胸腺瘤合并重症肌力发病机制中趋化因子CXCL13的作用及临床意义
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摘要
研究背景
重症肌无力(MG)是一种神经肌肉接头(neuromuscular junction, NMJ)功能紊乱的自身免疫性疾病。虽然该病的发病机制尚未完全明确,但是现在研究认为：胸腺增生及胸腺肿瘤的产生导致胸腺功能异常,从而产生乙酰胆碱受体抗体(AchRAb)的是重症肌无力的一个重要发病机制。这一结论已经得到了广泛共识。重症肌无力中乙酰胆碱受体抗体是针对N型乙酰胆碱受体(nAchR)糖蛋白的多克隆抗体。而抗体的产生需要体内B细胞的增殖、分化,在这个过程中需要各种细胞因子的参与。在这些细胞因子中趋化因子(chemokine)起到了重要作用。趋化因子是一个蛋白质家族,是由分子量多为8-10kDa的多肽组成。其主要功能是对表达有相应趋化因子受体的细胞的定向趋化作用。根据多肽中半胱氨酸的位置及排列顺序、数量的不同,趋化因子被分为4个不同的亚家族：CC趋化因子、CXC趋化因子、CX3C趋化因子及C趋化因子。CXCL13是CXC趋化因子中的一员。被称为B细胞趋化因子(B lymphocyte chemoattractant, BLC)。CXCL13的功能包括通过高内皮静脉捕获B细胞和滤泡辅助性T细胞(follicular helper T cell, Tfh),动员两者进入淋巴结的生发中心,诱导B细胞的活化,产生抗体。有文献报道,在重症肌无力患者体内CXCL13水平增高,且增生胸腺组织中CXCL13mRNA呈高表达。但在合并有胸腺瘤的MG患者中这一结论尚未得到证实。胸腺瘤患者中33%-75%合并MG,而另外一部分无重症肌无力症状。这种症状上的差异是我们研究重症肌无力发病机制的一个切入点。
目的
通过对比胸腺瘤并MG患者及单纯胸腺瘤患者(不合并有重症肌无力及其它自身免疫性疾病)体内血清中CXCL13的水平及瘤体内CXCL13mRNA的表达水平的差异来验证及探讨CXCL13在重症肌无力发病过程中是否起作用及其在未来治疗研究中的意义。
方法
收集郑州大学第一附属医院胸外科15例胸腺瘤合并得症肌无力患者以及10例单纯胸腺瘤患者(不合并有重症肌无力及其它自身免疫性疾病)治疗前和胸腺瘤切除治疗2个月后及15例健康体检者的血液标本,Elisa法检测血清中CXCL13的水平,RT-PCR半定量法检测各组胸腺瘤组织中的nRNA水平,数据以均数±标准差(x±s)表示,采用SPSS17.0进行统计学分析,各组间比较采用单因素方差分析,以p<0.05为有统计学意义。
结果
胸腺瘤合并重症肌无力患者血清中的CXCL13浓度水平明显高于对照组(P<0.05),在接受了胸腺切除手术2个月后,患者血清中CXCL13浓度水平较治疗之前下降(P<0.05),胸腺瘤合并重症肌无力患的者胸腺瘤组织中CXCL13mRNA的表达水平高于单纯胸腺瘤患者的胸腺瘤组织(P<0.05)。
结论
胸腺瘤伴重症肌无力组与单纯胸腺瘤组血清CXCL13水平和瘤体mRNA水平的显著差异,提示1.CXCL13在重症肌无力患者的发病中有重要意义；2.CXCL13可能成为重症肌无力患者血清学检测的一个指标；3. CXCL13可能成为治疗重症肌无力的一个重要靶点。
Background
Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder. Although the pathogenesis of this disease has not completely clear, But the conclusion that MG results from antibody-mediated, T cell-dependent immunologic attack on the endplate region of the postsynaptic membrane, have been broad consensus. In myasthenia gravis acetylcholine receptors antibody is n-type acetylcholine receptors (nAchR) glycoprotein polyclonal antibody. B lymphocyte is known to be the only kind of cell that could produce antibody, and it plays a very important role in humoral immunity. Chemotatic factor is a group of protein, which can stimulate cells migrating to the target tissue. Chemotatic factors Can be divided into C subfamily, CXC subfamily,CX3C 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. CXCL13is confirmed to be important for the formation and targeting of B-lymphocyte. It is reported that CXCL13plays a key role in several autoimmune disease, but there is rare report about the relationship between CXCL13and MG disease.33%-75%of the thymoma patients complicated with MG, while the other part of thymoma patients have no MG symptoms. Differences on such symptoms are an entry point for our study of myasthenia gravis pathogenesis.
Objective
This study aims to explore the meaning of CXCL13chemotactic factor on the occurrence of thymoma complicated with myasthenia gravis (MG) and analyze the relationship among CXCL13, thymoma and myasthenia gravis.
Methods
Each50serum samples were collected from the patients of thymoma complicated with MG presurgery and two months after the thymusectomy in the department of thoracic surgery of the first affiliated hospital of Zhengzhou university, and50serum samples of healthy person were also collected as a comparison. Elisa method was applied to detect the level of CXCL13in the serum; RT-PCR method was introduced to evaluate the CXCL13of thymoma tissue in mRNA level. The results of the statistical analyses are shown as mean+standard deviation (x±s). The analyses were conducted with SPSS17.0software. The means of the different groups were compared using One-way analysis of variance, and a value of p<0.05was considered statistically significant.
Result
The serum CXCL13level of thymoma complicated with MG was significantly higher than that of control groups(P<0.05), two months after the thymusectomy, The serum CXCL13level was decreased than presurgery (P<0.05), the mRNA expression level of CXCL13during the thymoma tissue of thymoma complicated with MG patients was higher than that in MG patients.
Conclusion
The serum CXCL13and mRNA level are statistically significance between thymoma complicated with MG and MG patients, indicating that the CXCL13has a significant meaning in the occurrence of thymoma complicated with MG.
重症肌无力(MG)是一种神经肌肉接头(neuromuscular junction, NMJ)功能紊乱的自身免疫性疾病。虽然该病的发病机制尚未完全明确,但是现在研究认为：胸腺增生及胸腺肿瘤的产生导致胸腺功能异常,从而产生乙酰胆碱受体抗体(AchRAb)的是重症肌无力的一个重要发病机制。这一结论已经得到了广泛共识。重症肌无力中乙酰胆碱受体抗体是针对N型乙酰胆碱受体(nAchR)糖蛋白的多克隆抗体。而抗体的产生需要体内B细胞的增殖、分化,在这个过程中需要各种细胞因子的参与。在这些细胞因子中趋化因子(chemokine)起到了重要作用。趋化因子是一个蛋白质家族,是由分子量多为8-10kDa的多肽组成。其主要功能是对表达有相应趋化因子受体的细胞的定向趋化作用。根据多肽中半胱氨酸的位置及排列顺序、数量的不同,趋化因子被分为4个不同的亚家族：CC趋化因子、CXC趋化因子、CX3C趋化因子及C趋化因子。CXCL13是CXC趋化因子中的一员。被称为B细胞趋化因子(B lymphocyte chemoattractant, BLC)。CXCL13的功能包括通过高内皮静脉捕获B细胞和滤泡辅助性T细胞(follicular helper T cell, Tfh),动员两者进入淋巴结的生发中心,诱导B细胞的活化,产生抗体。有文献报道,在重症肌无力患者体内CXCL13水平增高,且增生胸腺组织中CXCL13mRNA呈高表达。但在合并有胸腺瘤的MG患者中这一结论尚未得到证实。胸腺瘤患者中33%-75%合并MG,而另外一部分无重症肌无力症状。这种症状上的差异是我们研究重症肌无力发病机制的一个切入点。
目的
通过对比胸腺瘤并MG患者及单纯胸腺瘤患者(不合并有重症肌无力及其它自身免疫性疾病)体内血清中CXCL13的水平及瘤体内CXCL13mRNA的表达水平的差异来验证及探讨CXCL13在重症肌无力发病过程中是否起作用及其在未来治疗研究中的意义。
方法
收集郑州大学第一附属医院胸外科15例胸腺瘤合并得症肌无力患者以及10例单纯胸腺瘤患者(不合并有重症肌无力及其它自身免疫性疾病)治疗前和胸腺瘤切除治疗2个月后及15例健康体检者的血液标本,Elisa法检测血清中CXCL13的水平,RT-PCR半定量法检测各组胸腺瘤组织中的nRNA水平,数据以均数±标准差(x±s)表示,采用SPSS17.0进行统计学分析,各组间比较采用单因素方差分析,以p<0.05为有统计学意义。
结果
胸腺瘤合并重症肌无力患者血清中的CXCL13浓度水平明显高于对照组(P<0.05),在接受了胸腺切除手术2个月后,患者血清中CXCL13浓度水平较治疗之前下降(P<0.05),胸腺瘤合并重症肌无力患的者胸腺瘤组织中CXCL13mRNA的表达水平高于单纯胸腺瘤患者的胸腺瘤组织(P<0.05)。
结论
胸腺瘤伴重症肌无力组与单纯胸腺瘤组血清CXCL13水平和瘤体mRNA水平的显著差异,提示1.CXCL13在重症肌无力患者的发病中有重要意义；2.CXCL13可能成为重症肌无力患者血清学检测的一个指标；3. CXCL13可能成为治疗重症肌无力的一个重要靶点。
Background
Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder. Although the pathogenesis of this disease has not completely clear, But the conclusion that MG results from antibody-mediated, T cell-dependent immunologic attack on the endplate region of the postsynaptic membrane, have been broad consensus. In myasthenia gravis acetylcholine receptors antibody is n-type acetylcholine receptors (nAchR) glycoprotein polyclonal antibody. B lymphocyte is known to be the only kind of cell that could produce antibody, and it plays a very important role in humoral immunity. Chemotatic factor is a group of protein, which can stimulate cells migrating to the target tissue. Chemotatic factors Can be divided into C subfamily, CXC subfamily,CX3C 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. CXCL13is confirmed to be important for the formation and targeting of B-lymphocyte. It is reported that CXCL13plays a key role in several autoimmune disease, but there is rare report about the relationship between CXCL13and MG disease.33%-75%of the thymoma patients complicated with MG, while the other part of thymoma patients have no MG symptoms. Differences on such symptoms are an entry point for our study of myasthenia gravis pathogenesis.
Objective
This study aims to explore the meaning of CXCL13chemotactic factor on the occurrence of thymoma complicated with myasthenia gravis (MG) and analyze the relationship among CXCL13, thymoma and myasthenia gravis.
Methods
Each50serum samples were collected from the patients of thymoma complicated with MG presurgery and two months after the thymusectomy in the department of thoracic surgery of the first affiliated hospital of Zhengzhou university, and50serum samples of healthy person were also collected as a comparison. Elisa method was applied to detect the level of CXCL13in the serum; RT-PCR method was introduced to evaluate the CXCL13of thymoma tissue in mRNA level. The results of the statistical analyses are shown as mean+standard deviation (x±s). The analyses were conducted with SPSS17.0software. The means of the different groups were compared using One-way analysis of variance, and a value of p<0.05was considered statistically significant.
Result
The serum CXCL13level of thymoma complicated with MG was significantly higher than that of control groups(P<0.05), two months after the thymusectomy, The serum CXCL13level was decreased than presurgery (P<0.05), the mRNA expression level of CXCL13during the thymoma tissue of thymoma complicated with MG patients was higher than that in MG patients.
Conclusion
The serum CXCL13and mRNA level are statistically significance between thymoma complicated with MG and MG patients, indicating that the CXCL13has a significant meaning in the occurrence of thymoma complicated with MG.
引文
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