神经免疫调节网络中传入信号和信号传导模式的研究
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摘要
神经免疫学是二十世纪末期生命科学领域发展最为迅速的学科之一,神经免疫学科的基础理论“神经—内分泌—免疫调节网络”学说已经得到学术界的认同。在“神经—内分泌—免疫调节网络”研究的基础上,相关的实验证明了神经系统与免疫系统间存在功能调节作用。在神经免疫调节网络信号传导的解剖学构筑的研究中,调节网络的功能相关的传入信号和信号传入通路构成是领域研究争论的焦点之一。本论文在课题组前期不同免疫状态大鼠神经免疫调节功能相关脑区的定位研究工作的基础上,应用蛋白质组学研究中的表面加强激光解析电离—飞行时间—质谱技术(SELDI-TOF-MS)和基质辅助激光解析电离—飞行时间—质谱技术(MALDI-TOF-MS)及双向电泳(2-DE)分离技术等方法对不同免疫状态大鼠的外周血清和脑脊液组份进行比对分析,探索参与神经免疫调节的上传信号及传入通路构成模式,为进一步阐明神经免疫调节网络的解剖学构筑提供实验依据。
SELDI分析结果显示,免疫组动物外周血中观察到221个有显著性差异的信号峰,其中173个为表达量高于对照组的正向表达峰。实验各组大鼠脑脊液的分析结果未见有统计学意义的特异性差异峰表达;在实验组血清中检测到的特异性差异峰也未在脑脊液中观察到相对应的同步变化。在76个最高峰值为免疫2天的免疫功能相关性差异表达的免疫大鼠血清的信号峰中,根据差异信号峰的分子量、pI值和来源细胞在已知的神经介质、神经肽、激素和细胞因子等信号物质中进行分析筛选,推测可能成为神经免疫调节相关的传入信号物质。经2-DE分离和MELDI-TOF-MS进一步分析和鉴定免疫大鼠血清中18KD特异组份,分析报告了18种来源的19个相关肽段序列,共247氨基酸,但相关结果不能满足任何已知物质的氨基酸序列的排序。
我们的实验结果证明:
1)本论文采用SELDI技术对不同免疫状态组大鼠和正常对照组大鼠的血清进行对比分析的结果显示实验组表达了221个与免疫功能相关的差异信号峰;差异信号表达峰值的分布在免疫2天的有76个,免疫4天有1个,免疫6天有96个;差异峰值统计学分析具有极显著性差异,某些差异峰的特异性甚至表现为“全或无”的关系。这些实验结果支持了神经免疫调节网络传入信号模式研究中两个重要的代表性假说——“血行传导通路”和“神经传导通路”假说在神经免疫调节网络传入信号通路领域研究中达成的共识,即免疫活性细胞释放功能活动相关信号物质到体液(血液)中,进而启动神经免疫调节功能。
2)对不同实验组大鼠的脑脊液组份对比分析的结果显示,脑脊液中并不存在与免疫功能变化相关的神经免疫调节功能的传入信号物质,血液中免疫功能相关的信号物质的变化没有在脑脊液中平行反映。神经免疫调节功能相关信号传入模式不是“血液—脑脊液—接触脑脊液的神经元系统—中枢脑区”的血行传导方式。本论文神经免疫调节网络信号传导模式研究结果不支持“血行传导通路”假说。
3)根据最高峰值在免疫2天的免疫功能相关的差异信号峰的分子量、PI值和来源细胞,在已知的神经介质、神经肽、激素和细胞因子等信号物质中进行比对筛选,推测细胞因子IL-8、IL-15和IL-18等三个组份可能成为免疫系统释放的跨系统传递的神经免疫调节功能相关的传入信号物质。
4)本论文应用蛋白质组学研究技术的标准方法2-DE-MALDI-TOF-MS技术分析免疫大鼠血清中IL-1分子在神经免疫调节网络传入通路中的地位和作用,发现免疫活性细胞释放到血液中的IL-1不可能成为免疫系统释放的跨系统传递的信号物质,参与神经免疫调节网络功能,否定了“血行传导通路”和“神经传导通路”假说在神经免疫调节网络传入信号通路领域研究中关于IL-1的共识。
5)对免疫大鼠血清双向电泳分离的分子量约18KD,PI约5.0位置差异点进行质谱鉴定的结果显示,该差异点的氨基酸序列不符合数据库收集的任何已知物质的氨基酸序列,提示神经免疫调节网络传入通路的上传信号中,可能包括我们还不了解的新物质。
Neuroimmunology is one of the most developed subjects in life science at the end of the 20th century. Neuro-endocrine-immunological regulation network theory—the fundamental of neuroimmunology has achieved great identification by academic circles and correlative experiments and researches have also demonstrated the existence of function regulation effect between the system of nerve and immune. Based on research of neuroendocrine regulation network, relative investigation has proved that there is a functional regulatory relationship between the nerve system and immune system.The argument in this investigation field was focused on signal afferent pathway of neuro-immune modulation network. In our prophase stuty, we found that the lateral hypothalamic nucleus (LH) and amygdaloid nuclear complex (AA) of the rat hypothalamus are referred to the neuroimmunomodulation. Based on the prophase study, we contrast analyzed ingredient of peripheral blood and cerebrospinal fluid of different immunized stage rats by Mass Spectrometry technique and Two-dimensional SDS electrophoresis to explore the up-delivering signals and afferent pathway involved in neuroimmunoregulation and provide experiment data to elucidate furtherly the anatomic construction of neuroimmunoregulation network. In our study, we use normal humans' IgG as immunizing antigen to prepair immune animal model by tail injection, take serum and cerebrospinal fluid from rats after immunized 0, 2, 4, 6, 8 days. Contrast analyzed ingredient of peripheral serum and cerebrospinal fluid of different immunized stage rats by Surface Enhanced Laser Desorption Ionization-Time Of Flight-Mass Spectrometry ( SELDI-TOF-MS) technique, Two-dimensional electrophoresis and Matrix-Assisted Laser Desorption Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) technique are furtherly applied in analyzing the amino acid sequence of 18KD idio-ingredient and determining signal molecules. The core of the empirical study in this thesis is to identify the passible afferent signal and mechanisms of the afferent signal pathway of neuroimmunomodulation network and to provide experiment evidence for illumination the anatomic construction of the neuroimmunologic network.
Relative results show that there are 221 significant different peaks which have correlations with immunological function discovered in serum of immune animals by SELDI-TOF-MS. Among the total of 221 different peaks, 173 peaks are high expressions in experimental group and the others are reverse—increases in control group. But no special different peak which has statistical significance are found in cerebrospinal fluid of immune animals. Also it can't observe corresponding equal increase between the special different peaks tested in peripheral serum and cerebrospinal fluid of immune animals. we compare and analyze the possible afferent signals of the neuroimmunomodulation network in the known neuromediators、neuropeptides、hormones and cytokines with the connection of 76 positive differential expression ingredients with highest peak value at immuned 2 days in rat serums detected by SELDI-TOF-MS to suppose possible afferent signals of the neuroimmunomodulation network. Analysis results on 18KD specific dot of 2-DE by MALDI-TOF-MS report 19 correlated peptide sequences derived from 18 substances, the total of 247 amino acids. However, the correlated results can't satisfy any amino acid sequence arrangement of the known substances.
So with the analysis above, we consider that these foregoing results demonstrate that 1) The results of theses research include 221 significant different peaks which have correlations with immunological function discovered in serum of immune animals by SELDI-TOF-MS; there are 76 differential signals with highest peak value expressed at immuned 2 days, 1 differential signal at immuned 4 days, 96 differential signals at immuned 6 days; statistic analysis of differential peak has extremely significant difference, even specificity of some peaks manifests all or none character. All the results have supported the agreement with study on the afferent signal pathway of neuroimmunomodulation network "active immunocytes release relevant functional active signals into blood, then start neuroimmunomodulation work by some way. 2) There is lack of evidence to verify immune modulator could carry out neuro-immune modulation by passing through blood brain barrier directly; 3) Possible afferent signals of the neuroimmunomodulation network such as IL-8、IL-15 and IL-18 supposed with relative factors; 4) IL-1 released by active immunocytes in the blood are not the afferent signal from the immune system to participate in the neuroimmunomodulation; 5) It needs more study on the signal which origins from active immunocytes to trigger the regulatory function of the relevant brain area in neuroimmunomodulation network . The afferent signals may be some unknow subtances.
SELDI分析结果显示,免疫组动物外周血中观察到221个有显著性差异的信号峰,其中173个为表达量高于对照组的正向表达峰。实验各组大鼠脑脊液的分析结果未见有统计学意义的特异性差异峰表达;在实验组血清中检测到的特异性差异峰也未在脑脊液中观察到相对应的同步变化。在76个最高峰值为免疫2天的免疫功能相关性差异表达的免疫大鼠血清的信号峰中,根据差异信号峰的分子量、pI值和来源细胞在已知的神经介质、神经肽、激素和细胞因子等信号物质中进行分析筛选,推测可能成为神经免疫调节相关的传入信号物质。经2-DE分离和MELDI-TOF-MS进一步分析和鉴定免疫大鼠血清中18KD特异组份,分析报告了18种来源的19个相关肽段序列,共247氨基酸,但相关结果不能满足任何已知物质的氨基酸序列的排序。
我们的实验结果证明:
1)本论文采用SELDI技术对不同免疫状态组大鼠和正常对照组大鼠的血清进行对比分析的结果显示实验组表达了221个与免疫功能相关的差异信号峰;差异信号表达峰值的分布在免疫2天的有76个,免疫4天有1个,免疫6天有96个;差异峰值统计学分析具有极显著性差异,某些差异峰的特异性甚至表现为“全或无”的关系。这些实验结果支持了神经免疫调节网络传入信号模式研究中两个重要的代表性假说——“血行传导通路”和“神经传导通路”假说在神经免疫调节网络传入信号通路领域研究中达成的共识,即免疫活性细胞释放功能活动相关信号物质到体液(血液)中,进而启动神经免疫调节功能。
2)对不同实验组大鼠的脑脊液组份对比分析的结果显示,脑脊液中并不存在与免疫功能变化相关的神经免疫调节功能的传入信号物质,血液中免疫功能相关的信号物质的变化没有在脑脊液中平行反映。神经免疫调节功能相关信号传入模式不是“血液—脑脊液—接触脑脊液的神经元系统—中枢脑区”的血行传导方式。本论文神经免疫调节网络信号传导模式研究结果不支持“血行传导通路”假说。
3)根据最高峰值在免疫2天的免疫功能相关的差异信号峰的分子量、PI值和来源细胞,在已知的神经介质、神经肽、激素和细胞因子等信号物质中进行比对筛选,推测细胞因子IL-8、IL-15和IL-18等三个组份可能成为免疫系统释放的跨系统传递的神经免疫调节功能相关的传入信号物质。
4)本论文应用蛋白质组学研究技术的标准方法2-DE-MALDI-TOF-MS技术分析免疫大鼠血清中IL-1分子在神经免疫调节网络传入通路中的地位和作用,发现免疫活性细胞释放到血液中的IL-1不可能成为免疫系统释放的跨系统传递的信号物质,参与神经免疫调节网络功能,否定了“血行传导通路”和“神经传导通路”假说在神经免疫调节网络传入信号通路领域研究中关于IL-1的共识。
5)对免疫大鼠血清双向电泳分离的分子量约18KD,PI约5.0位置差异点进行质谱鉴定的结果显示,该差异点的氨基酸序列不符合数据库收集的任何已知物质的氨基酸序列,提示神经免疫调节网络传入通路的上传信号中,可能包括我们还不了解的新物质。
Neuroimmunology is one of the most developed subjects in life science at the end of the 20th century. Neuro-endocrine-immunological regulation network theory—the fundamental of neuroimmunology has achieved great identification by academic circles and correlative experiments and researches have also demonstrated the existence of function regulation effect between the system of nerve and immune. Based on research of neuroendocrine regulation network, relative investigation has proved that there is a functional regulatory relationship between the nerve system and immune system.The argument in this investigation field was focused on signal afferent pathway of neuro-immune modulation network. In our prophase stuty, we found that the lateral hypothalamic nucleus (LH) and amygdaloid nuclear complex (AA) of the rat hypothalamus are referred to the neuroimmunomodulation. Based on the prophase study, we contrast analyzed ingredient of peripheral blood and cerebrospinal fluid of different immunized stage rats by Mass Spectrometry technique and Two-dimensional SDS electrophoresis to explore the up-delivering signals and afferent pathway involved in neuroimmunoregulation and provide experiment data to elucidate furtherly the anatomic construction of neuroimmunoregulation network. In our study, we use normal humans' IgG as immunizing antigen to prepair immune animal model by tail injection, take serum and cerebrospinal fluid from rats after immunized 0, 2, 4, 6, 8 days. Contrast analyzed ingredient of peripheral serum and cerebrospinal fluid of different immunized stage rats by Surface Enhanced Laser Desorption Ionization-Time Of Flight-Mass Spectrometry ( SELDI-TOF-MS) technique, Two-dimensional electrophoresis and Matrix-Assisted Laser Desorption Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) technique are furtherly applied in analyzing the amino acid sequence of 18KD idio-ingredient and determining signal molecules. The core of the empirical study in this thesis is to identify the passible afferent signal and mechanisms of the afferent signal pathway of neuroimmunomodulation network and to provide experiment evidence for illumination the anatomic construction of the neuroimmunologic network.
Relative results show that there are 221 significant different peaks which have correlations with immunological function discovered in serum of immune animals by SELDI-TOF-MS. Among the total of 221 different peaks, 173 peaks are high expressions in experimental group and the others are reverse—increases in control group. But no special different peak which has statistical significance are found in cerebrospinal fluid of immune animals. Also it can't observe corresponding equal increase between the special different peaks tested in peripheral serum and cerebrospinal fluid of immune animals. we compare and analyze the possible afferent signals of the neuroimmunomodulation network in the known neuromediators、neuropeptides、hormones and cytokines with the connection of 76 positive differential expression ingredients with highest peak value at immuned 2 days in rat serums detected by SELDI-TOF-MS to suppose possible afferent signals of the neuroimmunomodulation network. Analysis results on 18KD specific dot of 2-DE by MALDI-TOF-MS report 19 correlated peptide sequences derived from 18 substances, the total of 247 amino acids. However, the correlated results can't satisfy any amino acid sequence arrangement of the known substances.
So with the analysis above, we consider that these foregoing results demonstrate that 1) The results of theses research include 221 significant different peaks which have correlations with immunological function discovered in serum of immune animals by SELDI-TOF-MS; there are 76 differential signals with highest peak value expressed at immuned 2 days, 1 differential signal at immuned 4 days, 96 differential signals at immuned 6 days; statistic analysis of differential peak has extremely significant difference, even specificity of some peaks manifests all or none character. All the results have supported the agreement with study on the afferent signal pathway of neuroimmunomodulation network "active immunocytes release relevant functional active signals into blood, then start neuroimmunomodulation work by some way. 2) There is lack of evidence to verify immune modulator could carry out neuro-immune modulation by passing through blood brain barrier directly; 3) Possible afferent signals of the neuroimmunomodulation network such as IL-8、IL-15 and IL-18 supposed with relative factors; 4) IL-1 released by active immunocytes in the blood are not the afferent signal from the immune system to participate in the neuroimmunomodulation; 5) It needs more study on the signal which origins from active immunocytes to trigger the regulatory function of the relevant brain area in neuroimmunomodulation network . The afferent signals may be some unknow subtances.
引文
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