann AS,et al. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression[J]. Proc Natl Acad Sci U S A. 2005,102: 2016-2021.
80. Usui T, Nishikomori R, Kitani A, et al.GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet[J]. Immunity. 2003,18:415-428.
81. Babu S, Kumaraswami V, Nutman TB. Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes[J]. Infect Immun. 2005,73:3394-3401.
82. Peng SL, Townsend MJ, Hecht JL, White IA, Glimcher LH. T-bet regulates metastasis rate in a murine model of primary prostate cancer[J]. Cancer Res. 2004,64:452-455.
83. Simmons WJ, Koneru M, Mohindru M, et al. Tim-3+T-bet+ tumorspecific Th1 cells colocalize with and inhibit development and growth of murine neoplasms[J]. J Immunol. 2005,174:1405-1415.
84. Dorfman DM, van den Elzen P, Weng AP, et al. Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas[J]. Am J Clin Pathol. 2003,120:866-873.
85. Atayar C, Poppema S, Blokzijl T, et al. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas[J]. Am J Pathol. 2005,166:127-134.
2. Penn AS,Chang HW,Loveace RE,et al.Antibodies to acetylcholine receptors in rabbits: immunochemical and electrophysiological studies[J].Ann N Y Acad Sci,1976,274:354-7.
3. Barchan D, Souroujon MC, Im SH,et al. Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha-subunit[J]. Proc Natl Acad Sci U S A, 1999,96(14):8086-91.
4. Maiti PK ,Feferman T,Im SH et al. Immunosuppression of rat myasthenia gravis by oral administration of a syngeneic acetylcholine receptor fragment[J]. J Neuroimmunol ,2004,152(1-2)112-20.
5. Shi FD,Li H,Wang H et al.Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells[J]. J Immunol, 1999 ,162(10):5757-5763.
6. Mosman TR,Coffman RL,Heterogenerty of Cytokine secretion patterns and functions of helper T cells[J] Adv Immunol,1989,46:111-147.
7. Romagnami S,Human Th1 and Th2 subsets:doubt no more[J]. Immunol Today, 1991,12(8):256-257
8. Brown JA, Dorfman DM,Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production[J]. J Immunol, 2003,170:1257-1266.
9. Zheng W,Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells[J] .Cell ,1997 ,89(4):587-596.
10. O’Garra A. Innunology:commit ye heppers[J] Nature 2000,404(6779):719-720.
11. Zhang DH,Yang L,Cohn L,et al ,Inhibition of allergic inflammation in a murine model of asthma by espression of a dominant–negative mutant of GATA-3[J]. Immunity,1999,11:473.
12. Yao D , Zhang X,Wei H,etal Antisense-induced blockage of GATA-3 expression could inhibit Th2 excusion of tumor cells in vitro and vivo[J], Cell Moll Immunol ,2005,2(3):189-196.
13. Avni O, Lee D, Macian F,et al. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes[J].Nat Immunol,2002,3(7): 643-651.
14. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γloci accompany Th1/Th2 differentiation[J]. J Immunol, 2002,169:647-650.
15. Cho JY, Grigura V, Murphy TL,et al.Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-γpromoter[J]. Int Immunol, 2003,15:1149-1160.
16.许文华韩莹莹汪思应,等.鼠源乙酰胆碱受体α亚基97-116肽段免疫Lewis鼠诱导实验性重症肌无力模型[J].中国神经精神疾病杂志,2006,32(2):179-180.
17. Lennon VA, Lindstrom JM, Seybold ME. Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs[J].Exp Med,1975, 141(6): 1365-1375.
18. Juel VC,Massev JM.Myasthenia gravis[J]. Orphanet J Rare Dis,2007 6,2:44.
19. Graus YM,De Baets MH. Myasthenia gravis: an autoimmune response against the acetylcholine receptor[J]. Immunol Res,1993,12(1):78-100.
20. Evmad B.Antibody in myasthenia gravis.Rev Neurol[J].2009,165(2):137-143.
21. Oda K, Korenaga S, Ito Y. Myasthenia gravis: passive transfer to mice of antibody to human and mouse acetylcholine receptor[J]. Neurology,1981,31(3):282-287.
22. Sthoeger Z,Neiman A ,Elbirt D et al. High prevalence of systemic lupus erythematosus in 78 myasthenia gravis patients: a clinical and serologic study[J]. Am J Med Sci,2006,331(1):4-9.
23. Trabelsi L, Charfi N, Triki Ch,et al. Myasthenia gravis and hyperthyroidism: two cases[J]. Ann Endocrinol (Paris),2006,67(3):265-269.
24. Kerkeni S, Marotte H. Miossec P. Improvement with rituximab in a patient with both rheumatoid arthritis and myasthenia gravis[J]. Muscle Nerve, 2008,38(4):1343-1345.
25.杨颖.重症肌无力发病机制的研究现状与展望[J].北京医学,2004,26(5):349-350.
26.唐冰杉.实验性自身免疫性重症肌无力动物模型的研究概况[J].国外医学神经病学神经外科分册[J]. 2002,29(3):265-268.
27. Shenoy M, Goluszko E, Christadoss P. The pathogenic role of acetylcholine receptor alpha chain epitope within alpha 146-162 in the development of experimental autoimmune myasthenia gravis in C57BL6 mice[J]. Clin Immunol Immunopatho,1994,73(3):338-43.
28. Vincent A. Unravelling the pathogenesis of myasthenia gravis[J]. Nat. Rev.Immunol. 2002, 2(10):797-804.
29. Baggi F,Annoni A.Ubiali F et al.immunization with rat,but not Torpedo-derived 97-116 peptide of the AchR alpha-subnuit induces experiment myasthenia gravis in Lewis rat[J] Ann N Y Acad Sci 2003,998:391-394.
30. Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis:Recommendations for clinical research standards[J]. Task Force of the Medical Scientific Advisory Board of theMyasthenia Gravis Foundation of America1[J]. Neurology, 2000,55(1):16-23.
31. Levinson AI, Zheng Y, Gaulton G,et al. Intrathymic expression of neuromuscular acetylcholine receptors and the immunpathogenesis of myasthenia gravis[J]. Immunol Res,2003,27(2-3):399-408.
32. Zheng Y, Wheatley LM, Liu T,et al. Acetylcholine receptor alpha subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-gamma[J]. Clin Immunol,1999,91(2):170-177.
33. Fleury MC,Tranchant C.Myasthenia gravis[J].Rev Prat,2008,58(20):2217-2224.
34.李清芬.特异性免疫应答的特点及机制[M].医学免疫学,2005:241-243.
35. Wang LH,Wang HB,Tian QH.Mechanism of cellular immunity accommodation in prophylactic effects of nasal tolerance with dual analogue on experimental autoimmune myasthenia gravis in Lewis rats[J] Zhonghua Yu Fang Yi Xue Za Zi 2004,38(4):244-247.
36. Dora Barchen, Miriam C.Souroujon,Sin-Hyeog Im,et al. Antigen-specific modulation of. experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor a-subunit[J]. Proc. Natl. Acad. Sci. USA 1999 , 96:8086–8091.
37. Link J.Interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in multiple sclerosis and myasthenia gravis[J]. Acta Neurol Scand Suppl 1994;158:1-58.
38. Wang ZY,Link H,Ljungdahl A et al. Induction of interferon-gamma, interleukin-4, and transforming growth factor-beta in rats orally tolerized against experimental autoimmune myasthenia gravis[J]. Cell Immunol 1994,157(2):353-368.
39. C.-G. MA,G.-X Zhang,B.-G. Xiao.Cellular mRNA expression of interferon-gamma(IFN-γ),IL-4 and transforming growth factor-beta(TGF-β)in rats nasally tolerized against experimental autoimmune myasthenia gravis(EAMG) [J].Cin ExpImmunol 1996,104:509-516.
40. Bian T, Yin K S, Jin S X,et al.Treatment of allergic airway inflammation and hyperresponsiveness by imiquimod modulating transcription factors T-bet and GATA-3[J].Chin Med J (Engl),2006, 119(8):640-648.
41. Szabo SJ, Kim ST, Costa GL, et al, Fathman a novel transcription factor,T-bet, directs Th1 lineage commitment[J] Cell,100:655-669.
42. Dorfman DM, Hwang ES, Shahsafaei A, et al.T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders [J] 2004 Am.J. Clin .Pathol,122:292-297.
43. Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells [J]Science, 2002,295:338-342.
44. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation[J] .Immunity,1998 9: 765-775.
45. Martins GA, Hutchins AS, Reiner SL.. Transcriptional activators of helper T cellfate are required for establishment but not maintenance of signature cytokine expression[J] J.Immunol,2005 ,175:5981-5985.
46. Morrisey EE, IP HS, Lu MM, et al. A zinc finger transcriptionfactor that is expressed in multiple cell lineages derived from lateral mesoderm[J]. Dev Biol 1996,(1770):309-322
47. Yang Z,Lin Gu,Romeo PH,et al. Human GATA- 3 trans-activation,DNA-binding, and nuclear location activities are organized into distinct structural domains[J].Mol Cell Biol,1994 ,14 (3 ):2201-2212.
48. Bettelli E, Sullivan B, Szabo SJ,et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis[J]. J Exp Med. 2004,200:79-87.
49. Nath N,Prasad R,Giri S,et al. T-bet is essential for the progression of experimental autoimmune encephalomyelitis[J].Immunology. 2006,118:384-391.
50. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes[J]. Immunity. 2004,21:719-731.
51. Nath N, Giri S, Prasad R,et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy[J]. J Immunol. 2004,172:1273-1286.
52. Dasgupta S,Roy A,Jana M,et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha[J]. Mol Pharmacol. 2007,72:934-946.
53. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production[J]. Proc Natl Acad Sci U S A. 2002,99: 5545-5550.
54. Chan RW,Lai FM,Li EK,et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis[J].Rheumatology(Oxford) 2006,45:951-957.
55. Nakamura Y,Ghaffar O,Olivenstein R,et al.Gene expression of the GATA-3 transcription factor is increased in atopic asthma[J].J Allergy Clin Immunol, 1999,103: 215-222.
56. Lee CC, Huang HY, Chiang BL. Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness[J]. Mol Ther,2008,16(1): 60-65.
57. Arakawa S,Hatano Y,Katagiri K.Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signalling in peripheral blood mononuclear cells of patients with atopic dermatitis[J].Clin Exp Immunol,2004,135(8):505-510.
58. Kimura J,Takada H,Nomura A,et al. Th1 and Th2 cytokine production is suppression at the level of transcription regulation in Kawasaki diease[J].Clin Exp Immunol,2004,137(2):444-449.
59. Zhou M, Ouyang W. The function role of GATA-3 in Th1 and Th2 differentiation[J]. Immunol Res,2003;28(1):25-37.
60. Yang Y, Ochando JC, Bromberg JS,et al. Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals[J]. Blood, 2007,110(7): 2494-2500.
1. Murphy KM, Reiner SL. The lineage decisions of helper T cells[J]. Nature Rev Immunol.2002,2:933-944.
2. Szabo SJ, Kim ST, Costa GL,et al. A novel transcription factor, T-bet, directs Th1 lineage commitment[J]. Cell.2000,100:655-669.
3. Grogan JL, Mohrs M, Harmon B,et al. Early transcription and silencing of cytokine genesunderlie polarization of T helper cell subsets[J]. Immunity.2001,14:205-215.
4. Mullen AC, High FA, Hutchins AS, et al. Role of T-bet incommitment of TH1 cells before IL-12-dependent selection [J]. Science.2001,292:1907-1910.
5. Afkarian M, Sedy JR, Yang J, et al. T-bet is a STAT1-induced regulator of IL-12R expression in na?ve CD4+ T cells[J]. Nat Immunol.2002,3:549-557.
6. Kikkawa E, Yamashita M, Kimura M, et al. T(h)1/T(h)2 cell differentiation of developing CD4 single-positive thymocytes[J]. Int Immunol.2002,14:943-951.
7. Avni O, Lee D, Macian F,et al. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes[J]. Nat Immunol.2002,3: 643-651.
8. Fields PE, Kim ST, Flavell RA. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γloci accompany Th1/Th2 differentiation[J]. J Immunol. 2002,169: 647-650.
9. Chang S, Aune TM. Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells[J]. Proc Natl Acad Sci U S A. 2005,102: 17095-17100.
10. Martins GA, Hutchins AS, Reiner SL. Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression[J]. J Immunol. 2005,175:5981-5985.
11. Cho JY, Grigura V, Murphy TL, Murphy K. Identification of cooperativemonomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-γpromoter[J]. Int Immunol. 2003,15:1149-1160.
12. Shnyreva M, Weaver WM, Blanchette M, et al. Evolutionarily conserved sequence elements that positively regulate IFN-γexpression in T cells[J]. Proc Natl Acad Sci U S A. 2004,101: 12622-12627.
13. Tong Y, Aune T, Boothby M. T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-γpromoter via a conserved T-box half-site[J]. Proc Natl Acad Sci U S A. 2005,102:2034-2039.
14. Mullen AC, Hutchins AS, High FA, et al. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction[J]. Nat Immunol. 2002,3:652-658.
15. Grenningloh R, Kang BY, Ho IC. Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses[J]. J Exp Med. 2005,201:615-626.
16. Hilliard BA, Mason N, Xu L, et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation[J]. J Clin Invest. 2002,110:843-850.
17. Mullen AC, Hutchins AS, Villarino AV, et al. Cell cycle controlling the silencing and functioning of mammalian activators[J]. Curr Biol. 2001,11:1695-1699.
18. Morinobu A, Kanno Y, O'Shea JJ. Discrete roles for histone acetylation in human T helper 1 cell-specific gene expression[J]. J Biol Chem. 2004,279:40640-40646.
19. Smits HH, van Rietschoten JG, Hilkens CM, et al. IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression[J]. Eur J Immunol. 2001,31:1055-1065.
20. Toshiyuki Owaki, Masayuki Asakawa,et al. IL-27 induces Th1 differentiation via p38 MAPK/T-bet-and intercellular adhesion molecule-1/LFA-1 /ERK1/2-dependent pathways[J]. J Immunol.2006,177:7579-7587.
21. Minter LM, Turley DM, Das P, et al. Inhibitors ofγ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21[J].NatImmunol.2005,6:680-688.
22. Quiroga MF, Martinez GJ, Pasquinelli V, et al. Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection[J]. J Immunol. 2004,173:4120-4129.
23. Kumanogoh A, Shikina T, Suzuki K, et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A- deficient mice[J]. Immunity. 2005,22:305-316.
24. Strengell M, Sareneva T, Foster D, et al.IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response[J]. J Immunol. 2002,169: 3600-3605.
25. Patel M, Xu D, Kewin P, et al. Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis[J]. Eur J Immunol. 2005,35: 3581-3590.
26. Chen CH, Seguin-Devaux C, Burke NA, et al. Transforming growth factorβblocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation[J]. J Exp Med. 2003,197:1689-1699.
27. Park IK, Shultz LD, Letterio JJ,et al. TGF-β1 inhibits T-bet induction by IFN-γin murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2domain-containing phosphatase-1[J]. J Immunol. 2005,175:5666-5674.
28. Lin JT, Martin SL, Xia L,et al. TGF-β1 uses distinct mechanisms to inhibit IFN-γexpression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet[J]. J Immunol. 2005,174:5950-5958.
29. Smeltz RB, Chen J, Shevach EM. Transforming growth factor-β1 enhances the interferon-γ-dependent, interleukin-12-independent pathway of T helper 1 cell differentiation. Immunology[J]. 2005,114:484-492.
30. Jones DC, Ding X, Zhang TY, et al. Peroxisome proliferator-activated receptorαnegatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation[J]. J Immunol. 2003,171:196-203.
31. Tanaka Y, So T, Lebedeva S,et al. Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice[J]. Blood. 2005,106: 1286-1295.
32. Szabo SJ, Sullivan BM, Stemmann C,et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γproduction in CD4 and CD8 T cells[J]. Science. 2002,295:338-342.
33. Yin Z, Chen C, Szabo SJ,et al. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γbyγδT cells[J]. J Immunol. 2002,168: 1566-1571.
34. Finotto S, Hausding M, Doganci A, et al. Asthmatic changes in mice lacking T-bet are mediated by IL-13[J]. Int Immunol. 2005,17:993-1007.
35. Sullivan BM, Juedes A, Szabo SJ,et al. Antigen-driven effector CD8 T cell function regulated by T-bet[J]. Proc Natl Acad Sci U S A. 2003,100:15818-15823.
36. Intlekofer AM, Takemoto N, Wherry EJ, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin[J]. Nat Immunol. 2005,6:1236-1244.
37. Hohler T, Reuss E, Adams P, et al. A genetic basis for IFN-γproduction and T-bet expression in humans. J Immunol. 2005; 175:5457-5462.
38. Sundrud MS, Grill SM, Ni D, et al. Genetic reprogramming of primary human T cells reveals functional plasticity in Th cell differentiation[J]. J Immunol. 2003,171:3542-3549.
39. Dorfman DM, Hwang ES, Shahsafaei A,et al. T-bet, a T-cell-associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders[J]. Am J Clin Pathol. 2004,122:292-297.
40. Harashima A, Matsuo Y, Drexler HG, et al. Transcription factor expression in B-cell precursor-leukemia cell lines: preferential expression of T-bet[J]. Leuk Res. 2005,29:841-848.
41. Durali D, de Goer de Herve MG, Giron-Michel J,et al. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment[J]. Blood. 2003,102:4084-4089.
42. Liu N, Ohnishi N, Ni L,et al. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells[J]. Nat Immunol. 2003,4:687-693.
43. Peng SL, Li J, Lin L,et al. The role of T-bet in B cells[J]. Nat Immunol. 2003,4:1041.
44. Fre′de′rique Larousserie, Pascaline Charlot, Emilie Bardel,et al. Differential effects of IL-27 on human B cell subsets[J]. J Immunol. 2006, 176:5890-5897.
45. Harris DP, Goodrich S, Gerth AJ,et al. Regulation of IFN-γproduction by B effector 1 cells: essential roles for T-bet and the IFN-γreceptor[J]. J Immunol. 2005,1746781-6790.
46. Xu W, Zhang JJ. Stat1-dependent synergistic activation of T-bet for IgG2a production during early stage of B cell activation[J]. J Immunol. 2005,175:7419-7424.
47. Peng SL, Szabo SJ, Glimcher LH. T-bet regulates IgG class switching and pathogenic autoantibody production[J]. Proc Natl Acad Sci U S A. 2002,99: 5545-5550.
48. Yoshimoto T, Okada K, Morishima N, et al. Induction of IgG2a class switching in B cells by IL-27[J]. J Immunol. 2004,173:2479-2485.
49. Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon-γin lymphoid and myeloid cells[J]. Proc Natl Acad Sci U S A. 2001,98: 15137-15142.
50. Lugo-Villarino G, Maldonado-Lopez R, Possemato R,et al.T-bet is required for optimal production of IFN-γand antigen-specific T cell activation by dendritic cells[J]. Proc Natl Acad Sci U S A. 2003,100:7749-7754.
51. Lugo-Villarino G, Ito S, Klinman DM, et al. The adjuvant activity of CpG DNArequires T-bet expression in dendritic cells[J]. Proc Natl Acad Sci U S A. 2005,102: 13248-13253.
52. Townsend MJ, Weinmann AS, Matsuda JL, et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells[J]. Immunity. 2004,20: 477-494.
53. Robbins SH, Tessmer MS, Van Kaer L,et al. Direct effects of T-bet and MHC class I expression, but not STAT1, on peripheral NK cell maturation[J]. Eur J Immunol. 2005,35:757-765.
54. Xiao L,Tan WP,Xiao X,et al. Effect of T-bet on biological functions of mouse macrophage Raw264.7[J].Ai Zheng.2006 ,25:1069-1075.
55. Bettelli E, Sullivan B, Szabo SJ,et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis[J]. J Exp Med. 2004,200:79-87.
56. Nath N,Prasad R,Giri S,et al. T-bet is essential for the progression of experimental autoimmune encephalomyelitis[J].Immunology. 2006,118:384-391.
57. Lovett-Racke AE, Rocchini AE, Choy J, et al. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes[J]. Immunity. 2004,21:719-731.
58. Weaver A, Goncalves da Silva A, Nuttall RK, et al. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization[J]. FASEB J. 2005,19:1668-1670.
59. Nath N, Giri S, Prasad R,et al. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy[J]. J Immunol. 2004,172:1273-1286.
60. Dasgupta S,Roy A,Jana M,et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-alpha[J]. Mol Pharmacol. 2007,72:934-946.
61. Neurath MF, Weigmann B, Finotto S, et al. The transcription factor T-bet regulatesmucosal T cell activation in experimental colitis and Crohn's disease[J]. J Exp Med. 2002,195:1129-1143.
62. Weigmann B, Nemetz A, Becker C, et al. A critical regulatory role of leucin zipper transcription factor c-Maf in Th1-mediated experimental colitis[J]. J Immunol. 2004,173:3446-3455.
63. Iijima H, Neurath MF, Nagaishi T, et al. Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1[J]. J Exp Med. 2004,199:471-482.
64. Honda K, Nakamura K, Matsui N, et al. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis[J]. Inflamm Bowel Dis. 2005,11:1044-1052.
65. Monteleone G, Monteleone I, Fina D, et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-γproduction in Crohn's disease[J]. Gastroenterology. 2005,128:687-694.
66. Melanitou E, Liu E, Miao D,et al. Absence of the T-bet gene coding for the Th1-related transcription factor does not affect diabetes-associated phenotypes in Balb/c mice[J]. Ann N Y Acad Sci. 2003,1005: 187-191.
67. Juedes AE, Rodrigo E, Togher L,et al.T-bet controls auto-aggressive CD8 lymphocyte responses in type 1 diabetes[J]. J Exp Med. 2004,199:1153-1162.
68. Sasaki Y, Ihara K, Matsuura N, et al. Identification of a novel type 1 diabetes susceptibility gene, T-bet[J]. Hum Genet. 2004,115: 177-184.
69. Wang J, Fathman JW, Lugo-Villarino G, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells[J]. J Clin Invest. 2006,116:414-421.
70. Hultgren OH, Verdrengh M, Tarkowski A. T-box transcriptionfactor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis[J]. Microbes Infect. 2004,6:529-535.
71. Kawashima M, Miossec P. mRNA quantification of T-bet, GATA-3, IFN-γ, andIL-4 shows a defective Th1 immune response in the peripheral blood from rheumatoid arthritis patients: link with disease activity[J]. J Clin Immunol. 2005,25: 209-214.
72. Li B, Yang P, Zhou H, et al. T-bet expression is upregulated in active Behcet's disease[J]. Br J Ophthalmol. 2003,87:1264-1267.
73. Li B, Yang P, Zhou H, et al. Upregulation of T-bet expression in peripheral blood mononuclear cells during Vogt-Koyanagi-Harada diseas[J]e. Br J Ophthalmol. 2005,89:1410-1412.
74. Chan RW,Lai FM,Li EK,et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis[J].Rheumatology(Oxford) 2006,45:951-7.
75. Kimura J, Takada H, Nomura A, et al. Th1 and Th2 cytokine production is suppressed at the level of transcriptional regulation in Kawasaki disease[J]. Clin Exp Immunol. 2004,137: 444-449.
76. Shirota H, Gursel M, Klinman DM. Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-γ-and IL-12-mediated signaling[J].J Immunol. 2004,173:5002-5007.
77. Hwang ES, Szabo SJ, Schwartzberg PL,et al. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science[J]. 2005,307:430-433.
78. Hwang ES, Hong JH, Glimcher LH. IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508[J]. J Exp Med. 2005,202:1289-1300.
79. Mehta DS, Wurster AL, Weinmann AS,et al. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression[J]. Proc Natl Acad Sci U S A. 2005,102: 2016-2021.
80. Usui T, Nishikomori R, Kitani A, et al.GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet[J]. Immunity. 2003,18:415-428.
81. Babu S, Kumaraswami V, Nutman TB. Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes[J]. Infect Immun. 2005,73:3394-3401.
82. Peng SL, Townsend MJ, Hecht JL, White IA, Glimcher LH. T-bet regulates metastasis rate in a murine model of primary prostate cancer[J]. Cancer Res. 2004,64:452-455.
83. Simmons WJ, Koneru M, Mohindru M, et al. Tim-3+T-bet+ tumorspecific Th1 cells colocalize with and inhibit development and growth of murine neoplasms[J]. J Immunol. 2005,174:1405-1415.
84. Dorfman DM, van den Elzen P, Weng AP, et al. Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas[J]. Am J Clin Pathol. 2003,120:866-873.
85. Atayar C, Poppema S, Blokzijl T, et al. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas[J]. Am J Pathol. 2005,166:127-134.