TNF系统与重症肌无力的相关性

肿瘤坏死因子(TNF)是具有多种生物功能的细胞因子,可调节MHC-Ⅰ、Ⅱ类抗原表达的能力,可刺激T细胞和B细胞以调节粘附因子表达等。TNF生物学功能是由其受体(TNFR)介导而发挥作用的。在重症肌无力发病机制中,TNF系统可能具有重要作用。通过对TNF基因多态性和受体的研究,可能引导我们对MG的预防、基因治疗干预及预后提供一定的理论基础。     

TNFAIP3基因rs2230926多态性与重症肌无力的相关性研究

目的探讨肿瘤坏死因子α诱导蛋白3(TNFAIP3)基因rs2230926位点多态性与重症肌无力(MG)的关系。方法采用聚合酶链反应-限制性内切酶(PCR-RFLP)技术分析125例MG患者与143名健康对照者rs2230926位点基因型。结果在中国北方地区汉族人群中TNFAIP3 rs2230926位点仅有T/T和T/G两个基因型。发病年龄≥40岁的MG患者中T/G基因型及G等位基因出现频率较发病年龄40岁的MG患者高(P0.05)。结论 TNFAIP3 rs2230926位点与中国北方地区晚发型MG患者发病相关。     

重症肌无力患者肿瘤坏死因子等位基因α-308多态性分析

目的研究肿瘤坏死因子α(TNFα)等位基因α-308多态性与重症肌无力(MG)发病的关系。方法MG患者100例及健康对照100名,行聚合酶链反应(PCR)扩增全血基因组TNFα启动子-328～-98片段(210bp),NcoⅠ限制性内切酶酶切-308位点,检测等位基因频率。结果MG患者TNFα-308A等位基因频率(0.32)高于健康对照组(0.21,P<0.05)。在发病年龄≥40岁患者组,该基因频率(0.34)较此年龄健康对照组(0.10)高(P<0.05),但此等位基因与患者性别分布无关。在疾病的类型中,等位基因A与Osserman分型以及是否合并胸腺病变无关。结论MG的发病可能与此基因相关,尤其是发病年龄大的患者。     

重症肌无力病情与血清IL-6、TNF-α的关系

目的观察白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)在不同程度重症肌无力(Myasthenia gravis,MG)早期血清中IL-6、TNF-α含量变化,探讨其对MG预后的影响。方法采用ELISA法、放射免疫法测定Ⅰ型26例,Ⅱa型41例,Ⅱb型58例,Ⅲ型14例,Ⅳ型15例MG病人入院第2d血清中IL-6、TNF-α含量水平,另设30例健康人作对照。同时于治疗前和治疗第21d进行绝对评分,观察IL-6、TNF-α不同含量水平对治疗效果的影响。结果与对照组比较,Ⅰ型血清中IL-6、TNF-α含量无显著性差异(P>0.05),Ⅱa型明显升高(P<0.05);Ⅱa型与Ⅱb型组含量比较差异不显著(P>0.05),但较Ⅲ型明显降低(P<0.01);Ⅲ型与Ⅳ型组比较差异不明显(P<0.05);IL-6、TNF-α含量越高,治疗效果越差(P<0.05,P<0.01)。结论MG病人早期血清中IL-6、TNF-α含量明显升高,病情越严重含量越高;IL-6、TNF-α含量越高,治疗效果越差。     

重症肌无力cICAM-1及TNF-α水平的检测

目的　探讨神经免疫性疾病重症肌无力 ( MG)患者血清中循环细胞间黏附分子 -1 ( c ICAM-1 )及肿瘤坏死因子 -α( TNF-α)水平变化 ,并观察伴或不伴胸腺瘤 MG患者特异性 T细胞的免疫应答及细胞因子对 MG的影响。方法　采用 ELISA法对 1 5例 MG患者血清 c ICAM-1和 TNF-α水平进行检测 ,并以 1 5例健康献血员作为对照。比较伴或不伴胸腺瘤 MG患者上述因子的变化。结果　 1 5例 MG患者血清 c ICAM-1水平显著高于对照组 ( P<0 .0 5 ) ,血清 TNF-α水平非常显著高于对照组 ( P<0 .0 1 )。MG伴胸腺瘤 MG患者 c ICAM-1及 TNF-α水平高于不伴胸腺瘤组 ,但无统计学意义 (均 P>0 .0 1 )。结论　 MG患者血中高水平 TNF-α可直接破坏乙酰胆碱受体 ( ACh R)或直接促进 B细胞分化、生长 ,从而增加乙酰胆碱受体抗体 ( ACh RAb)的产生。 c ICAM-1可能在中枢神经系统炎症反应的调节中起重要作用。     

肿瘤坏死因子与重症肌无力

近年来 ,肿瘤坏死因子 (TNF)的各种生物活性已被鉴定 ,并对TNF的基因及基因多态性有一定的阐述。经发现重症肌无力的发病、临床表现及预后均与TNF有一定的关系 ,本文就此研究作一综述。     

100例重症肌无力患者肿瘤坏死因子-α分泌活性的研究

目的比较重症肌无力(myasthenia gravis, MG)患者和正常人体内和体外经诱导后淋巴细胞分泌肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)的差别. 方法 (1) 采用ELISA法测定 100例MG患者治疗前、后及正常对照者血清TNF-α.(2)对 20例MG患者(有胸腺病变者10例,胸腺正常者10例)和20名正常对照者,于治疗前和胸腺切除/免疫治疗后分离外周血淋巴细胞,与植物血凝素(PHA)、抗乙酰胆碱受体(AChR)及空白对照共同培养后离心取上清,并以ELISA测定血清TNF-α水平. 结果 (1)血清TNF-α水平在MG组治疗前[(1.994±0.517) ng/mL]与对照组[(1.841±0.696) ng/mL]间差异无显著性.在MG组中,全身型患者血清TNF-α平均水平[(2.173±0.592) ng/mL]较眼肌型[(1.885±0.453) ng/mL]高;胸腺病变患者血清TNF-α水平[(2.210±0.583) ng/mL]较胸腺正常者[(1.787±0.495) ng/mL]高;MG患者接受胆碱酯酶抑制剂、激素或免疫抑制剂、胸腺手术等治疗后血清TNF-α水平[(1.738±0.553) ng/mL]较治疗前[(1.994±0.517) ng/mL]下降.(2)体外细胞培养结果表明MG组治疗前所产生的TNF-α水平较对照组高;胸腺病变组和胸腺正常组比较差异无显著性;经治疗后的胸腺正常组分泌的TNF-α水平较治疗前降低,胸腺病变组也降低. 结论 MG患者淋巴细胞经体外诱导后产生.TNF-α处于上调状态,在MG的发病中起作用或起促进作用.经过胸腺手术或免疫调控药物治疗(免疫相关治疗)后,TNF-α系统活跃性减低,病情好转.     

肿瘤坏死因子-α血清水平及其多态性与多发性硬化的相关性

目的 研究中国南方汉族人群中血清肿瘤坏死因子-α(TNF-α)水平及其G-308A位点基因多态性与多发性硬化之间的相关性.方法 采用双抗体夹心ABC-ELISA法测定68名无亲缘关系的急性发作期MS病人和55例非免疫系统疾病病人的血清(对照)TNF-α水平,同时应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测上述68例MS病人和106名无亲缘关系的广东籍健康汉族人的TNF-α基因型.结果 发作期MS患者血清中TNF-α水平与正常对照组有显著差异(P＜0.05),分别是(225±71)pg/ml和(185±73)pg/ml;TNF-α各等位基因型频率在MS组和正常人组比较无统计学意义(P＞0.05),病例组TNF-α基因A纯合基因型和A等位基因频率分别为4.4%和13.9%,正常对照组分别为0%和8.5%.结论 (1)血清中TNF-α水平与发作期MS患者相关.(2)中国南方汉族人群存在TNF-α基因G-308A位点突变.(3)从目前调查的例数中,中国南方汉族人群TNF-α基因G-308A多态性与广东人群中MS无关.     

TLR9基因rs352140位点多态性与重症肌无力的关系

目的探讨TLR9基因rs352140位点多态性与重症肌无力(MG)的关系。方法采用聚合酶链反应-限制性内切酶片段多态性(PCR-RFLP)方法检测MG患者TLR9基因rs352140位点的多态性,比较各基因型和等位基因在MG患者不同性别、发病年龄、胸腺瘤伴发情况、Osserman分型、最大严重程度等亚组中的分布并观察其与MG严重程度和糖皮质激素近期疗效的关系。结果 MG组和对照组间以及MG各亚组间基因型和等位基因频率无统计学差异(P0.05);糖皮质激素近期疗效差的患者中全身型比例高于眼肌型(OR=3.592,P=0.03),伴胸腺瘤者比例高于不伴胸腺瘤者(OR=4.350,P=0.016);糖皮质激素疗效差者治疗前平均定量MG评分(QMG)高于疗效好者(P=0.026);经多因素Logistic回归分析发现治疗前QMG评分越高激素疗效越差(OR=1.154,P=0.043)。结论 TLR9基因rs352140位点多态性与MG易感性无相关性,也与激素近期疗效无相关性。     

自身免疫调节因子基因多态性与重症肌无力的相关性

目的探索自身免疫调节因子AIRE基因rs3761389和rs1800520位点多态性与重症肌无力(MG)的易感性和严重程度的相关性。方法采用i MLDR技术对AIRE基因rs3761389和rs1800520位点进行基因分型,比较等位基因频率在480例MG患者(MG组)、487例健康对照者(对照组)以及MG各亚组的分布。在共显性、加性和过显性遗传模型下比较基因型频率。结果 rs3761389位点G等位基因MG组高于对照组,差异有统计学意义(P=0.035),基因型频率在加性模型下差异有统计学意义(P=0.046)。rs1800520位点MG组与对照组比较差异均无统计学意义。结论 AIRE基因rs3761389位点可能与MG的易感性相关,未发现其与MG严重程度相关;未发现rs1800520位点与MG的易感性和严重程度相关。     

糖皮质激素对重症肌无力患者血清肿瘤坏死因子及白介素-6水平的影响

目的 探讨糖皮质激素(GC)对重症肌无力(MG)患者血清肿瘤坏死因子(TNF)及白细胞介素-6(IL-6)水平的影响。方法 选择48 例MG 患者(治疗组),采用GC治疗,疗程1个月,观察治疗前后患者血清TNF及IL-6的水平,并在治疗前与42例健康者(对照组)比较。结果 治疗组治疗前患者血清TNF、IL-6水平均明显高于对照组(P<0.05),经GC治疗1个月后治疗组患者血清TNF、IL-6 水平降低,与治疗前比较有明显差异(P<0.05)。结论 GC可能通过抑制MG患者体内TNF及IL-6的产生来调节患者的免疫功能。     

重症肌无力患者sTNFRs的初步研究

目的探讨可溶性肿瘤坏死因子受体(sTNFRs)与重症肌无力(myasthenia gravis,MG)的关系。方法应用酶联免疫吸附试验(ELISA)检测76例不同临床类型的MG患者(MG组)和48名健康对照者(NC组)血清sT-NFRs水平,同时检测MG患者血清中乙酰胆碱受体抗体(AchRab)水平。并对MG患者病情按徐氏评分法进行量化。结果 (1)MG患者血清sTNFRs水平明显高于NC组(P0.01,及P0.05);其中病程1年组患者sTNFR1水平明显高于病程6个月组(P0.05);(2)绝对许氏评分≥31分者sTNFRs水平明显高于评分≤15分患者(P0.01,及P0.05)。结论 sTNFRs参与了MG的免疫发病过程,血清sTNFRs水平可反映MG患者的病情。     

No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia

Several linkage analyses in schizophrenia research point to a locus on chromosome 6p22, where the gene coding for tumor necrosis factor-α (TNF-α) is located. A marked influence of antipsychotic medication on TNF-α has been described. As the involvement of an immune process in the pathophysiology of schizophrenia has been discussed, a functional TNF-α polymorphism appears to be a candidate in genetic schizophrenia research. The G308A polymorphism of the TNF-α gene was described to be associated with increased TNF-α production. Boin and colleagues have already described a significant association between the polymorphic allele and schizophrenia, investigating 84 schizophrenic patients (21 % polymorphic allele) and 138 healthy volunteers (11 % polymorphic allele), recruited in Northern Italy. We carried out a replication study including 157 schizophrenic patients and 186 healthy persons, who were recruited in Southern Germany. Psychopathology was additionally monitored by PANSS. We were not able to replicate the findings of Boin et al., as we did not find any difference in allele frequency or genotype distribution between our schizophrenic patients (13.7 % polymorphic allele) and healthy controls (16.9 % polymorphic allele). Moreover, we did not find any association between genotype and psychopathology, as measured by PANSS. The different results between these two studies may be due to ethnic differences. Received: 22 April 2002 / Received in revised form: 3 September 2002 / Accepted: 4 September 2002 Correspondence to Markus J. Schwarz, M. D.     

Cytokines and the pathogenesis of myasthenia gravis

Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti-AChR antibodies is mediated by cytokines produced by CD4⁺ and CD8⁺ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL-4), an efficient growth promoter for B-cell proliferation and differentiation, is important for anti-AChR antibody production. IL-6 and IL-10 have similar effects. The Th1 cytokine IFN-γ is important in inducing B-cell maturation and in helping anti-AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN-γ is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL-4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL-2, tumor necrosis factor α (TNF-α), and TNF-β as well as the cytolytic compound perforin do not directly play a role in T-cell-mediated help for anti-AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor β (TGF-β) exerts immunosuppressive effects which include the down-regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon α (IFN-α). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up-modulate TGF-β or IFN-α and/or suppress cytokines that help B-cell proliferation could be useful to improve the clinical outcome. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 543–551, 1997     

重症肌无力患者HLA-B易感基因研究

目的探讨中国汉族重症肌无力(MG)患者及其不同亚型与人类白细胞抗原(HLA)-B等位基因的相关性。方法应用聚合酶链反应-序列特异性的寡核苷酸探针杂交法(PCR-SSOP)对91例中国汉族MG患者及171名健康对照者进行HLA-B等位基因分型,并采用病例-对照研究及显性遗传模式的方法系统分析HLA-B等位基因与MG患者不同临床亚型之间的相关性。结果按照性别、年龄、临床类型、抗乙酰胆碱受体(AChR)抗体及胸腺病变将患者组分为不同亚型后,结果显示HLA-B*46阳性率在男性、眼肌型、抗AChR抗体阴性及伴发胸腺瘤组中升高,HLA-B*08阳性率在早发型及全身型患者组中升高。与对照组比较,患者组HLA-B*35和B*38阳性率降低。结论 HLA-B*46基因可能是男性、眼肌型、抗AChR抗体阴性及伴发胸腺瘤的MG患者的易感基因或与易感基因相连锁;HLA-B*08可能是早发型及全身型MG患者的易感基因或与易感基因相连锁。HLA-B*35和B*38可能是MG的保护基因或与保护基因相连锁。     

Psychiatric disturbances associated with myasthenia gravis

Seventy-four myasthenic patients (54 F, 20 M; mean age 49.6 years) were evaluated using the diagnostic criteria of the DSM-III in order to investigate the prevalence of psychiatric disturbances in this order. Fifty-one had had thymectomies, of whom 28 females had hyperplasia, two females and five males had involution of the thymus, and 10 females and six males had thymomata. Psychiatric disturbances were observed in 38 subjects (51%), in particular, adjustment disorders with depressed mood and mixed emotional features (19%) (22% including adjustment disorder with anxious mood), affective disorders (13.5%) and personality disorders (18%).     

Juvenile myasthenia gravis with prepubertal onset

Juvenile myasthenia gravis (JMG) with prepubertal onset is an uncommon disease. We studied 19 patients with age at onset ranging from 1.5 to 9.2 years and compared their clinical characteristics and response to therapy with 114 cases with MG onset after the prepubertal age, up to 20 years. Neither sex prevalence nor autoimmune diseases other than MG were found in younger patients. Although ocular myasthenia was more frequent than in later-onset JMG, children with generalized symptoms were often severely affected and respiratory involvement was present in 8/19 patients. Anti-acetylcholine receptor antibodies were detected at a lower rate and, in contrast with results in older patients, seronegativity was more frequent among children with generalized disease. Three out of six patients with onset before the age of five showed spontaneous remission. Nine prepubertal patients underwent thymectomy and, as most of them also received immunosuppressive therapy, the influence of surgery on disease outcome remains unclear; in no case was thymoma found. This is in contrast to the good results after thymectomy and the presence of thymoma in the later-onset group. Eleven patients in the prepubertal series were treated with immunosuppressive therapy. At the end of follow-up, most patients were in good condition. The frequency of immunosuppressive therapy and the rate of good therapeutic results did not differ from those observed in older patients.     

Widely varying TNF-α levels in patients with myasthenia gravis

Animal studies have indicated an important role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of myasthenia gravis (MG), and trials of monoclonal antibodies that block TNF-α have shown clinical improvement. However, before a TNF-α blocking agent is proposed for treatment of MG, whether serum TNF-α level correlates with the patient’s condition should be confirmed. Therefore, we evaluated the relationship between the serum TNF-α level and clinical factors, including the quantitative MG score and the anti-acetylcholine receptor antibody level, in 33 MG patients. TNF-α levels ranged from 0.44 to 3.63 pg/mL and did not correlate with clinical factors. Overall, we found that serum TNF-α levels varied greatly among MG patients.