CXCL13与重症肌无力的相关性研究及实验性自身免疫性重症肌无力小鼠模型的建立
|
摘要
研究背景重症肌无力主要是由乙酰胆碱受体抗体介导的,补体参与,细胞免疫依赖性,针对神经肌肉接头处突触后膜上乙酰胆碱受体的自身免疫性疾病。目前,重症肌无力的确切发病机制尚未完全明确,但普遍认为该病的发生与乙酰胆碱受体抗体的产生密切相关。B淋巴细胞是唯一能够分泌抗体的细胞,在体液免疫中发挥着重要作用,尤其是在血清抗体阳性的重症肌无力的发病过程中扮演了重要角色。趋化因子是能使细胞发生趋化作用的细胞因子的总称,为一类结构功能相似,分子量在8～10kD的小分子蛋白质,其主要作用是趋化细胞迁移。根据多肽链一级结构的不同将趋化因子分为CXC亚家族和CC亚家族。其中CXC亚家族分子靠近N一端两个半胱氨酸之间有一个任意氨基酸,主要作用于中性粒细胞,并对淋巴细胞有趋化作用。趋化因子受体是一类介导趋化因子行使功能的GTP蛋白耦联的跨膜受体,通常表达于免疫细胞、内皮细胞等细胞膜上。趋化因子能与其受体相互作用,通常一种趋化因子受体能与多种趋化因子相结合,而一个趋化因子可能有多个高亲和性受体,他们共同构成复杂的网络系统。CXCL13是CXC趋化因子家族成员之一,已经被证实在B淋巴细胞寻靶和淋巴组织中B细胞区的形成中有着重要作用,但目前尚无明确的关于CXCL13与重症肌无力发病机制相互关系的报道。
实验性自身免疫性重症肌无力动物模型是研究重症肌无力发病机制的重要工具之一。目前,建立实验性自身免疫性重症肌无力动物模型有主动免疫和被动免疫两种方法,但是各有优缺点。一直以来,人类也在不断地探索,寻求建立完美的实验动物模型的方法,但尚未达成这一目标。
目的通过检测CXCL13在重症肌无力患者血清中的水平以及CXCL13 mRNA在胸腺组织表达水平,来探讨CXCL13在重症肌无力的发病中的地位和作用,并阐述其在治疗研究中的价值。本研究拟通过被动移植重症肌无力患者增生的胸腺的方法建立实验动物模型,为研究重症肌无力的发病机制提供了一种新的实验工具。
方法收集湘雅医院胸外科、神经内科重症肌无力患者治疗前及治疗后一周、一个月的血液标本各54份及健康体检者血液标本30份,用ELISA方法检测CXCL13在血清中的浓度。收集20例胸腺增生合并重症肌无力住院手术患者的胸腺标本及10例先天性心脏病手术患者胸腺组织标本,同时进行胸腺组织培养,用ELISA方法检测CXCL13在胸腺组织培养液上清中的水平,同时用RT-PCR的方法检测CXCL13mRNA在胸腺组织的表达水平,分析CXCL13、胸腺与重症肌无力三者之间的关系。将重症肌无力患者增生的胸腺组织被动移植到BALB/c裸小鼠腹腔建立重症肌无力动物模型,并通过症状观察、电生理检测、免疫组化、透射电镜和乙酰胆碱受体计数的方法来评价该动物模型,分析其用于重症肌无力发病机制研究中的意义。
结果54份重症肌无力患者血清中CXCL13的浓度水平明显高于正常对照组(p＜0.05),在接受了肾上腺皮质激素治疗或胸腺切除手术的一个月之后,患者血清中CXCL13浓度水平较治疗之前有明显下降(p＜0.01),而CXCL13在眼肌型重症肌无力和全身型重症肌无力患者血清中的浓度水平无明显差异(p＞0.05);CXCL13在重症肌无力患者胸腺组织培养上清液中浓度水平显著高于正常对照组(p＜0.01),而在培养液中加入地塞米松后,其浓度水平会明显下降,并且与地塞米松的剂量呈负相关,而且在增生的胸腺组织中,CXCL13 mRNA的表达水平也显著高于正常胸腺组织(p＜0.01);在建立重症肌无力实验动物模型的研究中,25只实验组小鼠有9只(36%)出现了肌无力的表现,并通过电生理检测、免疫组化、透射电镜和乙酰胆碱受体计数的方法检测证实其组织改变与人类重症肌无力组织改变相近。
结论CXCL13在重症肌无力患者血清中的浓度较正常人群明显增高,但在经过激素治疗和胸腺切除之后,其在血清中的浓度会缓慢下降,说明其可能可以作为重症肌无力患者血清指标,动态监测其水平变化可作为患者对治疗的反应性检测指标;CXCL13有可能成为评价重症肌无力患者预后的指标之一;在重症肌无力患者的增生胸腺组织中,存在着CXCL13 mRNA的大量表达,从而导致了CXCL13在组织培养上清液中及血清中水平增加,胸腺CXCL13的产生中扮演了重要角色。;地塞米松可直接抑制胸腺产生CXCL13;CXCL13有可能成为重症肌无力治疗研究的新靶点;通过将重症肌无力患者的胸腺组织被动转移至BALB/c裸小鼠腹腔的方法,可以成功建立实验性自身免疫性重症肌无力动物模型,此模型可作为研究胸腺与MG发病机制关系的实验工具。
创新点
1、首次通过ELISA方法和PT-PCR方法测定血清中CXCL13浓度水平及胸腺组织中CXCL13 mRNA的表达,从而评价了CXCL13、胸腺、重症肌无力三者之间的关系。
2、通过胸腺组织块培养模拟胸腺在体内生长的环境,并加用地塞米松进行干预,从而证明地塞米松可抑制胸腺产生CXCL13,为将来重症肌无力治疗的研究提供一个新的切入点。
3、首次采用将MG患者增生胸腺组织被动转移到BALB/c裸小鼠腹腔的方法成功建立了重症肌无力动物模型,该模型可更好地用于胸腺与MG发病关系的进一步研究,为MG发病机制的研究工作提供了新的研究工具。
展望
1、对MG患者进行血清CXCL13水平的长期动态监测,可能进一步评价其与症状波动之间的相关性。
2、CXCL13水平与胸腺瘤合并MG患者的相关性有待于进一步研究。
3、对于免疫抑制剂、放射治疗等干预措施,对CXCL13水平的影响尚需要深入探讨。
4、本研究中的动物模型还有待于进一步完善,以进一步提高建模成功率、缩短建模周期。
Background Myasthenia gravis(MG) is a neuromuscular disease with an autoimmune etiology.It is mediated by acetylcholine receptor antibody,which directed against nicotinic acetylcholine receptor. Although progress has been made in studying for MG,it is still unknown by us about its real pathogenesis.B-lymphocyte is known to be the only kind of cell that could secrete antibody,and it plays a key role in humoral immunity,especially in the patients with seropositive myasthenia gravis (SPMG).Chemotatic factor is a group of protein,which can stimulate cells migrating to the target tissue.Chemotatic factors can be divided into CXC subfamily and CC subfamily according to the difference of primary structure in polypeptide chain.Chemotatic factors in CXC subfamily can effect neutrophilic granulocyte and stimulate lymphocyte obtaining chemotaxis.Chemotatic factors could bind with their specified receptors to produce a marked effect of chemotaxis.CXCL13 is confirmed to be important for the formation and targeting of B-lymphocyte.It is reported that CXCL 13 plays a key role in several autoimmune disease,but there is no report about the relationship between CXCL13 and MG disease.
Experimental autoimmune myasthenia gravis animal model is an important tool to study pathogenesis of MG.There are several methods to establish the animal model at the moment,but none of these methods is perfect.
Objective To elucidate the relationship among CXCL13,thymus and MG,the concentration in serum and thymus tissue of CXCL13 in MG patients have been tested by way of ELISA.And we also test the level of expression of the CXCL13 mRNA in thymus tissues by way of RT-PCR. At the same time,we transfer the thymus tissue to the nude mice in order to establish a kind of animal model about experimental autoimmune myasthenia gravis(EAMG) for the further study in MG.
Methods 54 serum samples of patients with MG complicated with thymic hyperplasia were respectively collected in Xiangya hospital in one week post-treatment,one month post-treatment and pretherapy. The concentration in serum of CXCL13 is tested by ELISA.20 resected tissue samples of thymus of MG patients are examined by RT-PCR to observe the expression level of CXCL13.And the concentration in supernatant of thymic tissue culture of CXCL13 is also tested by ELISA. The fragments of hyperplasia thymic tissue were transferred into abdominal cavity of BALB/c nude mice in order to establish a kind of animal model about experimental autoimmune myasthenia gravis.And the methods of immunohistochemistry,transmission electron microscope, electromyogram and symptom observation were used to evaluate the animal model.
Results The CXCL13 concentration in serum of MG patients in pretherapy is thicker than the normal people(p＜0.05),but it will decrease obviously one month after the treatment of glucocorticoid or thyectomy (p＜0.01).There is no difference of CXCL13 concentration between ocular MG patients and generalized MG patients(p＞0.05).The CXCL13 concentration in supernatant of hyperplasia thymic tissue culture of MG patients is thicker than that in normal thymic tissue(p＜0.01).And the level of CXCL13 mRNA expression in hyperplasia thymic tissue is also higher than the normal one.If we add dexamethasone into the culture fluid,we can observe that the CXCL13 concentration in supernatant becomes thinner(p＜0.01).The more the dexamethasone we add,the thinner the CXCL13 concentration will be.In the experiment of establishing animal models of EAMG,we obtain 9 mice presenting the symptoms of MG(9/25),and it is confirmed to fit the morphological features of human MG by way of immunohistochemistry,transmission electron microscope and electromyogram.
Conclusions Because the serum CXCL13 concentration of MG patients is thicker than that in normal people,in addition,it will decrease obviously after treatment,we think that CXCL13 may be the serum maker of MG patients,and we could evaluate the effect of treatment and the prognosis by monitoring CXCL13 concentration in MG patients' serum.Because of over expression of CXCL13 mRNA in hyperplasia thymic tissue,which lead to increasing of CXCL13 concentration in supematant of hyperplasia thymic tissue culture,we think that the thymus may play a key role of MG.Dexamethasone could inhibit the expression of CXCL13 mRNA directly,and CXCL13 might be the new target of further research for the MG treatment.A new animal model of EAMG could be established by way of transplanting the fragment of hyperplasia thymic tissue into BALB/c nude mice,which might be a kind of new tool for the further research of MG,especially for the research of relationship between thymus and MG.
实验性自身免疫性重症肌无力动物模型是研究重症肌无力发病机制的重要工具之一。目前,建立实验性自身免疫性重症肌无力动物模型有主动免疫和被动免疫两种方法,但是各有优缺点。一直以来,人类也在不断地探索,寻求建立完美的实验动物模型的方法,但尚未达成这一目标。
目的通过检测CXCL13在重症肌无力患者血清中的水平以及CXCL13 mRNA在胸腺组织表达水平,来探讨CXCL13在重症肌无力的发病中的地位和作用,并阐述其在治疗研究中的价值。本研究拟通过被动移植重症肌无力患者增生的胸腺的方法建立实验动物模型,为研究重症肌无力的发病机制提供了一种新的实验工具。
方法收集湘雅医院胸外科、神经内科重症肌无力患者治疗前及治疗后一周、一个月的血液标本各54份及健康体检者血液标本30份,用ELISA方法检测CXCL13在血清中的浓度。收集20例胸腺增生合并重症肌无力住院手术患者的胸腺标本及10例先天性心脏病手术患者胸腺组织标本,同时进行胸腺组织培养,用ELISA方法检测CXCL13在胸腺组织培养液上清中的水平,同时用RT-PCR的方法检测CXCL13mRNA在胸腺组织的表达水平,分析CXCL13、胸腺与重症肌无力三者之间的关系。将重症肌无力患者增生的胸腺组织被动移植到BALB/c裸小鼠腹腔建立重症肌无力动物模型,并通过症状观察、电生理检测、免疫组化、透射电镜和乙酰胆碱受体计数的方法来评价该动物模型,分析其用于重症肌无力发病机制研究中的意义。
结果54份重症肌无力患者血清中CXCL13的浓度水平明显高于正常对照组(p＜0.05),在接受了肾上腺皮质激素治疗或胸腺切除手术的一个月之后,患者血清中CXCL13浓度水平较治疗之前有明显下降(p＜0.01),而CXCL13在眼肌型重症肌无力和全身型重症肌无力患者血清中的浓度水平无明显差异(p＞0.05);CXCL13在重症肌无力患者胸腺组织培养上清液中浓度水平显著高于正常对照组(p＜0.01),而在培养液中加入地塞米松后,其浓度水平会明显下降,并且与地塞米松的剂量呈负相关,而且在增生的胸腺组织中,CXCL13 mRNA的表达水平也显著高于正常胸腺组织(p＜0.01);在建立重症肌无力实验动物模型的研究中,25只实验组小鼠有9只(36%)出现了肌无力的表现,并通过电生理检测、免疫组化、透射电镜和乙酰胆碱受体计数的方法检测证实其组织改变与人类重症肌无力组织改变相近。
结论CXCL13在重症肌无力患者血清中的浓度较正常人群明显增高,但在经过激素治疗和胸腺切除之后,其在血清中的浓度会缓慢下降,说明其可能可以作为重症肌无力患者血清指标,动态监测其水平变化可作为患者对治疗的反应性检测指标;CXCL13有可能成为评价重症肌无力患者预后的指标之一;在重症肌无力患者的增生胸腺组织中,存在着CXCL13 mRNA的大量表达,从而导致了CXCL13在组织培养上清液中及血清中水平增加,胸腺CXCL13的产生中扮演了重要角色。;地塞米松可直接抑制胸腺产生CXCL13;CXCL13有可能成为重症肌无力治疗研究的新靶点;通过将重症肌无力患者的胸腺组织被动转移至BALB/c裸小鼠腹腔的方法,可以成功建立实验性自身免疫性重症肌无力动物模型,此模型可作为研究胸腺与MG发病机制关系的实验工具。
创新点
1、首次通过ELISA方法和PT-PCR方法测定血清中CXCL13浓度水平及胸腺组织中CXCL13 mRNA的表达,从而评价了CXCL13、胸腺、重症肌无力三者之间的关系。
2、通过胸腺组织块培养模拟胸腺在体内生长的环境,并加用地塞米松进行干预,从而证明地塞米松可抑制胸腺产生CXCL13,为将来重症肌无力治疗的研究提供一个新的切入点。
3、首次采用将MG患者增生胸腺组织被动转移到BALB/c裸小鼠腹腔的方法成功建立了重症肌无力动物模型,该模型可更好地用于胸腺与MG发病关系的进一步研究,为MG发病机制的研究工作提供了新的研究工具。
展望
1、对MG患者进行血清CXCL13水平的长期动态监测,可能进一步评价其与症状波动之间的相关性。
2、CXCL13水平与胸腺瘤合并MG患者的相关性有待于进一步研究。
3、对于免疫抑制剂、放射治疗等干预措施,对CXCL13水平的影响尚需要深入探讨。
4、本研究中的动物模型还有待于进一步完善,以进一步提高建模成功率、缩短建模周期。
Background Myasthenia gravis(MG) is a neuromuscular disease with an autoimmune etiology.It is mediated by acetylcholine receptor antibody,which directed against nicotinic acetylcholine receptor. Although progress has been made in studying for MG,it is still unknown by us about its real pathogenesis.B-lymphocyte is known to be the only kind of cell that could secrete antibody,and it plays a key role in humoral immunity,especially in the patients with seropositive myasthenia gravis (SPMG).Chemotatic factor is a group of protein,which can stimulate cells migrating to the target tissue.Chemotatic factors can be divided into CXC subfamily and CC subfamily according to the difference of primary structure in polypeptide chain.Chemotatic factors in CXC subfamily can effect neutrophilic granulocyte and stimulate lymphocyte obtaining chemotaxis.Chemotatic factors could bind with their specified receptors to produce a marked effect of chemotaxis.CXCL13 is confirmed to be important for the formation and targeting of B-lymphocyte.It is reported that CXCL 13 plays a key role in several autoimmune disease,but there is no report about the relationship between CXCL13 and MG disease.
Experimental autoimmune myasthenia gravis animal model is an important tool to study pathogenesis of MG.There are several methods to establish the animal model at the moment,but none of these methods is perfect.
Objective To elucidate the relationship among CXCL13,thymus and MG,the concentration in serum and thymus tissue of CXCL13 in MG patients have been tested by way of ELISA.And we also test the level of expression of the CXCL13 mRNA in thymus tissues by way of RT-PCR. At the same time,we transfer the thymus tissue to the nude mice in order to establish a kind of animal model about experimental autoimmune myasthenia gravis(EAMG) for the further study in MG.
Methods 54 serum samples of patients with MG complicated with thymic hyperplasia were respectively collected in Xiangya hospital in one week post-treatment,one month post-treatment and pretherapy. The concentration in serum of CXCL13 is tested by ELISA.20 resected tissue samples of thymus of MG patients are examined by RT-PCR to observe the expression level of CXCL13.And the concentration in supernatant of thymic tissue culture of CXCL13 is also tested by ELISA. The fragments of hyperplasia thymic tissue were transferred into abdominal cavity of BALB/c nude mice in order to establish a kind of animal model about experimental autoimmune myasthenia gravis.And the methods of immunohistochemistry,transmission electron microscope, electromyogram and symptom observation were used to evaluate the animal model.
Results The CXCL13 concentration in serum of MG patients in pretherapy is thicker than the normal people(p＜0.05),but it will decrease obviously one month after the treatment of glucocorticoid or thyectomy (p＜0.01).There is no difference of CXCL13 concentration between ocular MG patients and generalized MG patients(p＞0.05).The CXCL13 concentration in supernatant of hyperplasia thymic tissue culture of MG patients is thicker than that in normal thymic tissue(p＜0.01).And the level of CXCL13 mRNA expression in hyperplasia thymic tissue is also higher than the normal one.If we add dexamethasone into the culture fluid,we can observe that the CXCL13 concentration in supernatant becomes thinner(p＜0.01).The more the dexamethasone we add,the thinner the CXCL13 concentration will be.In the experiment of establishing animal models of EAMG,we obtain 9 mice presenting the symptoms of MG(9/25),and it is confirmed to fit the morphological features of human MG by way of immunohistochemistry,transmission electron microscope and electromyogram.
Conclusions Because the serum CXCL13 concentration of MG patients is thicker than that in normal people,in addition,it will decrease obviously after treatment,we think that CXCL13 may be the serum maker of MG patients,and we could evaluate the effect of treatment and the prognosis by monitoring CXCL13 concentration in MG patients' serum.Because of over expression of CXCL13 mRNA in hyperplasia thymic tissue,which lead to increasing of CXCL13 concentration in supematant of hyperplasia thymic tissue culture,we think that the thymus may play a key role of MG.Dexamethasone could inhibit the expression of CXCL13 mRNA directly,and CXCL13 might be the new target of further research for the MG treatment.A new animal model of EAMG could be established by way of transplanting the fragment of hyperplasia thymic tissue into BALB/c nude mice,which might be a kind of new tool for the further research of MG,especially for the research of relationship between thymus and MG.
引文
[1]Im SH,Barchan D,Maiti PK,et al.Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Thl differentiation and up-regulation of CTLA-4.J Immunol,2001,166:6893-6898
[2]Macdonald BK,Cockerell OC,Sander JW,et al.The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK.Brain,2000,123:665-676.
[3]Engel AG,Arahata K.The membrane attack complex of complement at the endplate in myasthenia gravis.Ann NY Acad Sci,1987,505:326-332.
[4]Drachman DB,Angus DW,Adams RN,et al.Myasthenia antibodies cross-link AchR to accelerate degradation.N Engl Med,2002,298:1116-1122.
[5]Drachman DB,Adams RN,Josifek LF,et al.Functional activities of autoantibodies to AchR and the clinical severity of myasthenia gravis.N Engl Med,2000,307:769-775.
[6]Legler,DF,et al.B cell-attracting chemokine 1,a human CXC chemokine expressed in lymphoid tissues,selectively attracts B lymphocytes via BLR1/CXCR5.J Exp Med 1998.187:655-660.
[7]Cyster JG.Chemokines and cell migration in secondary lymphoid organs.Science.1999;286:2098-2102
[8]Melchers F,Rolink AG,Schaniel C.The role of chemokines in regulating cell migration during humoral immune responses.Cell.1999;99:351-354
[9]Salomonsson S,Larsson P,Tengn(?)r,P,et al.Expression of the B Cell-Attracting Chemokine CXCL13 in the Target Organ and Autoantibody Production in Ectopic Lymphoid Tissue in the Chronic Inflammatory Disease Sj(o|¨)gren's Syndrome.Scand J Immunol,2002,55(4):336-342
[10]Forster R.,Mattis A.E.Kremmer,E,at al.CXCR5-Dependent Seeding of Follicular Niches by B and Th Cells Augments Antiviral B Cell Responses.Cell,1996,87(13):1037-1047
[11]Younger DS,Raksadawan N.Medical therapies in myasthenia gravis.Chest Surg Clin N Am.2001;11:329-336
[12]Richman DP,Agius MA.Treatment of autoimmune myasthenia gravis.Neurology.2003;61:1652-1661.
[13]Papatestas AE,,Genkins G,,Kornfeld P,et al.Effects of thymectomy in myasthenia gravis.Ann Surg.1987;206:79-88
[14]蒋耀光,王如文,赵云平,等.重症肌无力胸腺切除236例分析[J].中国胸心血管外科杂志,2004,11(1):32-34.
[15]Nakamura H,et al.Delayed remission after thymectomy for myasthenia gravis of purely ocular type[J].Thorac Cardrovasc Surg,1996,112:371
[16]Paas-Rozner M,Dayan M,Paas Y,et al.Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.Proc Natl Acad Sci USA,2000,97(5):2168-2173.
[17]Schonbeck S,Padberg F,Hohlfeld R,et al.Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice,a new model of myasthenia gravis.J Clin Invest,1992,90(1),245-250
[18]刘绛光,王晓辉,张宏,等.实验性自身免疫性重症肌无力动物模型[J].中国神经免疫学神经病学杂志.2005,12(3):90-92
[19]Lennon VA,Lindstrom JM,Seybold ME,et al.Experimental autoimmune myasthenia:a model of myasthenia gravis in rats and guinea pigs[J].J Exp Med,1975,141:1365-1372
[20]Karuman PM,Soo KC.Motor innervation of the trapezios muscle:a histochemical study[J].Head Neck,1996,19(3):254-258
[21]Ma J,Smith BP,Smith TL,et al.Juvenile and adult rat neuromuscular junctions density,distribution and morphology[J].Muscle Nerve.2002,26(6):804-809
[22]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.国外医学神经病学神经外科学分册.2002,29(3):265-268
[1] Im SH, Barchan D, Maiti PK, et al .Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Thl differentiation and up-regulation of CTLA-4. J Immunol,2001,166:6893-6898
[2] Macdonald BK, Cockerell OC, Sander JW, et al. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain, 2000,123:665-676.
[3] Yu mai wan C.Y., Chinnery P.F., Griffiths P.G., et al. Extraocular muscles have fundanmentally distinct properties that make them selectively vunnerable to certain disorders .Neuromuscular Disorders,2005,15: 17-23
[4] Lindstrom JM, Acetylcholine receptors and myasthenia. Muscle Nerve.2000 Apr;23(4):453-477
[5] Stacy S ,Gelb BE, Koop BA, et al .Split tolerance in a novel transgenic model of autoimmune myasthenia gravis .[J] J.Immunol,2002,169(11):6570-6579
[6] Paas-Rozner M, Sela M, Mozes E. The nature of the active suppression of Responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered different routes. [J] Proc Natl Acad Sci USA ,2001,98(22):12642-12647
[7] Tzartos M, Barkas T, Cung MT, et al. The main immunogenic region of acetylcholine receptor. Structure and role in myasthenia gravis. Autoimmunity, 2001 ,8: 259.
[8] Batetra B , Moretei M, Longhi R ,et al .Antibodies against neuronal nicotinic receptor subtypes in neurological disorders. J Neuroimmunol, 2000,102:89 -97
[9] Romi F .,Skeie GO., Arrli JA .,et al .Muscle auto antibodies in subgroups of MG patients. J Neurol, 2000,24 7:369-375.
[10] Bufler J, Pitz R, Czep M, et al. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels[J]. Ann Neurol, 1998, 43(4): 458-464.
[11] Drachman DB. Myasthenia gravis. N Eng J Med, 1994,330(25):1797-1810
[12] Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann NY Acad Sci,1987,505: 326-332.
[13] Drachman DB, Angus DW,Adams RN, et al. Myasthenia antibodies cross-link AchR to accelerate degradation. N Engl Med, 2002,298:1116-1122.
[14] Drachman DB, Adams RN, Josifek LF,et al. Functional activities of autoantibodies to AchR and the clinical severity of myasthenia gravis. N Engl Med, 2000, 307: 769-775.
[15] Moiola, Galbiati, Martino,et al. IL-12 is involved in the induction of experimental auto immune myasthenia gravis, an antibody-mediated disease. Eur J Immunol, 1998,28:2487.
[16] Vincent A, Willcox N, Hill M, et al. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. J Immunol Rev, 1998, 164: 157-168.
[17] Fostieri E, Beeson D, Socrates J, et al. The conformation of the main immunogenic region on the a subunit of muscle acetylcholine receptor is affected by neighboring receptor subunits. FEBS Lett. 2000, 481: 127-1 30.
[18] Romi F, Lars B, Skeie G, et al. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol, 2002,128: 82-89.
[19] Aarli JA, Skeie GO, Mygland A, et al. Muscle striation antibodies in myasthenia gravis Diagnostic and functional significance. Ann NY Acad Sci, 1998, 841:505-515.
[20] Lubke E, Freiburg A, Skeie GO, et al. Striational autoantibodies in myasthenia gravis patients recognize I-band titin epitopes. J Neuroimmunol, 1998, 81: 98-108.
[21] Somnier FE. Engel PJH. The occurrence of anti-titin antibodies and thymomas. a population survey of MG 1970-1999. Neurology, 2002, 59: 92-98.
[22] Romi F, Skeie GO, Aarli JA, et al. The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies. Arch Neural,2000,57:1596-1600.
[23]Menegazzi P,Larini F,Treves S,et al.Identification and characterization of three calmodulin binding sites of the skeletal muscle ryanodine receptor.Biochemistry,1994,33:9078-9084.
[24]Mygland A,Tysnes OB,Aarli JA,et al.Myasthenia gravis patients with a thymoma have antibodies against a high molecular weight protein in sarcoplasmic reticulum.J Neuroimmunol,1992,37:1-7
[25]Mygland A,Tysnes OB,Matre R,et al.Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma.Ann Neurol,1992,32:589-591
[26]Skeie GO,Lunde PK,Sejersted OM,et al.Myasthenia gravis sera containing antiryanodine receptor antibodies inhibit binding of[3H]-ryanodine to sarcroplasmic reticulum.Muscle Nerve,1998,21:329-335.
[27]Skeie GO,Lunde PK,Sejersted OM,et al.Autoimmunity against antiryanodine receptor in myasthenia gravis.Acta Physiol Scand,2001,171:379-384
[28]Mygland A,Kuwajima G,Mikeshiba K,et al.Thymoma express epitopes shared by the ryanodine receptor.J Neuroimmunol,1995,62:79-83.
[29]张祥,乔健,吕传真.重症肌无力患者血清中Ryanodine受体抗体检测及其临床意义.中华神经科杂志,2003,36(6):436-439.
[30]Hoch W,McConville J,Helms S,et al.Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.Nat Med,2001,7:365-368.
[31]Bowen DC,Park JS,Bodine S,et al.Localization and regulation of MuSK at Neuromuscular junction.Dev Biol,1998,199:309-319.
[32]McConvile J,Vincent A.Disease of the neuromuscular junction.Curr Opin Phamacol,2002,2:296-301
[33]McConvile J,Farrugia ME,Kishore U,et al.Detection and characterization of MuSK antibodies in seronagative myasthenia gavis.Ann Neurol,2004,55:580-584
[34]Matthews I,Chen S,Hewer R,et al.Muscle-specific receptor tyrosine kinase autoantibodies:a new immunoprecipitation assay.Clin Chim Acta 2004,348: 95-99.
[35]Zhou L,McConville J,Chaudhry V,et al.Clinical comparison of muscle-specific tyrosine kinase(MUSK) antibody-positive and -negative myasthenic patients.Muscle Nerve 2004;30:55-60
[36]Shiraishi H,Motomura M,Yoshimura T,et al.Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis.Ann Neurol 2005;57:289-293.
[37]Nemoto Y,Kuwabara S,Misawa S,et al.Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis.J Neurol Neurosurg Psychiatry 2005;76:714-718
[38]张云.重症肌无力与突触前膜抗体.四川解剖学杂志,2002,10(3):177-179.
[39]李大年.现代神经内科学.山东科学技术出版社,第一版.2002,934-938.
[40]Zhang W,Lju JL,Meager A,et al.Autoantibodies to IL-1 2 in myasthenia gravis patients with thymoma;effects on the IFN-γresponses of healthy CD4~+T cells.J Neuroimmun,2003,139:102-108.
[41]Rapoport B,Portolano S,McLachlan SM,et al.Combinational libraries:new insight into organ-specific autoantibodies.J Immunol Today,1995,16:43-49
[42]Elms A,Schalka BCG,Kirchner TH,et al.Thymus in myasthenia gravis.Isolation of T-lymphocyte lines specified for the nicotinic acetylcholine receptor from thymus of myasthenia gravis.[J].J Clin Invest,1988,81:902-908
[43]Balandina A,Lecart S,Dartevelle P,et al.Functional defect of regulatory CD_4~+CD_(25)~+T cells in the thymus of patients with autoimmune myasthenia gravis.Blood,2005,105:735-741.
[44]Link H,Xiao BG.Rat models as tool to develop new inununotherapies.[J].Immunol Rev,2001,184:117-128
[45]Wang HB,Shi FD,Li HL,et al.Role for interferon-γ in rat strains with different susceptibility to experimental autoimmune myasthenia gravis[J].Clin Immunol,2000,95(2):156.
[46]Reyes-Reyna SM,Krolick KA.Chemokine production by rat myocytes exposed to interferon-gamma[J].Clin Immunol,2000,94(2):105.
[47]王炜,南振鸿,凌振芬,等.干扰素γ对重症肌无力患者自身抗体的调节作用及相关性分析[J].中国神经免疫学和神经病学杂志,2000,7(4):234.
[48]Poea-Guyon S,Christadoss P,Panse RL,et al.Effects of cytokines on acetylcholine receptor expression:implications for myasthenia gravis[J].J Immunol,2005,174:5941.
[49]Gu D,Wogensen L,Calcutt NA,et al.Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.J Exp Med 1995,181(2):547-557
[50]Balasa B,Deng C,Lee J,et al.Interferon-gamma is necessary for the genesis of acetycholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.[J]J Exp Med,1997,186(3):385-391
[51]Goluszko E,Deng C,Possin MA,et al.Tumor necrosis receptor p55 and p75deficiency protects mice from developing experimental autoimmune myasthenia gravis[J].J Neuroimmunol,2002,122(1-2):85.
[52]赖祥青,杨明山,徐金枝。等.重症肌无力患者免疫发病机理的研究[J].中国病理生理学杂志.2001,17(7):662.
[53]Duan RS,Wang HB,Yang JS,et al.Anti-TNF-α antibodies suppress the development of experimental autoimmune myasthenia gravis[J].J Autoimmun,2002,19(4):169-174.
[54]Bongioanni P,Ricciardi R,Pellegrino D,et al.T-cell tumor necrosis factor-αreceptor binding in myasthenic patients[J].J Neuroimmunol,1999,93(1-2):203-207
[55]Zhang J,Zhou WB,Wang HL,The effects of T cell subpopulations and recombinant interleukin(IL)-2 on peripheral B cell function in patients with myasthenia gravis.Hum Antibodies.1997;8(2):90-94
[56]Im SH,Barchan D,Feferman T,et al.Protective molecular mimicry in experimental myasthenia gravis.Neroimmunol,2002,126(1-2):99-106
[57]Paas-Rozner M,Sela M,Mozes E.The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes.Proc Natl Acad Sci USA,2001,98(22):12642-12647
[58] Moiola L, Karachunski P, Protti MP, et al. Epitopeson the beta subunit of human muscle acetylcholine receptor recognized by CD_4~+cells of myasthenia gravis patients and healthy subjects. J Clin Invest, 1994,93:1020-1028
[59] Poussin MA, Goluszko E, David CS, et al. HLA-DQ6 Transgenic Mice Resistance to Experimental Autoimmune Myasthenia Gravis is Linked to Reduced Acetylcholine Receptor-specific IFN-y,IL -2 and IL-10 Production. J Autoimmunity 2 001 Nov; 17 (3):175-180.
[60] Dinarello CA. Interleukine 1 and Interleukine 18 as mediators of inflammation and the aging process[J]. Am J Clin Nutri. 2006, 83(2): 447.
[61] Maiti PK, Im SH. SouroujonMC, et al. A monodonal antibody specific for rat IL-18 BP and its application in determining serum IL-18 BP[J]. Immunol Lett, 2003, 85:65.
[62] Sebastian J , Guido S. Increased serum levels of the interferon- [gamma]-inducing cytokine Interleukine-18 in myasthenia gravis [J]. Neurology, 2002, 59(2): 287.
[63] Im SH, Barchen D, Maiti PK, et al. Suppression of experimental autoimmune myasthenia gravis, a B cell-mediated autoimmune diseases by blocked of IL-18[J]. FASEBJ, 2001, 15(12): 2140-2148.
[64] Stegall T, Krolick KA. Myocytes respond to both interleukin-4 and interferon-gamma: cytokine respon-siveness with the potential to influence the severity and course of experimental myasthenia gravis[J]. Clin Immunol, 2000, 94(2): 133.
[65] Ostlie N, Milani M, Wang W, et al. Absence of IL-4 facilitates the development of chronic autoimmune myasthenia gravis in C57BL/6 mice[J]. J Immunology, 2003, 170(1): 604-612.
[66] Steinberger I, Brenner T, Lorberboum-Galski HL, et al. Interleukin 2 pseudomortas rxotoxin (IL2-PE664Glu) chimeric protein kills B cells from patients with myasthenia gravis[J]. Cell Immunol, 1996,169(1): 55-61.
[67] Poussin MA, Goluszko E, Franco JU, et al. Role of IL-5 during primary and secondary immune response to acetylcholine receptor.[J].J Neuroinmmunol 2002,12 5(1-2):51-58.
[68]Saaaano P,Paparo F,Ramineri V,et al.Interleukine-6(IL-6) may be a link between myasthenia gravis and myoepithelioma of the parotid gland[J].Med Hypothesis,2007,68(2):314.
[69]张栩,孙兆林,丛志强,等.重症肌无力患者外周血单个核细胞TGF-β及IL-6水平的测定[J].青岛大学医学院学报,2003,69(4):386.
[70]Zhang GX,Xiao BG,Yu LY,et al.Interleukin 10 aggravates experimental autoimmune myasthenia gravis through inducing Yh2 and B cell responses to AChR[J].J Neuroimmunol,2001,113(1):10-18.
[71]Huang DR,Zhou YH,Xia SQ,et al.Makers in the promote region of interleukin-10 gene in myasthenia gravis:inplications of diverse effects of IL-10 in the pathogenesis of the disease[J].Neuroimmunol,1999,94(1-2):82-87.
[72]Poussin MA,Fuller CL,Goluszko E,et al.Suppressed clinical experimental autoimmune myasthenia gravis in bm12 mice is linked to reduced intracellular calcium mobilization and IL-10 and IFN-gamma release by acetylcholine receptor-specific T cells.J Neuroimmunol,2003,134:104-110.
[73]Shea-Donohue T,Thomas K,Cody MJ,et al.Mice deficient in the CXCR2ligand,CXCL1(KC/GRO-alpha),exhibit increased susceptibility to dextran sodium sulfate(DSS) induced colitis.Innate Immun 2008,14:117-124
[74]Buanne P,Di Carlo E,Caputi L,et al.Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice.J Leukoc Biol 2007,82:1239-1246
[75]Bizzarri C,Beccari AR,Bertini R,et al.ELR+ CXC chemokines and their receptors(CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets.Pharmacol Yher 2006,112:139-149
[76]Sun J,Ramnath RD,Bhatia M.Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils.Am J Physiol Cell Physiol 2007,293:C696-C704
[77]Kenrin S,Kenji H,Motoharu K,et al.Lymphoid Chemokine B Cell-Attracting Chemokine-1(CXCL13) Is Expressed in Germinal Center of Ectopic Lymphoid Follicles Within the Synovium of Chronic Arthritis Patients.J Immunol,2001,166(1):650-655
[78]Ragheb S,Lisak RP.The thymus and myasthenia gravis.Chest Surg Clin N Am,2001,11(2):311-327.
[79]Navaneetham D,Penn AS,Howard JF Jr,et al.Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit.Muscle Nerve,2001,24(2):203-210.
[80]Mesnard-Rouiller L,Bismuth J,Wakkach A,et al.Thymic myoid cells express high levels of muscle gene.Neuroimmunol,2004,148(1-2):97-105.
[81]许贤豪.加强重症肌无力临床和基础的协作研究.[J].中国神经免疫学和神经病学杂志,2000,7(4):195
[82]陈清棠,余宗颐等.第1版.临床神经病学.北京:北京科学技术出版社.2000,780-785
[83]Oh SJ,Kim DE,Kuruoglu R,et al.Diagnostic sensitivity of the laboratory tests in myasthenia gravis.Muscle Nerve 1992,15:720-724
[84]Stalberg EJ,Trontelj V,Schwartz MS.Single muscle fibre recording of the jitter phenomenon in patients with myasthenia gravis and in members of their families.Ann N Y Acad Sci.1976,274:189-202
[85]Vincent,A,Leite,MI.Neuromuscular junction autoimmune disease:muscle specific kinase antibodies and treatments for myasthenia gravis.Curr Opin Neurol.2005 Oct:18(5):519-525
[86]黄如训,梁秀龄,刘焯霖,主编.临床神经病学,重症肌无力.北京:人民卫生出版社。1996:416-423
[87]Aquilonius SM,Hartvig P,Clinical pharmacokinetics of cholinesterase inhibitors.Clin Pharmacokinet.1986,11:236-249
[88]Hartvig P,Wiklund L,Aquilonius SM,et al.Clinical Pharmacokinetics of acetylcholinesterase inhibitors.Prog Brain Res.1990,84:139-143
[89]Richman DP,Agius MA,Treatment of autoimmune myasthenia gravis. Neurology,2003,61:1652-1661.
[90]Ciafaloni E,Massey JM,Tucker-Lipscomb B,et al.Mycophenolate mofetil for myasthenia gravis:an open-label pilot study.Neurology,2001,56:97
[91]许贤豪主编.神经免疫学.北京医科大学和中国协和医科大学联合出版社
[92]华玲,王利力,刘玉祯.大剂量免疫球蛋白静脉注射治疗重症肌无力的疗效观察.中国现代神经疾病杂志2006,6(2):148-150
[93]潘瑞福,林智.免疫球蛋白治疗免疫性神经肌肉疾病的安全及有效性探讨。中国临床康复,2003,7(28):3884-3885
[94]Patrick J,Lindstrom JM,Culp B,et al.Studies on purefred acetylcholine receptor and antiacetylcholine receptor antibody.Proc Nat Acad Sci,1973,70:3334
[95]Rowland LP.Controversies about the treatment of myasthenia gravis.J Neurol Neurosurg Psychiatry.1980,43:644-659
[96]Miller RG,Milner Brown HS,Dau PC.Antibody-negative acquired myasthenia gravis:successful therapy with plasma exchange.Muscle Nerve.1981,4(3):255
[97]Konishi T,Nishitani H,Matsubara F,et al.Myasthenia gravis:relation between jitter in single-fiber EMG and antibody-acetylcholine receptor.Neurology.198131:386-392
[98]Satoyoshi E,Nakazato H.Radiationthymectomy and myasthenia gravis.Japan:University of kokyo press,1981:399
[99]张润希,李保华.重症肌无力治疗的现状和进展.临床神经病学杂志,1999.12(5):313-314
[100]Chin HC,Chen WH,Yeh JH.The six year experenice of plasmapheresis in patients with myasthenia gravis.Ther Apher,2000,4:29
[101]熊克品,龚荣福.重症肌无力外科治疗48例临床分析.[J].皖南医学院学报,2002,21:120.
[102]Gronseth GS,Barohn RJ.Practice parameter:thymectomy for autoimmune myasthenia gravis(an evidence-based review):report of the Quality Standards Subcommittee of the American Academy of Neurology.Neurology.2000,55:7-15
[103]Verma P,Oger J.Treatment of acquired autoimmune myasthenia gravis:a topic review.Can J Neurol Sci.1992,19:360-375
[104]Genkins G,Kornfeld P,Papatestas AE,et al.Clinlcal experience in more than 2000 patients with myasthenia gravis.Ann NY Acad Sci.1987,505:500-514
[105]Osterhuis HJ.Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci.1981,377:678-690
[106]Papastestas AE,Cenkins G,Homfeld P,at al.Effects of thymectomy in myasthenia gravis[J].Ann Surg,1987,206:79-81.
[107]Paletto AE,Maggi G.Thymectomy in the treatment of myasthenia gravis:results in 320 patients[J].Int Surg,1982,67:13.
[108]Neto PI,Roblel PPJ,Pajulo CM,et al.Prognostic factors for myasthenia gravis treated by:review of 61 cases[J].Ann Yhorac Surg,1999,67:1568-1571.
[109]Masaoka A,Yamakawa Y,Niwa H,at al.Thymectomy for myasthenia gravis patients:a 20-year review[J].Ann Yhorac Surg,1996,64:853-859.
[110]Nakamura H,Taniguehl Y,Suzuki Y,et al.Delayed remission after themectomy for myasthenia gravis of the Purely ocular type[J].J Thorac Cardiovase Surg,1996,112:371-375.
[111]郭占林,张玉龙,高旭东,等.扩大胸腺切除治疗重症肌无力的结果分析[J].中华胸心血管外科杂志,2002,18(2):83-85.
[112]陆轩,毛履琰.胸腺切除治疗重症肌无力远期疗效及影响因素的分析[J].中华外科杂志,1999,37(3):159-161.
[113]天燕雏,赵凤瑞,束晓根,等.胸腺瘤并重症肌无力危象的围手术期治疗[J].中华胸心血管外科杂志,2001,17:42.
[114]姚亚其,陈志明,庞烈文,等.胸腺切除治疗重症肌无力的远期疗效[J].中华外科杂志,1999,37(6):353.
[115]蒋耀光,王如文,赵云平,等.重症肌无力胸腺切除236例分析[J].中国胸心血管外科杂志,2004,11(1):32-34.
[116]Nakamura H,Fukuda M,Suzuki Y,et al.The long-term resuits of thymectomy for myasthenia gravis[J].Kyobu Geka,1995,48:184-189.
[117]曾涟乾,黄壮士,张斌,等.胸腺与胸腺瘤合并重症肌无力临床的探讨[J]. 中国胸心血管外科杂志,2003,19(1):19-20
[118]孙衍庆主编.现代胸心外科[M].第1版,北京.人民军医出版社,2000,734-744.
[119]First WH,Thirumalai S,Pochring CB,et al.Thymectomy for myasthenia gravis patient:factors influencing outcome[J].Ann Thorac Surg,1994,57:334-336.
[120]Nakamura H,et al.Delayed remission after thymectomy for myasthenia gravis of purely ocular type[J].Thorac Cardrovasc Surg,1996,112:371
[2]Macdonald BK,Cockerell OC,Sander JW,et al.The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK.Brain,2000,123:665-676.
[3]Engel AG,Arahata K.The membrane attack complex of complement at the endplate in myasthenia gravis.Ann NY Acad Sci,1987,505:326-332.
[4]Drachman DB,Angus DW,Adams RN,et al.Myasthenia antibodies cross-link AchR to accelerate degradation.N Engl Med,2002,298:1116-1122.
[5]Drachman DB,Adams RN,Josifek LF,et al.Functional activities of autoantibodies to AchR and the clinical severity of myasthenia gravis.N Engl Med,2000,307:769-775.
[6]Legler,DF,et al.B cell-attracting chemokine 1,a human CXC chemokine expressed in lymphoid tissues,selectively attracts B lymphocytes via BLR1/CXCR5.J Exp Med 1998.187:655-660.
[7]Cyster JG.Chemokines and cell migration in secondary lymphoid organs.Science.1999;286:2098-2102
[8]Melchers F,Rolink AG,Schaniel C.The role of chemokines in regulating cell migration during humoral immune responses.Cell.1999;99:351-354
[9]Salomonsson S,Larsson P,Tengn(?)r,P,et al.Expression of the B Cell-Attracting Chemokine CXCL13 in the Target Organ and Autoantibody Production in Ectopic Lymphoid Tissue in the Chronic Inflammatory Disease Sj(o|¨)gren's Syndrome.Scand J Immunol,2002,55(4):336-342
[10]Forster R.,Mattis A.E.Kremmer,E,at al.CXCR5-Dependent Seeding of Follicular Niches by B and Th Cells Augments Antiviral B Cell Responses.Cell,1996,87(13):1037-1047
[11]Younger DS,Raksadawan N.Medical therapies in myasthenia gravis.Chest Surg Clin N Am.2001;11:329-336
[12]Richman DP,Agius MA.Treatment of autoimmune myasthenia gravis.Neurology.2003;61:1652-1661.
[13]Papatestas AE,,Genkins G,,Kornfeld P,et al.Effects of thymectomy in myasthenia gravis.Ann Surg.1987;206:79-88
[14]蒋耀光,王如文,赵云平,等.重症肌无力胸腺切除236例分析[J].中国胸心血管外科杂志,2004,11(1):32-34.
[15]Nakamura H,et al.Delayed remission after thymectomy for myasthenia gravis of purely ocular type[J].Thorac Cardrovasc Surg,1996,112:371
[16]Paas-Rozner M,Dayan M,Paas Y,et al.Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.Proc Natl Acad Sci USA,2000,97(5):2168-2173.
[17]Schonbeck S,Padberg F,Hohlfeld R,et al.Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice,a new model of myasthenia gravis.J Clin Invest,1992,90(1),245-250
[18]刘绛光,王晓辉,张宏,等.实验性自身免疫性重症肌无力动物模型[J].中国神经免疫学神经病学杂志.2005,12(3):90-92
[19]Lennon VA,Lindstrom JM,Seybold ME,et al.Experimental autoimmune myasthenia:a model of myasthenia gravis in rats and guinea pigs[J].J Exp Med,1975,141:1365-1372
[20]Karuman PM,Soo KC.Motor innervation of the trapezios muscle:a histochemical study[J].Head Neck,1996,19(3):254-258
[21]Ma J,Smith BP,Smith TL,et al.Juvenile and adult rat neuromuscular junctions density,distribution and morphology[J].Muscle Nerve.2002,26(6):804-809
[22]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.国外医学神经病学神经外科学分册.2002,29(3):265-268
[1] Im SH, Barchan D, Maiti PK, et al .Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Thl differentiation and up-regulation of CTLA-4. J Immunol,2001,166:6893-6898
[2] Macdonald BK, Cockerell OC, Sander JW, et al. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain, 2000,123:665-676.
[3] Yu mai wan C.Y., Chinnery P.F., Griffiths P.G., et al. Extraocular muscles have fundanmentally distinct properties that make them selectively vunnerable to certain disorders .Neuromuscular Disorders,2005,15: 17-23
[4] Lindstrom JM, Acetylcholine receptors and myasthenia. Muscle Nerve.2000 Apr;23(4):453-477
[5] Stacy S ,Gelb BE, Koop BA, et al .Split tolerance in a novel transgenic model of autoimmune myasthenia gravis .[J] J.Immunol,2002,169(11):6570-6579
[6] Paas-Rozner M, Sela M, Mozes E. The nature of the active suppression of Responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered different routes. [J] Proc Natl Acad Sci USA ,2001,98(22):12642-12647
[7] Tzartos M, Barkas T, Cung MT, et al. The main immunogenic region of acetylcholine receptor. Structure and role in myasthenia gravis. Autoimmunity, 2001 ,8: 259.
[8] Batetra B , Moretei M, Longhi R ,et al .Antibodies against neuronal nicotinic receptor subtypes in neurological disorders. J Neuroimmunol, 2000,102:89 -97
[9] Romi F .,Skeie GO., Arrli JA .,et al .Muscle auto antibodies in subgroups of MG patients. J Neurol, 2000,24 7:369-375.
[10] Bufler J, Pitz R, Czep M, et al. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels[J]. Ann Neurol, 1998, 43(4): 458-464.
[11] Drachman DB. Myasthenia gravis. N Eng J Med, 1994,330(25):1797-1810
[12] Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann NY Acad Sci,1987,505: 326-332.
[13] Drachman DB, Angus DW,Adams RN, et al. Myasthenia antibodies cross-link AchR to accelerate degradation. N Engl Med, 2002,298:1116-1122.
[14] Drachman DB, Adams RN, Josifek LF,et al. Functional activities of autoantibodies to AchR and the clinical severity of myasthenia gravis. N Engl Med, 2000, 307: 769-775.
[15] Moiola, Galbiati, Martino,et al. IL-12 is involved in the induction of experimental auto immune myasthenia gravis, an antibody-mediated disease. Eur J Immunol, 1998,28:2487.
[16] Vincent A, Willcox N, Hill M, et al. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. J Immunol Rev, 1998, 164: 157-168.
[17] Fostieri E, Beeson D, Socrates J, et al. The conformation of the main immunogenic region on the a subunit of muscle acetylcholine receptor is affected by neighboring receptor subunits. FEBS Lett. 2000, 481: 127-1 30.
[18] Romi F, Lars B, Skeie G, et al. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol, 2002,128: 82-89.
[19] Aarli JA, Skeie GO, Mygland A, et al. Muscle striation antibodies in myasthenia gravis Diagnostic and functional significance. Ann NY Acad Sci, 1998, 841:505-515.
[20] Lubke E, Freiburg A, Skeie GO, et al. Striational autoantibodies in myasthenia gravis patients recognize I-band titin epitopes. J Neuroimmunol, 1998, 81: 98-108.
[21] Somnier FE. Engel PJH. The occurrence of anti-titin antibodies and thymomas. a population survey of MG 1970-1999. Neurology, 2002, 59: 92-98.
[22] Romi F, Skeie GO, Aarli JA, et al. The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies. Arch Neural,2000,57:1596-1600.
[23]Menegazzi P,Larini F,Treves S,et al.Identification and characterization of three calmodulin binding sites of the skeletal muscle ryanodine receptor.Biochemistry,1994,33:9078-9084.
[24]Mygland A,Tysnes OB,Aarli JA,et al.Myasthenia gravis patients with a thymoma have antibodies against a high molecular weight protein in sarcoplasmic reticulum.J Neuroimmunol,1992,37:1-7
[25]Mygland A,Tysnes OB,Matre R,et al.Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma.Ann Neurol,1992,32:589-591
[26]Skeie GO,Lunde PK,Sejersted OM,et al.Myasthenia gravis sera containing antiryanodine receptor antibodies inhibit binding of[3H]-ryanodine to sarcroplasmic reticulum.Muscle Nerve,1998,21:329-335.
[27]Skeie GO,Lunde PK,Sejersted OM,et al.Autoimmunity against antiryanodine receptor in myasthenia gravis.Acta Physiol Scand,2001,171:379-384
[28]Mygland A,Kuwajima G,Mikeshiba K,et al.Thymoma express epitopes shared by the ryanodine receptor.J Neuroimmunol,1995,62:79-83.
[29]张祥,乔健,吕传真.重症肌无力患者血清中Ryanodine受体抗体检测及其临床意义.中华神经科杂志,2003,36(6):436-439.
[30]Hoch W,McConville J,Helms S,et al.Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.Nat Med,2001,7:365-368.
[31]Bowen DC,Park JS,Bodine S,et al.Localization and regulation of MuSK at Neuromuscular junction.Dev Biol,1998,199:309-319.
[32]McConvile J,Vincent A.Disease of the neuromuscular junction.Curr Opin Phamacol,2002,2:296-301
[33]McConvile J,Farrugia ME,Kishore U,et al.Detection and characterization of MuSK antibodies in seronagative myasthenia gavis.Ann Neurol,2004,55:580-584
[34]Matthews I,Chen S,Hewer R,et al.Muscle-specific receptor tyrosine kinase autoantibodies:a new immunoprecipitation assay.Clin Chim Acta 2004,348: 95-99.
[35]Zhou L,McConville J,Chaudhry V,et al.Clinical comparison of muscle-specific tyrosine kinase(MUSK) antibody-positive and -negative myasthenic patients.Muscle Nerve 2004;30:55-60
[36]Shiraishi H,Motomura M,Yoshimura T,et al.Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis.Ann Neurol 2005;57:289-293.
[37]Nemoto Y,Kuwabara S,Misawa S,et al.Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis.J Neurol Neurosurg Psychiatry 2005;76:714-718
[38]张云.重症肌无力与突触前膜抗体.四川解剖学杂志,2002,10(3):177-179.
[39]李大年.现代神经内科学.山东科学技术出版社,第一版.2002,934-938.
[40]Zhang W,Lju JL,Meager A,et al.Autoantibodies to IL-1 2 in myasthenia gravis patients with thymoma;effects on the IFN-γresponses of healthy CD4~+T cells.J Neuroimmun,2003,139:102-108.
[41]Rapoport B,Portolano S,McLachlan SM,et al.Combinational libraries:new insight into organ-specific autoantibodies.J Immunol Today,1995,16:43-49
[42]Elms A,Schalka BCG,Kirchner TH,et al.Thymus in myasthenia gravis.Isolation of T-lymphocyte lines specified for the nicotinic acetylcholine receptor from thymus of myasthenia gravis.[J].J Clin Invest,1988,81:902-908
[43]Balandina A,Lecart S,Dartevelle P,et al.Functional defect of regulatory CD_4~+CD_(25)~+T cells in the thymus of patients with autoimmune myasthenia gravis.Blood,2005,105:735-741.
[44]Link H,Xiao BG.Rat models as tool to develop new inununotherapies.[J].Immunol Rev,2001,184:117-128
[45]Wang HB,Shi FD,Li HL,et al.Role for interferon-γ in rat strains with different susceptibility to experimental autoimmune myasthenia gravis[J].Clin Immunol,2000,95(2):156.
[46]Reyes-Reyna SM,Krolick KA.Chemokine production by rat myocytes exposed to interferon-gamma[J].Clin Immunol,2000,94(2):105.
[47]王炜,南振鸿,凌振芬,等.干扰素γ对重症肌无力患者自身抗体的调节作用及相关性分析[J].中国神经免疫学和神经病学杂志,2000,7(4):234.
[48]Poea-Guyon S,Christadoss P,Panse RL,et al.Effects of cytokines on acetylcholine receptor expression:implications for myasthenia gravis[J].J Immunol,2005,174:5941.
[49]Gu D,Wogensen L,Calcutt NA,et al.Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.J Exp Med 1995,181(2):547-557
[50]Balasa B,Deng C,Lee J,et al.Interferon-gamma is necessary for the genesis of acetycholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.[J]J Exp Med,1997,186(3):385-391
[51]Goluszko E,Deng C,Possin MA,et al.Tumor necrosis receptor p55 and p75deficiency protects mice from developing experimental autoimmune myasthenia gravis[J].J Neuroimmunol,2002,122(1-2):85.
[52]赖祥青,杨明山,徐金枝。等.重症肌无力患者免疫发病机理的研究[J].中国病理生理学杂志.2001,17(7):662.
[53]Duan RS,Wang HB,Yang JS,et al.Anti-TNF-α antibodies suppress the development of experimental autoimmune myasthenia gravis[J].J Autoimmun,2002,19(4):169-174.
[54]Bongioanni P,Ricciardi R,Pellegrino D,et al.T-cell tumor necrosis factor-αreceptor binding in myasthenic patients[J].J Neuroimmunol,1999,93(1-2):203-207
[55]Zhang J,Zhou WB,Wang HL,The effects of T cell subpopulations and recombinant interleukin(IL)-2 on peripheral B cell function in patients with myasthenia gravis.Hum Antibodies.1997;8(2):90-94
[56]Im SH,Barchan D,Feferman T,et al.Protective molecular mimicry in experimental myasthenia gravis.Neroimmunol,2002,126(1-2):99-106
[57]Paas-Rozner M,Sela M,Mozes E.The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes.Proc Natl Acad Sci USA,2001,98(22):12642-12647
[58] Moiola L, Karachunski P, Protti MP, et al. Epitopeson the beta subunit of human muscle acetylcholine receptor recognized by CD_4~+cells of myasthenia gravis patients and healthy subjects. J Clin Invest, 1994,93:1020-1028
[59] Poussin MA, Goluszko E, David CS, et al. HLA-DQ6 Transgenic Mice Resistance to Experimental Autoimmune Myasthenia Gravis is Linked to Reduced Acetylcholine Receptor-specific IFN-y,IL -2 and IL-10 Production. J Autoimmunity 2 001 Nov; 17 (3):175-180.
[60] Dinarello CA. Interleukine 1 and Interleukine 18 as mediators of inflammation and the aging process[J]. Am J Clin Nutri. 2006, 83(2): 447.
[61] Maiti PK, Im SH. SouroujonMC, et al. A monodonal antibody specific for rat IL-18 BP and its application in determining serum IL-18 BP[J]. Immunol Lett, 2003, 85:65.
[62] Sebastian J , Guido S. Increased serum levels of the interferon- [gamma]-inducing cytokine Interleukine-18 in myasthenia gravis [J]. Neurology, 2002, 59(2): 287.
[63] Im SH, Barchen D, Maiti PK, et al. Suppression of experimental autoimmune myasthenia gravis, a B cell-mediated autoimmune diseases by blocked of IL-18[J]. FASEBJ, 2001, 15(12): 2140-2148.
[64] Stegall T, Krolick KA. Myocytes respond to both interleukin-4 and interferon-gamma: cytokine respon-siveness with the potential to influence the severity and course of experimental myasthenia gravis[J]. Clin Immunol, 2000, 94(2): 133.
[65] Ostlie N, Milani M, Wang W, et al. Absence of IL-4 facilitates the development of chronic autoimmune myasthenia gravis in C57BL/6 mice[J]. J Immunology, 2003, 170(1): 604-612.
[66] Steinberger I, Brenner T, Lorberboum-Galski HL, et al. Interleukin 2 pseudomortas rxotoxin (IL2-PE664Glu) chimeric protein kills B cells from patients with myasthenia gravis[J]. Cell Immunol, 1996,169(1): 55-61.
[67] Poussin MA, Goluszko E, Franco JU, et al. Role of IL-5 during primary and secondary immune response to acetylcholine receptor.[J].J Neuroinmmunol 2002,12 5(1-2):51-58.
[68]Saaaano P,Paparo F,Ramineri V,et al.Interleukine-6(IL-6) may be a link between myasthenia gravis and myoepithelioma of the parotid gland[J].Med Hypothesis,2007,68(2):314.
[69]张栩,孙兆林,丛志强,等.重症肌无力患者外周血单个核细胞TGF-β及IL-6水平的测定[J].青岛大学医学院学报,2003,69(4):386.
[70]Zhang GX,Xiao BG,Yu LY,et al.Interleukin 10 aggravates experimental autoimmune myasthenia gravis through inducing Yh2 and B cell responses to AChR[J].J Neuroimmunol,2001,113(1):10-18.
[71]Huang DR,Zhou YH,Xia SQ,et al.Makers in the promote region of interleukin-10 gene in myasthenia gravis:inplications of diverse effects of IL-10 in the pathogenesis of the disease[J].Neuroimmunol,1999,94(1-2):82-87.
[72]Poussin MA,Fuller CL,Goluszko E,et al.Suppressed clinical experimental autoimmune myasthenia gravis in bm12 mice is linked to reduced intracellular calcium mobilization and IL-10 and IFN-gamma release by acetylcholine receptor-specific T cells.J Neuroimmunol,2003,134:104-110.
[73]Shea-Donohue T,Thomas K,Cody MJ,et al.Mice deficient in the CXCR2ligand,CXCL1(KC/GRO-alpha),exhibit increased susceptibility to dextran sodium sulfate(DSS) induced colitis.Innate Immun 2008,14:117-124
[74]Buanne P,Di Carlo E,Caputi L,et al.Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice.J Leukoc Biol 2007,82:1239-1246
[75]Bizzarri C,Beccari AR,Bertini R,et al.ELR+ CXC chemokines and their receptors(CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets.Pharmacol Yher 2006,112:139-149
[76]Sun J,Ramnath RD,Bhatia M.Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils.Am J Physiol Cell Physiol 2007,293:C696-C704
[77]Kenrin S,Kenji H,Motoharu K,et al.Lymphoid Chemokine B Cell-Attracting Chemokine-1(CXCL13) Is Expressed in Germinal Center of Ectopic Lymphoid Follicles Within the Synovium of Chronic Arthritis Patients.J Immunol,2001,166(1):650-655
[78]Ragheb S,Lisak RP.The thymus and myasthenia gravis.Chest Surg Clin N Am,2001,11(2):311-327.
[79]Navaneetham D,Penn AS,Howard JF Jr,et al.Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit.Muscle Nerve,2001,24(2):203-210.
[80]Mesnard-Rouiller L,Bismuth J,Wakkach A,et al.Thymic myoid cells express high levels of muscle gene.Neuroimmunol,2004,148(1-2):97-105.
[81]许贤豪.加强重症肌无力临床和基础的协作研究.[J].中国神经免疫学和神经病学杂志,2000,7(4):195
[82]陈清棠,余宗颐等.第1版.临床神经病学.北京:北京科学技术出版社.2000,780-785
[83]Oh SJ,Kim DE,Kuruoglu R,et al.Diagnostic sensitivity of the laboratory tests in myasthenia gravis.Muscle Nerve 1992,15:720-724
[84]Stalberg EJ,Trontelj V,Schwartz MS.Single muscle fibre recording of the jitter phenomenon in patients with myasthenia gravis and in members of their families.Ann N Y Acad Sci.1976,274:189-202
[85]Vincent,A,Leite,MI.Neuromuscular junction autoimmune disease:muscle specific kinase antibodies and treatments for myasthenia gravis.Curr Opin Neurol.2005 Oct:18(5):519-525
[86]黄如训,梁秀龄,刘焯霖,主编.临床神经病学,重症肌无力.北京:人民卫生出版社。1996:416-423
[87]Aquilonius SM,Hartvig P,Clinical pharmacokinetics of cholinesterase inhibitors.Clin Pharmacokinet.1986,11:236-249
[88]Hartvig P,Wiklund L,Aquilonius SM,et al.Clinical Pharmacokinetics of acetylcholinesterase inhibitors.Prog Brain Res.1990,84:139-143
[89]Richman DP,Agius MA,Treatment of autoimmune myasthenia gravis. Neurology,2003,61:1652-1661.
[90]Ciafaloni E,Massey JM,Tucker-Lipscomb B,et al.Mycophenolate mofetil for myasthenia gravis:an open-label pilot study.Neurology,2001,56:97
[91]许贤豪主编.神经免疫学.北京医科大学和中国协和医科大学联合出版社
[92]华玲,王利力,刘玉祯.大剂量免疫球蛋白静脉注射治疗重症肌无力的疗效观察.中国现代神经疾病杂志2006,6(2):148-150
[93]潘瑞福,林智.免疫球蛋白治疗免疫性神经肌肉疾病的安全及有效性探讨。中国临床康复,2003,7(28):3884-3885
[94]Patrick J,Lindstrom JM,Culp B,et al.Studies on purefred acetylcholine receptor and antiacetylcholine receptor antibody.Proc Nat Acad Sci,1973,70:3334
[95]Rowland LP.Controversies about the treatment of myasthenia gravis.J Neurol Neurosurg Psychiatry.1980,43:644-659
[96]Miller RG,Milner Brown HS,Dau PC.Antibody-negative acquired myasthenia gravis:successful therapy with plasma exchange.Muscle Nerve.1981,4(3):255
[97]Konishi T,Nishitani H,Matsubara F,et al.Myasthenia gravis:relation between jitter in single-fiber EMG and antibody-acetylcholine receptor.Neurology.198131:386-392
[98]Satoyoshi E,Nakazato H.Radiationthymectomy and myasthenia gravis.Japan:University of kokyo press,1981:399
[99]张润希,李保华.重症肌无力治疗的现状和进展.临床神经病学杂志,1999.12(5):313-314
[100]Chin HC,Chen WH,Yeh JH.The six year experenice of plasmapheresis in patients with myasthenia gravis.Ther Apher,2000,4:29
[101]熊克品,龚荣福.重症肌无力外科治疗48例临床分析.[J].皖南医学院学报,2002,21:120.
[102]Gronseth GS,Barohn RJ.Practice parameter:thymectomy for autoimmune myasthenia gravis(an evidence-based review):report of the Quality Standards Subcommittee of the American Academy of Neurology.Neurology.2000,55:7-15
[103]Verma P,Oger J.Treatment of acquired autoimmune myasthenia gravis:a topic review.Can J Neurol Sci.1992,19:360-375
[104]Genkins G,Kornfeld P,Papatestas AE,et al.Clinlcal experience in more than 2000 patients with myasthenia gravis.Ann NY Acad Sci.1987,505:500-514
[105]Osterhuis HJ.Observations of the natural history of myasthenia gravis and the effect of thymectomy.Ann NY Acad Sci.1981,377:678-690
[106]Papastestas AE,Cenkins G,Homfeld P,at al.Effects of thymectomy in myasthenia gravis[J].Ann Surg,1987,206:79-81.
[107]Paletto AE,Maggi G.Thymectomy in the treatment of myasthenia gravis:results in 320 patients[J].Int Surg,1982,67:13.
[108]Neto PI,Roblel PPJ,Pajulo CM,et al.Prognostic factors for myasthenia gravis treated by:review of 61 cases[J].Ann Yhorac Surg,1999,67:1568-1571.
[109]Masaoka A,Yamakawa Y,Niwa H,at al.Thymectomy for myasthenia gravis patients:a 20-year review[J].Ann Yhorac Surg,1996,64:853-859.
[110]Nakamura H,Taniguehl Y,Suzuki Y,et al.Delayed remission after themectomy for myasthenia gravis of the Purely ocular type[J].J Thorac Cardiovase Surg,1996,112:371-375.
[111]郭占林,张玉龙,高旭东,等.扩大胸腺切除治疗重症肌无力的结果分析[J].中华胸心血管外科杂志,2002,18(2):83-85.
[112]陆轩,毛履琰.胸腺切除治疗重症肌无力远期疗效及影响因素的分析[J].中华外科杂志,1999,37(3):159-161.
[113]天燕雏,赵凤瑞,束晓根,等.胸腺瘤并重症肌无力危象的围手术期治疗[J].中华胸心血管外科杂志,2001,17:42.
[114]姚亚其,陈志明,庞烈文,等.胸腺切除治疗重症肌无力的远期疗效[J].中华外科杂志,1999,37(6):353.
[115]蒋耀光,王如文,赵云平,等.重症肌无力胸腺切除236例分析[J].中国胸心血管外科杂志,2004,11(1):32-34.
[116]Nakamura H,Fukuda M,Suzuki Y,et al.The long-term resuits of thymectomy for myasthenia gravis[J].Kyobu Geka,1995,48:184-189.
[117]曾涟乾,黄壮士,张斌,等.胸腺与胸腺瘤合并重症肌无力临床的探讨[J]. 中国胸心血管外科杂志,2003,19(1):19-20
[118]孙衍庆主编.现代胸心外科[M].第1版,北京.人民军医出版社,2000,734-744.
[119]First WH,Thirumalai S,Pochring CB,et al.Thymectomy for myasthenia gravis patient:factors influencing outcome[J].Ann Thorac Surg,1994,57:334-336.
[120]Nakamura H,et al.Delayed remission after thymectomy for myasthenia gravis of purely ocular type[J].Thorac Cardrovasc Surg,1996,112:371
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |