米诺环素对实验性自身免疫性脑脊髓炎大鼠凋亡相关蛋白表达的影响
|
摘要
目的
探讨米诺环素对实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis, EAE)大鼠中枢神经系统(Central nervous system, CNS)凋亡相关蛋白Fas和Bcl-2表达的影响,以及对CNS内组织损伤的作用。
方法
将50只雌性Wistar大鼠随机分为正常对照组10只,EAE模型组20只,米诺环素治疗组20只；以豚鼠全脊髓匀浆(Guinea pig spinal cord homogenate, GPSCH)为抗原免疫大鼠建立EAE模型。然后治疗组给予米诺环素灌胃,而对照组和模型组则给予相同剂量的生理盐水灌胃。观察各组大鼠发病情况,采取HE染色及髓鞘染色观察组织病理学变化,以免疫组化检测各组大鼠CNS内Fas和Bcl-2蛋白的表达。
结果
EAE模型组的行为学评分高于米诺环素治疗组(P=0.018)。HE染色可见治疗组CNS内炎性细胞浸润较模型组减少；髓鞘染色则见各发病大鼠CNS组织结构疏松,出现弥漫性脱髓鞘改变,其中评分较高的大鼠病变相对严重,且米诺环素治疗组较EAE模型组稍轻。Fas的表达各组平均光密度和阳性细胞数模型组均高于治疗组(P<0.05),脑干和脊髓的平均光密度在治疗组和对照组之间没有明显差异(P>0.05)。Bcl-2的表达除脑干阳性细胞数外各部位平均光密度和细胞数治疗组均高于模型组,而对照组低于模型组(P<0.05),模型组和治疗组脑干的阳性细胞数高于对照组(P<0.05)。
结论
米诺环素可以使EAE大鼠CNS内Fas蛋白的表达下调、Bcl-2蛋白的表达上调；并可能通过介导Fas和Bcl-2的表达干预凋亡调节免疫反应,减轻CNS组织损伤而对EAE起到一定的治疗作用。
Objective
To investigate the effect of minocycline on expression of Fas and Bcl-2 in CNS of rats with experimental autoimmune encephalomyelitis(EAE), and the effect to damage in CNS of EAE.
Methods
Fifty female Wistar rats were divided into three groups randomly, normal control group(10), EAE model group(20) and minocycline-treatment group(20). EAE was induced in rats by immunization with guinea pig spinal cord homogenate (GPSCH). The rats in the treatment group were given minocycline (90mg/kg, the first day; 45mg/kg, the following days) by gavage, and the rats in the control and model groups were given normal saline by gavage. The symptom of rats in three groups was observed and the pathological changes were determined by HE staining and myelin staining, and the expression of Fas and Bcl-2 in the CNS were estimated by immunohistochemical method.
Results
The behavioral scores of model group were higher than treatment group (P=0.018). In the treatment group inflammation cells were less than model group around the vessels observed by HE staining; the structure of tissue in the CNS of rats with high scores becomes soft and diffuse demyelination, and the treatment group in which was litter damage than model group observed by myelin staining. The expression of Fas:compared with treatment group, the average density and positive cells were higher in every part of model group (P<0.05); There was no significant difference in the average density of brain stem and spinal cord between treatment and control group (P>0.05). The expression of Bcl-2:the average density and positive cells of treatment group were more than model group in every part except brain stem, and the control group was lower than model group (P<0.05); the positive cells in brain stem of model and treatment group were more than normal control group (P<0.05)
Conclusions
Minocycline can regulate the expression of Fas and Bcl-2 proteins in EAE; it may have influence on apoptosis in EAE and then exert immunoregulatory actions on it. Minocycline can reduce the damage in CNS of EAE and may have therapeutic effects on EAE.
探讨米诺环素对实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis, EAE)大鼠中枢神经系统(Central nervous system, CNS)凋亡相关蛋白Fas和Bcl-2表达的影响,以及对CNS内组织损伤的作用。
方法
将50只雌性Wistar大鼠随机分为正常对照组10只,EAE模型组20只,米诺环素治疗组20只；以豚鼠全脊髓匀浆(Guinea pig spinal cord homogenate, GPSCH)为抗原免疫大鼠建立EAE模型。然后治疗组给予米诺环素灌胃,而对照组和模型组则给予相同剂量的生理盐水灌胃。观察各组大鼠发病情况,采取HE染色及髓鞘染色观察组织病理学变化,以免疫组化检测各组大鼠CNS内Fas和Bcl-2蛋白的表达。
结果
EAE模型组的行为学评分高于米诺环素治疗组(P=0.018)。HE染色可见治疗组CNS内炎性细胞浸润较模型组减少；髓鞘染色则见各发病大鼠CNS组织结构疏松,出现弥漫性脱髓鞘改变,其中评分较高的大鼠病变相对严重,且米诺环素治疗组较EAE模型组稍轻。Fas的表达各组平均光密度和阳性细胞数模型组均高于治疗组(P<0.05),脑干和脊髓的平均光密度在治疗组和对照组之间没有明显差异(P>0.05)。Bcl-2的表达除脑干阳性细胞数外各部位平均光密度和细胞数治疗组均高于模型组,而对照组低于模型组(P<0.05),模型组和治疗组脑干的阳性细胞数高于对照组(P<0.05)。
结论
米诺环素可以使EAE大鼠CNS内Fas蛋白的表达下调、Bcl-2蛋白的表达上调；并可能通过介导Fas和Bcl-2的表达干预凋亡调节免疫反应,减轻CNS组织损伤而对EAE起到一定的治疗作用。
Objective
To investigate the effect of minocycline on expression of Fas and Bcl-2 in CNS of rats with experimental autoimmune encephalomyelitis(EAE), and the effect to damage in CNS of EAE.
Methods
Fifty female Wistar rats were divided into three groups randomly, normal control group(10), EAE model group(20) and minocycline-treatment group(20). EAE was induced in rats by immunization with guinea pig spinal cord homogenate (GPSCH). The rats in the treatment group were given minocycline (90mg/kg, the first day; 45mg/kg, the following days) by gavage, and the rats in the control and model groups were given normal saline by gavage. The symptom of rats in three groups was observed and the pathological changes were determined by HE staining and myelin staining, and the expression of Fas and Bcl-2 in the CNS were estimated by immunohistochemical method.
Results
The behavioral scores of model group were higher than treatment group (P=0.018). In the treatment group inflammation cells were less than model group around the vessels observed by HE staining; the structure of tissue in the CNS of rats with high scores becomes soft and diffuse demyelination, and the treatment group in which was litter damage than model group observed by myelin staining. The expression of Fas:compared with treatment group, the average density and positive cells were higher in every part of model group (P<0.05); There was no significant difference in the average density of brain stem and spinal cord between treatment and control group (P>0.05). The expression of Bcl-2:the average density and positive cells of treatment group were more than model group in every part except brain stem, and the control group was lower than model group (P<0.05); the positive cells in brain stem of model and treatment group were more than normal control group (P<0.05)
Conclusions
Minocycline can regulate the expression of Fas and Bcl-2 proteins in EAE; it may have influence on apoptosis in EAE and then exert immunoregulatory actions on it. Minocycline can reduce the damage in CNS of EAE and may have therapeutic effects on EAE.
引文
[1]Tsunoda I, Libbey JE, Kuang LQ, et al. Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis[J]. Am J Pathol,2005,167(6): 1631-1646.
[2]Zipp F. Apoptosis in multiple sclerosis[J]. Cell Tissue Res, 2000,301(1):163-171.
[3]P Ye, D'Ercole A. J. Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. [J]. Endocrinology 1999,140(7):3063-3072.
[4]White CA, McCombe PA, Pender MP. Microglia are more susceptible than macrophages to apoptosis in the central nervous system in experimental autoimmune encephalomyelitis through a mechanism not involving Fas (CD95) [J]. Int Immunol,1998,10(7):935-941.
[5]Oren A, White LR, Aasly J. Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy[J]. J Neurological Sci,2001, 186(1-2):31-36.
[6]Hovelmeyer N, Hao Z, Kranidioti K, et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis [J]. J Immunol,2005,175(9):5875-5884.
[7]Bonetti B, Pohl J, Gao YL, et al. Cell death during autoimmune demyelination:effector but not target cells are eliminated by apoptosis [J]. J Immunol,1997,159(11):5733-5741.
[8]陈慧芳,吕佩源,陈竞清,等.EAE大鼠外周免疫器官淋巴细胞凋亡的研究[J].脑与神经疾病杂志,2007,15(3)：200-202.
[9]Suvannavejh GC, Canto MC Dal, Mat is LA, et al. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis[J]. J Clin Invest,2000,105(2): 223-231.
[10]Sabelko KA, Kelly KA, Nahm MH, et al. Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system[J]. J Immunol,1997,159(7):3096-3099.
[11]杨藻宸.医用药理学[M].第4版.北京：人民卫生出版社,2005：943.
[12]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology, 2004, 3(12):744-51.
[13]Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes:a pilot study[J]. Mult Scler,2007,13(4) 517-526.
[14]Wisniewski HM, Keith AB. Chronic relapsing experimental allergic encephalomyelitis:an experimental model of multiple sclerosis[J]. Ann Neurol,1977,1(2):144-148.
[15]曹翠丽,王惠,马常升,等.实验性变态反应性脑脊髓炎大鼠模型的建立[J].解剖学杂志,2001,24(1)：77-81.
[16]邢清和,郑荣远,王永铭,等.Wistar大鼠过敏性脑脊髓炎动物模型的建立[J].上海医科大学学报,2000,27(6)：471-472.
[17]Hooper DC, Spitsin S, Kean RB, et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis [J]. Proc Natl Acad Sci USA,1998,95 (2):675-680.
[18]Yu CY, Whitacre CC. Sex, MHC and complement C4 in autoimmune diseases [J]. Trends Immunol,2004,25(12):694-699.
[19]李婛,曾丽,邹东华.外源性雄激素对EAE大鼠血中CD4+CD25+T细胞的影响[J].中国神经精神疾病杂志,2008,34(2)：115-117.
[20]李敏.实验性变态反应性脑脊髓炎模型研究进展[J].国际免疫学杂志,2010,33(2)：133-135.
[21]Gomes AC, Jonsson G, Mjornheim S, et al. Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis [J]. J Neuroimmunol,2003,135(1-2):126-134.
[22]谭清华,赵忠新,张玲珍.Fas和FasL在多发性硬化患者表达的意义[J].中华神经科杂志,2003,36(1)：14-16.
[23]Okuda Y, Apatoff BR, Posnett DN. Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis [J]. J Neuroimmunol,2006, 171(1-2):163-170.
[24]Julia E, Montalban X, Al-Zayat H, et al. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis[J]. J Neuroimmunol,2006,180(1-2):147-158.
[25]Hesse A, Wagner M, Held J, et al. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent [J]. Neurobiol Dis,2010, 37(2):362-369.
[26]李振,赵忠新,黄流清,等.多发性硬化患者外周血T淋巴细胞凋亡 和Fas的表达[J].山西医科大学报,2007,38(7)：585-587.
[27]Sharief MK, Matthews H, Noori MA. Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis [J]. J Neuroimmunol,2003,134(1-2):158-165.
[28]于欢,任惠民,罗玉敏,等.米诺环素对红藻氨酸诱导的癫痈大鼠海马组织凋亡相关蛋白表达的影响[J].中国临床神经科学,2006,14(4)：362-367.
[29]Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis [J]. J Neuroimmunol,2002, 130(1-2):202-210.
[30]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. Neurosci Res,2008,86(13) 2992-3001.
[31]Semra YK, Seidi OA, Sharief MK. Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis [J]. J Neuroimmunol,2001,113(2):268-274.
[32]Semra YK, Seidi OA, Sharief MK. Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins[J]. J Neuroimmunol,2002, 122(1-2):159-166.
[33]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. J Neurosci Res,2008,86(13): 2992-3001.
[34]秦新月,董为伟.实验性变应性脑脊髓炎脑白质细胞凋亡的实验性干预研究[J].重庆医学,2005,34(6)：857-859.
[35]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology, 2004, 3(12):744-751.
[36]Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation[J]. Neurobiol Dis,2007,25(3):514-525.
[37]Orsucci D, Calsolaro V, Mancuso M, et al. Neuroprotective effects of tetracyclines:molecular targets, animal models and human disease[J]. CNS Neurol Disord Drug Targets,2009,8(3): 222-231.
[38]Yong vw, Giuliani F, Xue M, et al. Experimental models of neuroprotection relevant to multiple sclerosis[J]. Neurology, 2007,68:S32-S37.
[39]Chen X, Pi R, Liu M, et al. Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in mice [J]. J Neuroimmunol,2010, 226(1-2):104-109.
[40]Chen X, Hu X, Zou Y, et al. Combined treatment with minocycline and prednisone attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice[J]. J Neuroimmunol,2009, 210(1-2):22-29.
[1]Zipp F. Apoptosis in multiple sclerosis[J]. Cell Tissue Res, 2000,301(1):163-171.
[2]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. Neurosci Res,2008, 86(13): 2992-3001.
[3]Bonetti B, Pohl J, Gao YL, et al. Cell death during autoimmune demyelination:effector but not target cells are eliminated by apoptosis [J]. J Immunol,1997,159(11):5733-5741.
[4]Suvannavejh GC, Canto MC Dal, Matis LA, et al. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis[J]. J Clin Invest,2000,105(2): 223-231.
[5]陈慧芳,吕佩源,陈竞清,等.EAE大鼠外周免疫器官淋巴细胞凋亡的研究[J].脑与神经疾病杂志,2007,15(3)：200-202.
[6]Saresella M, Marventano I, Speciale L, et al. Programmed cell death of myelin basic protein-specific T lymphocytes is reduced in patients with acute multiple sclerosis [J]. J Neuroimmunol, 2005,166(1-2):173-179.
[7]White CA, McCombe PA, Pender MP. The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis[J]. J Neuroimmunol, 1998,82(1):47-55.
[8]谭清华,赵忠新,张玲珍.Fas和FasL在多发性硬化患者表达的意义[J].中华神经科杂志,2003,36(1)：14-16.
[9]Oren A, White LR, Aasly J. Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy[J]. J Neurological Sci,2001, 186(1-2):31-36.
[10]Hesse A, Wagner M, Held J, et al. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent [J]. Neurobiol Dis,2010,37(2):362-369.
[11]Semra YK, Seidi OA, Sharief MK. Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis [J]. J Neuroimmunol,2001,113(2):268-274.
[12]Semra YK, Seidi OA, Sharief MK. Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins[J]. J Neuroimmunol,2002, 122(1-2):159-166.
[13]Okuda Y, Apatoff BR, Posnett DN. Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis [J]. J Neuroimmunol,2006, 171(1-2):163-170.
[14]Zhang F, Shi Y, Wang L, et al. Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis [J]. Plos one,2011,6(2):e16795.
[15]Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis [J]. J Neuroimmunol,2002,130(1-2):202-210.
[16]Balkowiec-Iskra E, Kurkowska-Jastrzebska I, Joniec I, et al. MPTP-induced central dopamine depletion exacerbates experimental autoimmune encephalomyelitis (EAE) in C57BL mice[J]. Inflammation research, 2007, 56(8):311-317.
[17]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. J Neurosci Res,2008,86(13): 2992-3001.
[18]Sabelko KA, Kelly KA, Nahm MH, et al. Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system[J]. J Immunol,1997,159(7):3096-3099.
[19]Waldner H, Sobel RA, Howard E, et al. Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis [J]. J Immunol,1997,159(7):3100-3103.
[20]Sharief MK, Douglas M, Noori M, et al. The expression of pro-and anti-apoptosis Bcl-2 family proteins in lymphocytes from patients with multiple sclerosis[J]. J Neuroimmunol,2002, 125(1):155-162.
[21]Hoftberger R, Aboul-Enein F, Brueck W, et al. Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions[J]. Brain Pathol,2004,14(1):43-50.
[22]Buntinx M, Gielen E, Hummelen P Van, et al. Cytokine-induced cell death in human oligodendroglial cell lines. II: Alterations in gene expression induced by interferon-gamma and tumor necrosis factor-alpha[J]. J Neurosci Res,2004,76(6): 846-861.
[23]秦新月,董为伟.实验性变应性脑脊髓炎脑白质细胞凋亡的实验性干预研究[J].重庆医学,2005,34(6)：857-859.
[24]Tsunoda I, Libbey JE, Kuang LQ, et al. Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis[J]. Am J Pathol,2005,167(6): 1631-1646.
[25]王敦敬,胡学强,陆正齐.慢性实验性变应性脑脊髓炎猴脊髓非病灶部位轴突损伤的机制[J].中山大学学报·医学科学版2006,27(6)：649-651.
[26]Sharief MK, Noori MA, Zoukos Y. Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interf eron-β therapy [J]. J Neuroimmunol,2002,129(1-2):224-231.
[27]Sharief MK, Semra YK, Seidi OA, et al. Interferon-beta therapy down regulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis[J]. J Neuroimmunol,2001, 120(1-2):199-207.
[28]Zipp F, Martin R, Lichtenfels R, et al. Human autoreactive and foreign antigen-specific T cells resist apoptosis induced by soluble recombinant CD95 ligand[J]. J Immunol,1997,159(5): 2108-2115.
[29]Fritzschingab Benedikt, Korporalb Mirjam, Haasb Jurgen, et al. Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals[J]. J Neuroimmunol,2006, 251(1) 91-97.
[30]Steckley D, Karajgikar M, Dale LB, et al. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis[J]. J Neurosci,2007,27(47):12989-12999.
[31]Zhou Tong, Song Ling, Yang Pingar, et al. Bisindolylmaleimide Ⅷ facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases [J]. Nat Med,1999,5(1): 42-48.
[32]Holeik M. Targeting endogenous inhibitors of apoptosis for treatment of cancer, stroke and multiple sclerosis[J]. Expert Opin Ther Targets,2004,8(3):241-253.
[33]Cid C, Alvarez-Cermeno JC, Regidor I, et al. Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients [J]. J Neuroimmunol,2003, 136(1):119-124.
[34]Yong vw, Giuliani F, Xue M, et al. Experimental models of neuroprotection relevant to multiple sclerosis[J]. Neurology, 2007,68:S32-S37.
[35]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology,2004,3(12):744-751.
[36]Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation [J]. Neurobiol Dis,2007,25(3):514-525.
[37]Orsucci D, Calsolaro V, Mancuso M, et al. Neuroprotective effects of tetracyclines:molecular targets, animal models and human disease [J]. CNS Neurol Disord Drug Targets,2009,8(3): 222-231.
[38]Chen X, Pi R, Liu M, et al. Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in mice [J]. J Neuroimmunol,2010, 226(1-2):104-109.
[39]Chen X, Hu X, Zou Y, et al. Combined treatment with minocycline and prednisone attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice[J]. J Neuroimmunol,2009, 210(1-2):22-29.
[40]Vanderlocht J, Hellings N, Hendriks JJ, et al. Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis[J]. J Neurosci Res,2006,83(5):763-774.
[41]惠红霞,刘扬清,李作孝.多发性硬化患者外周血T细胞Fas表达及血清sFas水平[J].中华神经科杂志,2006,39(12)：844-846.
[2]Zipp F. Apoptosis in multiple sclerosis[J]. Cell Tissue Res, 2000,301(1):163-171.
[3]P Ye, D'Ercole A. J. Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. [J]. Endocrinology 1999,140(7):3063-3072.
[4]White CA, McCombe PA, Pender MP. Microglia are more susceptible than macrophages to apoptosis in the central nervous system in experimental autoimmune encephalomyelitis through a mechanism not involving Fas (CD95) [J]. Int Immunol,1998,10(7):935-941.
[5]Oren A, White LR, Aasly J. Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy[J]. J Neurological Sci,2001, 186(1-2):31-36.
[6]Hovelmeyer N, Hao Z, Kranidioti K, et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis [J]. J Immunol,2005,175(9):5875-5884.
[7]Bonetti B, Pohl J, Gao YL, et al. Cell death during autoimmune demyelination:effector but not target cells are eliminated by apoptosis [J]. J Immunol,1997,159(11):5733-5741.
[8]陈慧芳,吕佩源,陈竞清,等.EAE大鼠外周免疫器官淋巴细胞凋亡的研究[J].脑与神经疾病杂志,2007,15(3)：200-202.
[9]Suvannavejh GC, Canto MC Dal, Mat is LA, et al. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis[J]. J Clin Invest,2000,105(2): 223-231.
[10]Sabelko KA, Kelly KA, Nahm MH, et al. Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system[J]. J Immunol,1997,159(7):3096-3099.
[11]杨藻宸.医用药理学[M].第4版.北京：人民卫生出版社,2005：943.
[12]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology, 2004, 3(12):744-51.
[13]Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes:a pilot study[J]. Mult Scler,2007,13(4) 517-526.
[14]Wisniewski HM, Keith AB. Chronic relapsing experimental allergic encephalomyelitis:an experimental model of multiple sclerosis[J]. Ann Neurol,1977,1(2):144-148.
[15]曹翠丽,王惠,马常升,等.实验性变态反应性脑脊髓炎大鼠模型的建立[J].解剖学杂志,2001,24(1)：77-81.
[16]邢清和,郑荣远,王永铭,等.Wistar大鼠过敏性脑脊髓炎动物模型的建立[J].上海医科大学学报,2000,27(6)：471-472.
[17]Hooper DC, Spitsin S, Kean RB, et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis [J]. Proc Natl Acad Sci USA,1998,95 (2):675-680.
[18]Yu CY, Whitacre CC. Sex, MHC and complement C4 in autoimmune diseases [J]. Trends Immunol,2004,25(12):694-699.
[19]李婛,曾丽,邹东华.外源性雄激素对EAE大鼠血中CD4+CD25+T细胞的影响[J].中国神经精神疾病杂志,2008,34(2)：115-117.
[20]李敏.实验性变态反应性脑脊髓炎模型研究进展[J].国际免疫学杂志,2010,33(2)：133-135.
[21]Gomes AC, Jonsson G, Mjornheim S, et al. Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis [J]. J Neuroimmunol,2003,135(1-2):126-134.
[22]谭清华,赵忠新,张玲珍.Fas和FasL在多发性硬化患者表达的意义[J].中华神经科杂志,2003,36(1)：14-16.
[23]Okuda Y, Apatoff BR, Posnett DN. Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis [J]. J Neuroimmunol,2006, 171(1-2):163-170.
[24]Julia E, Montalban X, Al-Zayat H, et al. Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis[J]. J Neuroimmunol,2006,180(1-2):147-158.
[25]Hesse A, Wagner M, Held J, et al. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent [J]. Neurobiol Dis,2010, 37(2):362-369.
[26]李振,赵忠新,黄流清,等.多发性硬化患者外周血T淋巴细胞凋亡 和Fas的表达[J].山西医科大学报,2007,38(7)：585-587.
[27]Sharief MK, Matthews H, Noori MA. Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis [J]. J Neuroimmunol,2003,134(1-2):158-165.
[28]于欢,任惠民,罗玉敏,等.米诺环素对红藻氨酸诱导的癫痈大鼠海马组织凋亡相关蛋白表达的影响[J].中国临床神经科学,2006,14(4)：362-367.
[29]Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis [J]. J Neuroimmunol,2002, 130(1-2):202-210.
[30]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. Neurosci Res,2008,86(13) 2992-3001.
[31]Semra YK, Seidi OA, Sharief MK. Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis [J]. J Neuroimmunol,2001,113(2):268-274.
[32]Semra YK, Seidi OA, Sharief MK. Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins[J]. J Neuroimmunol,2002, 122(1-2):159-166.
[33]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. J Neurosci Res,2008,86(13): 2992-3001.
[34]秦新月,董为伟.实验性变应性脑脊髓炎脑白质细胞凋亡的实验性干预研究[J].重庆医学,2005,34(6)：857-859.
[35]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology, 2004, 3(12):744-751.
[36]Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation[J]. Neurobiol Dis,2007,25(3):514-525.
[37]Orsucci D, Calsolaro V, Mancuso M, et al. Neuroprotective effects of tetracyclines:molecular targets, animal models and human disease[J]. CNS Neurol Disord Drug Targets,2009,8(3): 222-231.
[38]Yong vw, Giuliani F, Xue M, et al. Experimental models of neuroprotection relevant to multiple sclerosis[J]. Neurology, 2007,68:S32-S37.
[39]Chen X, Pi R, Liu M, et al. Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in mice [J]. J Neuroimmunol,2010, 226(1-2):104-109.
[40]Chen X, Hu X, Zou Y, et al. Combined treatment with minocycline and prednisone attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice[J]. J Neuroimmunol,2009, 210(1-2):22-29.
[1]Zipp F. Apoptosis in multiple sclerosis[J]. Cell Tissue Res, 2000,301(1):163-171.
[2]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. Neurosci Res,2008, 86(13): 2992-3001.
[3]Bonetti B, Pohl J, Gao YL, et al. Cell death during autoimmune demyelination:effector but not target cells are eliminated by apoptosis [J]. J Immunol,1997,159(11):5733-5741.
[4]Suvannavejh GC, Canto MC Dal, Matis LA, et al. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis[J]. J Clin Invest,2000,105(2): 223-231.
[5]陈慧芳,吕佩源,陈竞清,等.EAE大鼠外周免疫器官淋巴细胞凋亡的研究[J].脑与神经疾病杂志,2007,15(3)：200-202.
[6]Saresella M, Marventano I, Speciale L, et al. Programmed cell death of myelin basic protein-specific T lymphocytes is reduced in patients with acute multiple sclerosis [J]. J Neuroimmunol, 2005,166(1-2):173-179.
[7]White CA, McCombe PA, Pender MP. The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis[J]. J Neuroimmunol, 1998,82(1):47-55.
[8]谭清华,赵忠新,张玲珍.Fas和FasL在多发性硬化患者表达的意义[J].中华神经科杂志,2003,36(1)：14-16.
[9]Oren A, White LR, Aasly J. Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy[J]. J Neurological Sci,2001, 186(1-2):31-36.
[10]Hesse A, Wagner M, Held J, et al. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent [J]. Neurobiol Dis,2010,37(2):362-369.
[11]Semra YK, Seidi OA, Sharief MK. Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis [J]. J Neuroimmunol,2001,113(2):268-274.
[12]Semra YK, Seidi OA, Sharief MK. Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins[J]. J Neuroimmunol,2002, 122(1-2):159-166.
[13]Okuda Y, Apatoff BR, Posnett DN. Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis [J]. J Neuroimmunol,2006, 171(1-2):163-170.
[14]Zhang F, Shi Y, Wang L, et al. Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis [J]. Plos one,2011,6(2):e16795.
[15]Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis [J]. J Neuroimmunol,2002,130(1-2):202-210.
[16]Balkowiec-Iskra E, Kurkowska-Jastrzebska I, Joniec I, et al. MPTP-induced central dopamine depletion exacerbates experimental autoimmune encephalomyelitis (EAE) in C57BL mice[J]. Inflammation research, 2007, 56(8):311-317.
[17]Das A, Guyton MK, Matzelle DD, et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis[J]. J Neurosci Res,2008,86(13): 2992-3001.
[18]Sabelko KA, Kelly KA, Nahm MH, et al. Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system[J]. J Immunol,1997,159(7):3096-3099.
[19]Waldner H, Sobel RA, Howard E, et al. Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis [J]. J Immunol,1997,159(7):3100-3103.
[20]Sharief MK, Douglas M, Noori M, et al. The expression of pro-and anti-apoptosis Bcl-2 family proteins in lymphocytes from patients with multiple sclerosis[J]. J Neuroimmunol,2002, 125(1):155-162.
[21]Hoftberger R, Aboul-Enein F, Brueck W, et al. Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions[J]. Brain Pathol,2004,14(1):43-50.
[22]Buntinx M, Gielen E, Hummelen P Van, et al. Cytokine-induced cell death in human oligodendroglial cell lines. II: Alterations in gene expression induced by interferon-gamma and tumor necrosis factor-alpha[J]. J Neurosci Res,2004,76(6): 846-861.
[23]秦新月,董为伟.实验性变应性脑脊髓炎脑白质细胞凋亡的实验性干预研究[J].重庆医学,2005,34(6)：857-859.
[24]Tsunoda I, Libbey JE, Kuang LQ, et al. Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis[J]. Am J Pathol,2005,167(6): 1631-1646.
[25]王敦敬,胡学强,陆正齐.慢性实验性变应性脑脊髓炎猴脊髓非病灶部位轴突损伤的机制[J].中山大学学报·医学科学版2006,27(6)：649-651.
[26]Sharief MK, Noori MA, Zoukos Y. Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interf eron-β therapy [J]. J Neuroimmunol,2002,129(1-2):224-231.
[27]Sharief MK, Semra YK, Seidi OA, et al. Interferon-beta therapy down regulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis[J]. J Neuroimmunol,2001, 120(1-2):199-207.
[28]Zipp F, Martin R, Lichtenfels R, et al. Human autoreactive and foreign antigen-specific T cells resist apoptosis induced by soluble recombinant CD95 ligand[J]. J Immunol,1997,159(5): 2108-2115.
[29]Fritzschingab Benedikt, Korporalb Mirjam, Haasb Jurgen, et al. Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals[J]. J Neuroimmunol,2006, 251(1) 91-97.
[30]Steckley D, Karajgikar M, Dale LB, et al. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis[J]. J Neurosci,2007,27(47):12989-12999.
[31]Zhou Tong, Song Ling, Yang Pingar, et al. Bisindolylmaleimide Ⅷ facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases [J]. Nat Med,1999,5(1): 42-48.
[32]Holeik M. Targeting endogenous inhibitors of apoptosis for treatment of cancer, stroke and multiple sclerosis[J]. Expert Opin Ther Targets,2004,8(3):241-253.
[33]Cid C, Alvarez-Cermeno JC, Regidor I, et al. Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients [J]. J Neuroimmunol,2003, 136(1):119-124.
[34]Yong vw, Giuliani F, Xue M, et al. Experimental models of neuroprotection relevant to multiple sclerosis[J]. Neurology, 2007,68:S32-S37.
[35]Yong VW, Wells J, Giuliani F, et al. The promise of minocycline in neurology [J]. Lancet Neurology,2004,3(12):744-751.
[36]Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation [J]. Neurobiol Dis,2007,25(3):514-525.
[37]Orsucci D, Calsolaro V, Mancuso M, et al. Neuroprotective effects of tetracyclines:molecular targets, animal models and human disease [J]. CNS Neurol Disord Drug Targets,2009,8(3): 222-231.
[38]Chen X, Pi R, Liu M, et al. Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in mice [J]. J Neuroimmunol,2010, 226(1-2):104-109.
[39]Chen X, Hu X, Zou Y, et al. Combined treatment with minocycline and prednisone attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice[J]. J Neuroimmunol,2009, 210(1-2):22-29.
[40]Vanderlocht J, Hellings N, Hendriks JJ, et al. Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis[J]. J Neurosci Res,2006,83(5):763-774.
[41]惠红霞,刘扬清,李作孝.多发性硬化患者外周血T细胞Fas表达及血清sFas水平[J].中华神经科杂志,2006,39(12)：844-846.