MG胸腺骨骼肌抗原表达及相应抗体改变的临床意义研究
摘要
重症肌无力(Myasthenia Gravis,MG)是一种以横纹肌神经肌肉传导障碍为特点的自身免疫性疾病。目前认为机体产生针对骨骼肌抗原成分的抗体或产生乙酰胆碱受体抗体(AChR-ab)是其发病的重要原因。抗体产生的免疫学基础是淋巴细胞与抗原物质接触,但最近的研究发现正常肌细胞内的骨骼肌成分不能刺激机体产生抗骨骼肌抗体,神经肌肉接头突触后膜上的烟碱型AChR 也不能与血液中淋巴细胞接触而产生特异性的AChR-ab。基于下述原因我们推测胸腺可能表达了骨骼肌的抗原成分或AChR 的抗原成份,然后在胸腺内抗原递呈细胞的协助下由B细胞产生抗骨骼肌抗体或AChR-ab,这些原因是:1. MG 患者常伴有胸腺异常,其中70%的患者伴有胸腺生发中心的淋巴滤泡增生, 约15%患者伴有胸腺瘤,另有约10%表现为胸腺萎缩。2. 胸腺切除术可使约88.7%的MG 患者临床症状明显缓解。3. 胸腺切除术后,MG 患者周围血AChR-ab滴度明显下降。本课题通过研究胸腺内骨骼肌抗原及AChR 的表达,患者外周血血清中多种抗肌抗体和AChR-ab 滴度的测定,比较抗原、抗体与临床症状的关系,探讨胸腺抗原成分、外周血血清中抗体在MG 发病中的作用,为MG 的发病机制研究提供帮助,为临床外科治疗MG 提供理论基础。
本研究首先通过光镜和电镜观察了MG 胸腺的病理形态和超微结构改变,揭示MG 患者胸腺与正常胸腺在细胞组织结构方面的差异。针对MG 胸腺组织中异常增多的肌样细胞,采用免疫组织化学染色法检测骨骼肌相关蛋白Myosin、Desmin 和AChR、的表达情况,初步探讨这些抗原成分是否参与启动针对AChR 的自身免疫反应。采用RT-PCR 法检测了胸腺组织中AChR 各亚单位mRNA 表达水平,了解胸腺组织中AChR亚单位变化的意义。尽管AChR-ab 被公认是MG 的主要致病因子,但是MG 患者血清中AChR-ab 的滴度并不完全与肌无力的严重程度相一致,这说明可能还有其它致病因子存在,如肌球蛋白抗体(Myosin-ab)等可能参与MG 发病。胸腺切除术作为一种目前临床上公认的治疗MG 的有效手段,对MG 患者免疫功能有何影响,一直是临床十分关注的问题。采用ELISA 法检测MG 患者血清中AChR-ab、肌球蛋白抗体的滴度,比较术前、术后的变化,结合临床病理资料进行统计分析,探讨上述两种抗体在MG
Myasthenia gravis (MG) is a kind of autoimmue disease with the characteristic of the dysfunctional neuromuscular transmission. The explanation of it’s etiology focuses on the antibodies against the skeletal antigens involving AChR-ab. However recent study discovered that the skeletal antigen in normal skeletal cells could not induce the secretion of any related antibody, nor did the nicotine AChR antigen on the post synapse membrane. The following findings suggested the thymus in the MG patients might express some components of skeletal antigen stimulating B cell to secret autoimmue antibody under the help of APC in the thymus. These findings can be concluded as: 1. Pathological findings could always be uncovered in the MG thymus, in that lymph foilicie hyperplasia could be found in 70% of them, thymoma in 15% and thymus hypoplasia in 10%; 2. Approximately 88.7% of the MG patients could achieve prominent symptom release after thymectomy; 3. The titer of AChR-ab would significantly decrease after thymectomy. To make a further study on the etiology of MG as well as explore the theory basis for thymectomy, this protocol tended to examine the expression of skeletal antigen and AChR, measure the titer of multiple anti-muscle antibody as well as the AChR-ab in the peripheral blood plasma, analyze the possible relation between clinical symptoms and the etiological antigen and antibodies which might take a part in the pathological process of the MG.
Via light scope and eletronic microscope the pathologic changes and ultromicro -structure were observed, indicating prominent difference between MG thymus and the normal contral. A prominent characteristic is the hyperplasia of thymic myoid cells. Immunohistochemistry was performed in these cells to detect the antigen of Myosin, desmin and AChR which might take a part in stimulating the autoimmne reaction against AChR. RT-PCR was applied to detect the transcripts of genes coding AChR subuits, which indicated the structure of AChR in thymus cell. Though it has been well established that the
AChR-ab is the key etiologic factor causing MG, the titer of AChR-ab in plasma dose not cmpletely macth the sever dgree of MG, indicating the effects of other etiologic factors such as the Myosin-ab. Since thymectomy has been regarded as the effective method to treat MG it is very essential to make it clear that whether it can improve the immune status in the MG patients. Using ELISA the plasma AChR-ab and Myosin-ab were detected. These results combined with other clinic pathological data were analyzed and compared to find out the clinic meaning of these two antibodies and the impaction of thymectomy on immnue status. Using western-blot the expression of skeletal antigen protein was quantified and their relation with the plasma antibody titer were studied. The prognostic implication of these antigens was also discussed. The release rate after thymectomy, gender, age, Osseman classification as well as the duration of MG symptoms prio to operation were all statistically analyzed vi X2 test to explore their relation. Main results and comments: 1. Plenty of hyperplasia blood capillary hyperplasia, prominent germinal centers and lymph foilicie were unvovered under the light scope. Scattered plasma cells were identified by electronic miceroscope containing many circular and equal sized immune secretory granule covered by membrana limitans. The similar secretory granules were also found outside these cells. In the 38 slides skeletal muscle protein was examined by immunohistochemistry stain, the numbers of pasitive cells were added via counting 10 obserbing sights. AChR significantly increased from 12.30±1.75 in the contral tissues to 33.05±2.48 in the MG thymus.Myosin significantly increased from 11.05±1.43 in the contral tissues to 25.03±2.51 in the MG thymus. Desmin significantly increased from 9.05±1.39 to 24.76±2.10 in the MG thymus. The AChR subunits of a+, a-,ε, β,γ,δin the MG thymus were all significantly highter than that in the normal contral tissues.These results proved the thymus as a target organ the autoimmune antibodies would attack. The abnormally increased expression of skeletal muscle antigen might excess the threshold of autotolerance playing an important role in the etiology of MG. 2. As to the level of plasma AChR-ab, through the analysis of 63 cases of MG, type Ⅰ(0.32±0.052)was significantly lower compared to IIa (0.41±0.051) and Ⅱb (0.42±0.054). The expression of AChR-ab varied significantly among different pathological types of MG--it was significantly higher in the myoma tissues compared to that in hyperplasia
tissues(P<0.05);Afte thymectomy the AChR-ab decreased significantly especially in the patients with thymus hyperplasia. 3. Myosin is a component of thin filament. Its antibody, Myosin-ab, was significantly lower (P<0.05) in type I MG(0.27±0.032)compared to that in typeⅡa MG (0.39±0.061) or typeⅡb (0.40±0.042). Myosin-ab in patients of thymoma was significantly higher than that in patients of thymus hyperplasia (P<0.05). A significant relationship was uncovered between Myosin-ab and AChR-ab, in that the titer of Myosin-ab significantly decreased after thymectomy, especially in the patients with thymoma. The decrease of Myosin-ab was more significant than AChR-ab, indicating the level of plasma Myosin-ab was positively correlated with the theroputic effects of thymectomy, and the level of Myosin-ab could be much more easier to reflect the theraputic effects. 4. Multifactor analysis of 216 patients with simple MG showed that the CR and RR in 1, 3 and 5 years after operation was 21.2%、43.0%、43.4% and 87.6%、91.9%、92.1% respectively. A delayed respones occurred in the treatment of MG indicating long-term follow-up. The theraputic effect of thymectomy was significantly related with the duration of symptoms prio to operation and the Osserman classification, not related with the age and the pathological types. 5. AChR and Myosin were discovered to be overexpressed in MG tissues compared to normal contral, indicating that the antigen was so overexpressed in the MG tissues that it excessed the threshold of autotolerence. This might be a possible reason for the etiology of MG. So the theraputic effects of thymectomy might lie in the elimination of overexpressed T cell-related autoantigen.
本研究首先通过光镜和电镜观察了MG 胸腺的病理形态和超微结构改变,揭示MG 患者胸腺与正常胸腺在细胞组织结构方面的差异。针对MG 胸腺组织中异常增多的肌样细胞,采用免疫组织化学染色法检测骨骼肌相关蛋白Myosin、Desmin 和AChR、的表达情况,初步探讨这些抗原成分是否参与启动针对AChR 的自身免疫反应。采用RT-PCR 法检测了胸腺组织中AChR 各亚单位mRNA 表达水平,了解胸腺组织中AChR亚单位变化的意义。尽管AChR-ab 被公认是MG 的主要致病因子,但是MG 患者血清中AChR-ab 的滴度并不完全与肌无力的严重程度相一致,这说明可能还有其它致病因子存在,如肌球蛋白抗体(Myosin-ab)等可能参与MG 发病。胸腺切除术作为一种目前临床上公认的治疗MG 的有效手段,对MG 患者免疫功能有何影响,一直是临床十分关注的问题。采用ELISA 法检测MG 患者血清中AChR-ab、肌球蛋白抗体的滴度,比较术前、术后的变化,结合临床病理资料进行统计分析,探讨上述两种抗体在MG
Myasthenia gravis (MG) is a kind of autoimmue disease with the characteristic of the dysfunctional neuromuscular transmission. The explanation of it’s etiology focuses on the antibodies against the skeletal antigens involving AChR-ab. However recent study discovered that the skeletal antigen in normal skeletal cells could not induce the secretion of any related antibody, nor did the nicotine AChR antigen on the post synapse membrane. The following findings suggested the thymus in the MG patients might express some components of skeletal antigen stimulating B cell to secret autoimmue antibody under the help of APC in the thymus. These findings can be concluded as: 1. Pathological findings could always be uncovered in the MG thymus, in that lymph foilicie hyperplasia could be found in 70% of them, thymoma in 15% and thymus hypoplasia in 10%; 2. Approximately 88.7% of the MG patients could achieve prominent symptom release after thymectomy; 3. The titer of AChR-ab would significantly decrease after thymectomy. To make a further study on the etiology of MG as well as explore the theory basis for thymectomy, this protocol tended to examine the expression of skeletal antigen and AChR, measure the titer of multiple anti-muscle antibody as well as the AChR-ab in the peripheral blood plasma, analyze the possible relation between clinical symptoms and the etiological antigen and antibodies which might take a part in the pathological process of the MG.
Via light scope and eletronic microscope the pathologic changes and ultromicro -structure were observed, indicating prominent difference between MG thymus and the normal contral. A prominent characteristic is the hyperplasia of thymic myoid cells. Immunohistochemistry was performed in these cells to detect the antigen of Myosin, desmin and AChR which might take a part in stimulating the autoimmne reaction against AChR. RT-PCR was applied to detect the transcripts of genes coding AChR subuits, which indicated the structure of AChR in thymus cell. Though it has been well established that the
AChR-ab is the key etiologic factor causing MG, the titer of AChR-ab in plasma dose not cmpletely macth the sever dgree of MG, indicating the effects of other etiologic factors such as the Myosin-ab. Since thymectomy has been regarded as the effective method to treat MG it is very essential to make it clear that whether it can improve the immune status in the MG patients. Using ELISA the plasma AChR-ab and Myosin-ab were detected. These results combined with other clinic pathological data were analyzed and compared to find out the clinic meaning of these two antibodies and the impaction of thymectomy on immnue status. Using western-blot the expression of skeletal antigen protein was quantified and their relation with the plasma antibody titer were studied. The prognostic implication of these antigens was also discussed. The release rate after thymectomy, gender, age, Osseman classification as well as the duration of MG symptoms prio to operation were all statistically analyzed vi X2 test to explore their relation. Main results and comments: 1. Plenty of hyperplasia blood capillary hyperplasia, prominent germinal centers and lymph foilicie were unvovered under the light scope. Scattered plasma cells were identified by electronic miceroscope containing many circular and equal sized immune secretory granule covered by membrana limitans. The similar secretory granules were also found outside these cells. In the 38 slides skeletal muscle protein was examined by immunohistochemistry stain, the numbers of pasitive cells were added via counting 10 obserbing sights. AChR significantly increased from 12.30±1.75 in the contral tissues to 33.05±2.48 in the MG thymus.Myosin significantly increased from 11.05±1.43 in the contral tissues to 25.03±2.51 in the MG thymus. Desmin significantly increased from 9.05±1.39 to 24.76±2.10 in the MG thymus. The AChR subunits of a+, a-,ε, β,γ,δin the MG thymus were all significantly highter than that in the normal contral tissues.These results proved the thymus as a target organ the autoimmune antibodies would attack. The abnormally increased expression of skeletal muscle antigen might excess the threshold of autotolerance playing an important role in the etiology of MG. 2. As to the level of plasma AChR-ab, through the analysis of 63 cases of MG, type Ⅰ(0.32±0.052)was significantly lower compared to IIa (0.41±0.051) and Ⅱb (0.42±0.054). The expression of AChR-ab varied significantly among different pathological types of MG--it was significantly higher in the myoma tissues compared to that in hyperplasia
tissues(P<0.05);Afte thymectomy the AChR-ab decreased significantly especially in the patients with thymus hyperplasia. 3. Myosin is a component of thin filament. Its antibody, Myosin-ab, was significantly lower (P<0.05) in type I MG(0.27±0.032)compared to that in typeⅡa MG (0.39±0.061) or typeⅡb (0.40±0.042). Myosin-ab in patients of thymoma was significantly higher than that in patients of thymus hyperplasia (P<0.05). A significant relationship was uncovered between Myosin-ab and AChR-ab, in that the titer of Myosin-ab significantly decreased after thymectomy, especially in the patients with thymoma. The decrease of Myosin-ab was more significant than AChR-ab, indicating the level of plasma Myosin-ab was positively correlated with the theroputic effects of thymectomy, and the level of Myosin-ab could be much more easier to reflect the theraputic effects. 4. Multifactor analysis of 216 patients with simple MG showed that the CR and RR in 1, 3 and 5 years after operation was 21.2%、43.0%、43.4% and 87.6%、91.9%、92.1% respectively. A delayed respones occurred in the treatment of MG indicating long-term follow-up. The theraputic effect of thymectomy was significantly related with the duration of symptoms prio to operation and the Osserman classification, not related with the age and the pathological types. 5. AChR and Myosin were discovered to be overexpressed in MG tissues compared to normal contral, indicating that the antigen was so overexpressed in the MG tissues that it excessed the threshold of autotolerence. This might be a possible reason for the etiology of MG. So the theraputic effects of thymectomy might lie in the elimination of overexpressed T cell-related autoantigen.
引文
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61. Marx A. Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas. Lab Invest,1990, 62:279–286.
62. Mygland A.Thymomas express epitopes shared by the ryanodine receptor. J Neuroimmunol,1995,62:79–83.
63. Buckley C.Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol,2001, 50(1):64–72.
64. Spuler S.Thymoma-associated myasthenia gravis: transplantation of thymoma and extrathymomal thymic tissue into SCID mice. Am J Pathol,1996,148:1359–1365.
65. 张镜如,乔健天.生理学.第四版,北京,人民卫生出版社,1996,42-45.
66. De Lancrolle,Felsen R.Effects of antibodies to Myosin light chain kinase in contractility and Myosin phosphorylation in chemically permeabilized smooth muscle.Circ Res,1999,68:457-463.
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68. Ohta M, Ohta K, Itoh N,et al. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-Myosin, actoMyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta,2003, 187(3):255-264.
69. Penn AS, Schotland DL, Lamme S. Antimuscle and antiacetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve,1996,9(5):407-415.
70. Mohan S,Barohn RJ,Krolick KA.Unexoected crossreacting between Myosin and a main immunogenic region(MIR) of the acetylcholine receptor by antisera obtained from myasthenia gravis patients. Clin.Immunol Immunopath,2002,64(5):218-224.
71. Mohan S,Barohn RJ,Jackson CE,et al.Evaluation of Myosin reactive antibodies from a panel of myasThenia gravis patients.Clin.Immunol ImmunopaTh,1994,70:266.
72. Dan-Goor M,Muhlrad A.Antibody directed against the 142-148 sequence of the Myosin heavy chain interferes with Myosin-actin interaction. Biochem, 1991, 30: 400-408.
73. Koren E,Koscce M,Wolfsin-Reichlin M,et al.Muine and hyman antibodies to native DNA that cross-react with the A and D S nRNP Polypeptides cause direct injury of cultured kidney cells.J Immunolog,1995,154(9):4857-1862.
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75. 高波廷,杨明山,徐金枝,等. MG 患者胸腺切除术后血清自身抗体水平变化和临床转归分析.中国神经精神疾病杂志,1995,21(3):141-143.
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82. 韩钊,徐文帧,刘鸣,等.MG 患者周围血中CD4+T 淋巴细胞亚群的研究.中国神经兔疫学和神经病学杂志,1999,6(2):82-85.
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85. 张清勇,魏云,王铁栓,等.MG 胸腺摘除前后血清抗乙酰胆碱受体抗体、抗突触前膜抗体及可溶性白细胞介素2 受体的变化.中华实验外科杂志,1999,16(3):220-221.
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87. Isabel P,Neito k.Prognosis factors for myasthenia gravis treated by thymectomy:review of 61cases.Ann Thorac Surg,1999,67:1568-1571.
88. De Perrot M,Liu J,Bril V,et al. Prognostic significance of thymomas in patients with myasthenia gravis.Ann Thorac Surg,2002,74(5):1658-1662.
89. Roth T,Achermann R,Stein,et al.Thirteen years follow-up after radical transsternal thymectomy for myasthenia gravis.Do short-term results predict long-term outcome.Eur J Cardiothorac Surg,2002,21(4):664-670.
90. Bril V,Kojic J,Dhanani A.The long-term clinical outcome of myasthemia gravis in patients with thymoma. Neurology,1998,51(10):1198-1200.
91. 王如文,蒋耀光,薛志强,等.胸腺瘤合并MG 与单纯MG 的临床特征及手术疗效分析.中华外科杂志,2004,42:1-4.
92. Budde JM,Morris CD,Gal AA,et al.Predictors of outcome in thymectomy for myasthemia gravis.Ann Thorac Surg,2001,72(7):197-202.
93. Tansel T,Onursal E,Barlas S, et al. Results of surgical treatment for nonthym-omatous myasthenia gravis.Surg Today, 2003,33(9):666-70.
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56. 林航,涂来慧.酶联免疫吸附实验检测MG 患者血清抗丝蛋白抗体.中华神经精神科杂志,1992,25(5):281-283.
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59. 张义芳,叶贤坤,赵振军,等.MG 乙酰胆碱受体抗体的研究临床研究. 河北医科大学学报, 2001, 22(5):292-293.
60. Djabiri F.Association of the AChR alpha subunit gene (CHRNA), DQA1*0101, and the DR3 haplotype in myasthenia gravis: evidence for a three gene disease model in a subgroup of patients. J Autoimmun,1997,10:407–413.
61. Marx A. Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas. Lab Invest,1990, 62:279–286.
62. Mygland A.Thymomas express epitopes shared by the ryanodine receptor. J Neuroimmunol,1995,62:79–83.
63. Buckley C.Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol,2001, 50(1):64–72.
64. Spuler S.Thymoma-associated myasthenia gravis: transplantation of thymoma and extrathymomal thymic tissue into SCID mice. Am J Pathol,1996,148:1359–1365.
65. 张镜如,乔健天.生理学.第四版,北京,人民卫生出版社,1996,42-45.
66. De Lancrolle,Felsen R.Effects of antibodies to Myosin light chain kinase in contractility and Myosin phosphorylation in chemically permeabilized smooth muscle.Circ Res,1999,68:457-463.
67. Dell A,Antonc SM,Gautt CJ,et al.Autoimmune determinants of rheumatic carditis: Localization of epitopes in human cardiac Myosin.Eur Heart J,1997,12:158-166.
68. Ohta M, Ohta K, Itoh N,et al. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-Myosin, actoMyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta,2003, 187(3):255-264.
69. Penn AS, Schotland DL, Lamme S. Antimuscle and antiacetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve,1996,9(5):407-415.
70. Mohan S,Barohn RJ,Krolick KA.Unexoected crossreacting between Myosin and a main immunogenic region(MIR) of the acetylcholine receptor by antisera obtained from myasthenia gravis patients. Clin.Immunol Immunopath,2002,64(5):218-224.
71. Mohan S,Barohn RJ,Jackson CE,et al.Evaluation of Myosin reactive antibodies from a panel of myasThenia gravis patients.Clin.Immunol ImmunopaTh,1994,70:266.
72. Dan-Goor M,Muhlrad A.Antibody directed against the 142-148 sequence of the Myosin heavy chain interferes with Myosin-actin interaction. Biochem, 1991, 30: 400-408.
73. Koren E,Koscce M,Wolfsin-Reichlin M,et al.Muine and hyman antibodies to native DNA that cross-react with the A and D S nRNP Polypeptides cause direct injury of cultured kidney cells.J Immunolog,1995,154(9):4857-1862.
74. De Lancrolle,Felsen R.Effects of antibodies to Myosin light chain kinase in contractility and Myosin phosphorylation in chemically permeabilized smooth muscle.Circ Res,1999,68:457-463.
75. 高波廷,杨明山,徐金枝,等. MG 患者胸腺切除术后血清自身抗体水平变化和临床转归分析.中国神经精神疾病杂志,1995,21(3):141-143.
76. 邵孟平,毛履玫,吕传真,等.胸腺切除后血清乙酰胆碱受体抗体改变及与疗效关系. 中华胸心血管外科杂志,1995,11( l):12-13.
77. Ozdemir N, Kara M, Dikmen E, et al. Predictors of clinical outcome following extended thymectomy in myasthenia gravis.Eur J Cardiothorac Surg,2003,23(2):233-237.
78. Masaoka A, Yamakawa Y, Niwa H, et al. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg, 1996, 62(3): 853–859.
79. Olanow CW,Wechsler AS,Roses AD.A prospective study of thymectomy and serum acetylcholine receptor antibodies in myasthenia gravis.Ann Surg,1992,196:113-117.
80. Vincent A,Newsom-Davis J,Newton P,et al.Acetylcholine receptor antibody and clinical response to thymetomy in myasthenia gravis.Neurology,1993,33:1276-1280.
81. Limburg PC,Osterhuis HJ,Hummel-Tappel E,et al.Relationship between changes in anti-acetylcholine receptor antibody concentration and disease severity.Ann NY Acad Sci,1991,377:859-865.
82. 韩钊,徐文帧,刘鸣,等.MG 患者周围血中CD4+T 淋巴细胞亚群的研究.中国神经兔疫学和神经病学杂志,1999,6(2):82-85.
83. 国红,孙红,许贤豪,等.MG 特异性免疫应答.免疫学杂志,2000,16(2):114-118.
84. Mechens A,Loliger C,Pichmeier U,et al.The impact of HLA on long term outcome after thymectomy for myasthenia gravis.J Neuroimmunol,1998(1):177-181.
85. 张清勇,魏云,王铁栓,等.MG 胸腺摘除前后血清抗乙酰胆碱受体抗体、抗突触前膜抗体及可溶性白细胞介素2 受体的变化.中华实验外科杂志,1999,16(3):220-221.
86. Ferguson MK.Transcervical thymectomy.Semi Thorac Cardiovasc Surg,1999,11 (1): 59-64.
87. Isabel P,Neito k.Prognosis factors for myasthenia gravis treated by thymectomy:review of 61cases.Ann Thorac Surg,1999,67:1568-1571.
88. De Perrot M,Liu J,Bril V,et al. Prognostic significance of thymomas in patients with myasthenia gravis.Ann Thorac Surg,2002,74(5):1658-1662.
89. Roth T,Achermann R,Stein,et al.Thirteen years follow-up after radical transsternal thymectomy for myasthenia gravis.Do short-term results predict long-term outcome.Eur J Cardiothorac Surg,2002,21(4):664-670.
90. Bril V,Kojic J,Dhanani A.The long-term clinical outcome of myasthemia gravis in patients with thymoma. Neurology,1998,51(10):1198-1200.
91. 王如文,蒋耀光,薛志强,等.胸腺瘤合并MG 与单纯MG 的临床特征及手术疗效分析.中华外科杂志,2004,42:1-4.
92. Budde JM,Morris CD,Gal AA,et al.Predictors of outcome in thymectomy for myasthemia gravis.Ann Thorac Surg,2001,72(7):197-202.
93. Tansel T,Onursal E,Barlas S, et al. Results of surgical treatment for nonthym-omatous myasthenia gravis.Surg Today, 2003,33(9):666-70.
94. Nakamure H,Taniguchi Y,Suzuki Y,et al.Delayed remission after thymectomy for myasthenia gravis of the purely ocular type. J Thorac Cardiovasc Surg, 1996,11:12-14.
95. Muldder.Thymectomy for myasthenia gravis:recent observation and comparisons with past experience.Ann Thorac Surg,1999,48:551-556.
96. 陆轩,毛履琰.胸腺切除治疗MG 远期疗效及影响因素的分析.中华外科杂志,1999,37(3);159-161.
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