Nogo-66蛋白的免疫原性及对慢性高眼压SD大鼠RGCs免疫保护的实验研究
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摘要
青光眼的RGCs损伤与中枢神经系统(central nervous system ,CNS)变性改变相似,少量神经元损伤启动了损伤事件的自扩散链(self-propagating chain, SPC),导致邻近神经纤维的损伤。由于CNS自身保护性免疫功能低下,当部分神经元发生变性,其邻近的神经元受损机会明显增大,即变性损伤的神经细胞引发了更大范围和更深层次的继发性变性(secondary degeneration,SD)。所以即使临床上通过手术或者药物治疗,解除高眼压(ocular hypertensive;OHT)的初始危害因素(primary risk factors,PRF),青光眼的病程仍继续进展。
Bakalash(2003)应用感光细胞间维生素A类结合蛋白(interphotoreceptor retinoid-binding protein IRBP)对高眼压大鼠眼内接种后发现,视网膜神经节细胞的高眼压性损伤被遏制。同时,实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)仅偶尔发生于敏感大鼠,Bakalash据此认为,对神经损伤而言,损伤部位内源性抗原激活特异性T淋巴细胞介导的神经免疫保护是有效治疗策略。
神经损伤后继发变性由诸多因素导致,其中,髓磷脂抑制因子Nogo是CNS损伤后不能存活和再生失败的主要原因。Nogo-A、-B、-C具有共同的细胞膜外结构:Nogo-66,是由66个氨基酸残基构成的细胞膜外拓扑结构。损伤后的中枢神经,Nogo-66大量表达,通过与NgR结合,介导了Nogo的中枢神经抑制活性,是形成CNS损伤后SPC的启动因素之一。而由于中枢神经系统免疫赦免特征,损伤后大量表达的Nogo不能被识别,损伤特异性T淋巴细胞的神经保护功能未被激活,神经损伤的自扩散链没有得到有效的干预。
本课题组前期已证实慢性高眼压损伤后的视网膜有广泛的Nogo蛋白表达,并与损伤程度密切相关。并且通过Nogo-66质粒重组和表达了Nogo-66蛋白,经测序与内源性Nogo-66氨基酸序列完全相同。本研究试图验证重组Nogo-66蛋白是否具有免疫原性。是否能够通过Nogo-66蛋白接种,增强特异性T淋巴细胞介导的免疫反应,达到对受损的RGCs保护作用。主要研究如下:
首先应用ProPred web interface程序,ProPred MHC Class-II Binding PeptidePrediction Server抗原表位分析软件进行我们前期重组的Nogo-66蛋白抗原表位分析,证明Nogo-66的氨基酸序列具有明确的T淋巴细胞抗原表位。在此基础上做了以下研究:
一、Nogo-66蛋白对培养视网膜小胶质细胞活化研究使用不同浓度的Nogo-66蛋白与视网膜小胶质细胞共培养,检测小胶质细胞共刺激分子OX40L表达情况及小胶质细胞形态变化与Nogo-66蛋白浓度-效应的关系;
二、Nogo-66蛋白对SD大鼠免疫功能的影响使用Nogo-66蛋白接种SD大鼠,分析接种后SD大鼠的脾淋巴细胞的细胞周期,及特异性血清抗体浓度改变及其时间-效应关系。观察Nogo-66蛋白不同接种浓度SD大鼠是否出现EAE及EAU改变,以及实质性脏器的组织结构改变。
三、慢性高眼压对SD大鼠视网膜小胶质细胞免疫功能研究建立SD大鼠慢性高眼压模型,免疫组织化学方法观察高眼压过程中视网膜专职抗原提呈细胞-视网膜小胶质细胞的功能特征。
四、Nogo-66蛋白对慢性高眼压SD大鼠视网膜RGCs保护作用的研究按照皮下接种Nogo-66蛋白后时间-效应关系,进行眼玻璃体内追加免疫,检测慢性高眼压SD大鼠的视网膜免疫特征改变。并通过四甲基葡聚糖罗丹明标记计数视网膜神经节细胞及视觉诱发电位检测视觉功能,分析判断Nogo-66蛋白的对慢性高眼压SD大鼠视网膜的免疫保护作用。
主要结果及结论如下:
一、Nogo-66蛋白对视网膜小胶质细胞具有免疫原性经视网膜小胶质细胞培养证明;Nogo-66蛋白能够激活视网膜小胶质细胞使体积增大,当Nogo-66蛋白浓度至2000ng/ml出现巨噬细胞样改变。并刺激视网膜小胶质细胞表达表面黏附分子OX40L,Nogo-66蛋白质对视网膜小胶质细胞具有的免疫原性。
二、Nogo-66蛋白能够促进SD大鼠特异性免疫反应Nogo-66蛋白接种SD大鼠后,采用流式细胞术分析SD大鼠脾淋巴细胞的细胞周期,结果显示:Nogo-66蛋白能够刺激大鼠产生致敏T淋巴细胞,提高血清Nogo-66蛋白特异性IgG抗体浓度。另外,在有效浓度刺激下,正常SD大鼠大脑、小脑、脊髓及各实质脏器均未发生实验性自身免疫性脑脊髓炎(xperimental autoimmune encephalomyelitis,EAE)特征性改变、视网膜无实验性变应性色素层炎(experimental allergic uveitis,EAU)发生。
三、慢性高眼压激活视网膜小胶质细胞吞噬功能,损伤抗原提呈功能。在慢性高眼压损害下大鼠视网膜内颗粒层和内丛状层小胶质细胞表达表面黏附分子CD11b,证明吞噬功能被激活。小胶质细胞在慢性高眼压的过程中始终不表达抗原提呈分子MHC-Ⅱ,因此认为,慢性高眼压损伤产生的自身抗原不能激活小胶质细胞的抗原提呈功能,可能是CNS免疫赦免所致。
四、Nogo-66蛋白对慢性高眼压SD大鼠视网膜RGCs有免疫保护作用在激光造模时对慢性高眼压大鼠皮下接种Nogo-66,100μg,7天时玻璃体内注射0.005% Nogo-66蛋白溶液2μL,1月时再次玻璃体内接种Nogo-66后,检测视网膜小胶质细胞发现CD11b主要表达在神经纤维层,MHC-Ⅱ在神经纤维层少量表达。6月时,通过四甲基葡聚糖罗丹明标记RGCs,450nm绿色光激发下拍照计数视网膜RGCs发现:Nogo-66接种组SD大鼠视网膜中央区和周边区RGCs存活率分别为80.79%±2.34% 86.00%±6.79%,较对照组提高5.89%±3.04%～10.98%±4.36%,统计学分析二者有显著差异。F-VEP结果证实:Nogo-66接种组P波峰值提高及N1波潜时缩短,与对照组相比有显著差异(P<0.05)。实验组RGCs得到保护,视网膜功能损害减小。
The character of damage in glaucoma show strong resemblance to degenerated central nervous system (CNS). Just a few damaged retinal ganglion cells(RGCs) will trigger the self-propagating chain of hazard events and lead to the injury of vicinity nerve cells.
As the immune privilege of CNS, the primary degeneration will result in cytotoxicity of internal environment. It is mean, the degenerated nerve cells initiate a series of secondary degeneration (SD) and the latter trigger more wider-bound and deeper layer injury. So it seems that the SD means the injuryed nerve cells intiate the autoimmune response and the autoimmune response intiate turn into futhermore injury. Even if the classic ways in clinical, we have no other achievement but remove the intraocular hypertension of glaucoma ,it still on its way of SD ahead come from the degeneration of RGCs leads to special cytotoxicity microenvironment.
Bakalash(2003)found that immunized Rats with high IOP-induced RGC loss was reduced by vaccination with R16(a peptide derived from interphotoreceptor retinoid-binding protein) and the benefit of protection against IOP-induced RGC loss outweighed the cost of the monophasic experimental autoimmune uveitis (EAU) that transiently developed in a susceptible rat strain.
There are lots of factors act in the secondary degeneration coming from nervous degeneration . the most significance one is myelin inhibitor Nogo which express Nogo-A, Nogo-B and Nogo-C whose common Nogo-66 topology outside cellular membrane. In CNS post-trauma, Nogo-66 present and bind NgR leading to inhibiting result in nerve cells’survival. It has been named as self-propagating chain( SPC) . As a immune privilege apparatus, the CNS can not identify Nogo-66 as a damaging antigen which result in antigenic specificity T lymph cell keep unreactiveness. No available intervention is practiced to break the SPC which lead a infernal circle between secondary damage and damaging antigen.
Our study on immunoprotection in nervous damage has discovered that Nogo was widely expressed during chronic ocular hypertension in retina and according to the level of ocular hypertension. Accordingly to these results, we designed to immune the injuried RGCs with exogenous Nogo-66 that we got by genetic recombination owing the same amino acid array with the endogenous ones. So we get the Nogo-66 special T lymph cells activation and T cell mediated autoimmune responce that break the injuring SPC and achieve effective immunoprotection to damaged RGCs.
We have got T lymph cell epitope in Nogo-66 through ProPred MHC Class-II Binding Peptide Prediction Server software by ProPred web interface procedure. Coming from achieved work, What we do in this study lately as follow: 1. Characterizated the OX40L expressing on microglia and the volume of every group cells under the in different level of protein Nogo-66 with immunocytochemistry (ICC),contrasting with the normal and the different strength of protein Nogo-66 cell culture fluid by different density. 2. To study the influence of Nogo-66 to the retinal immunologic character of SD rats by immunising the experimental animals by Nogo-66 protein and detect IgG in blood serum for verifying the change in humoral-mediated immunity,detecting the percentage of T cell in S and G2/M stage to know the change about potential improving of cell mediated immunity at the pre-immunse and post-immunised different time points. While the experimental autoimmune encephalomyelitis( EAE) and experimental autoimmune uveitis( EAU) was detected post the vaccinated with Nogo-66 of different level of density. 3. The study about the character of immune in retinal microglia during chronic ocular hypertension in SD rats:Building the animal model of chronic ocular hypertension by 532-laser light coaglation and detected the CD11b and MHC-Ⅱexpression in the retinal’s microglia by immuno- histochemistry , Dextran Tetramethyl Rhodamine (DTR ) labeled the RGCs and amounted them to comparison the experiment and control groups. 4. The study on the immune character of retinal microglia and immunoprotection to RGCs in SD rats with chronic ocular hypertension. Based on those immune character of Protein Nogo-66, injection were acted to the chronic intraocular hypertension SD rats as animal model by 532-laser. Then we detected the CD11b expression in the retinal’s microglia by immunohistochemistry , Dextran Tetramethyl Rhodamine (DTR ) labeled the RGCs and amounted them. To contrasted the amount of microglia cell for phagocytose and the residual RGCs between control and experiment group.
The main results and conclusions are as follows:
1. Comparing with the control group, retinal microglia expressing more significant level charged by protein Nogo-66. the activated microglia showed bigger volume and less cell process ,contrasting the different experiment groups. The megalophage( MP) like cells appeared when concentration of Nogo-66 arrived 2000ng/ml. meanwhile, retinal microglia could be activated by protein Nogo-66 and expressing higher level OX40L,maybe contribution on the immune situation.
2. The immunition of Nogo-66 protein improving both the humoral- mediated immunity and cell-mediated immunity be proved by in vivo. The immuned SD rats IgG show higher concentration in serum and T cells of S stage in splenic lymphocyte ( SPL) than control groups. Meanwhile, under the different concentration of Nogo-66, no experimental autoimmune encephalomyelitis( EAE) or experimental autoimmune uveitis( EAU) occurrenced.
3. Retinal microglia get actived function of swallow while lost the function of antigen presention under the chronic ocular hypertension. As ocular hypertension continuing, retinal microglia expressed adhesion molecule CD11b showing phagocytosis action. Whilemean, through the process of ocular hypertension, retinal microglia expressed no MHC-Ⅱthat maybe come from immune privilege CNS.
4. The immunoprotection of Nogo-66 to RGCs in SD rats with chronic ocular hypertension. Vaccinating the Nogo-66 to SD rats 7d before the ocular hypertension( OHT), and strengthen it 1m after the OHT by 100μg,We got retinal microglia charactered with expressed MHC-Ⅱand less expressed CD11b in internal granular layer(IGL) and inner plexiform layer(IPL), as the stronger expressed CD11b in the nerve fiber layer (NFL). The vaccination show immunoprotection to RGCs , which verified by the amount of RGCs and LP1 as well as AP1 of FVEP 2m after OHT.
Bakalash(2003)应用感光细胞间维生素A类结合蛋白(interphotoreceptor retinoid-binding protein IRBP)对高眼压大鼠眼内接种后发现,视网膜神经节细胞的高眼压性损伤被遏制。同时,实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)仅偶尔发生于敏感大鼠,Bakalash据此认为,对神经损伤而言,损伤部位内源性抗原激活特异性T淋巴细胞介导的神经免疫保护是有效治疗策略。
神经损伤后继发变性由诸多因素导致,其中,髓磷脂抑制因子Nogo是CNS损伤后不能存活和再生失败的主要原因。Nogo-A、-B、-C具有共同的细胞膜外结构:Nogo-66,是由66个氨基酸残基构成的细胞膜外拓扑结构。损伤后的中枢神经,Nogo-66大量表达,通过与NgR结合,介导了Nogo的中枢神经抑制活性,是形成CNS损伤后SPC的启动因素之一。而由于中枢神经系统免疫赦免特征,损伤后大量表达的Nogo不能被识别,损伤特异性T淋巴细胞的神经保护功能未被激活,神经损伤的自扩散链没有得到有效的干预。
本课题组前期已证实慢性高眼压损伤后的视网膜有广泛的Nogo蛋白表达,并与损伤程度密切相关。并且通过Nogo-66质粒重组和表达了Nogo-66蛋白,经测序与内源性Nogo-66氨基酸序列完全相同。本研究试图验证重组Nogo-66蛋白是否具有免疫原性。是否能够通过Nogo-66蛋白接种,增强特异性T淋巴细胞介导的免疫反应,达到对受损的RGCs保护作用。主要研究如下:
首先应用ProPred web interface程序,ProPred MHC Class-II Binding PeptidePrediction Server抗原表位分析软件进行我们前期重组的Nogo-66蛋白抗原表位分析,证明Nogo-66的氨基酸序列具有明确的T淋巴细胞抗原表位。在此基础上做了以下研究:
一、Nogo-66蛋白对培养视网膜小胶质细胞活化研究使用不同浓度的Nogo-66蛋白与视网膜小胶质细胞共培养,检测小胶质细胞共刺激分子OX40L表达情况及小胶质细胞形态变化与Nogo-66蛋白浓度-效应的关系;
二、Nogo-66蛋白对SD大鼠免疫功能的影响使用Nogo-66蛋白接种SD大鼠,分析接种后SD大鼠的脾淋巴细胞的细胞周期,及特异性血清抗体浓度改变及其时间-效应关系。观察Nogo-66蛋白不同接种浓度SD大鼠是否出现EAE及EAU改变,以及实质性脏器的组织结构改变。
三、慢性高眼压对SD大鼠视网膜小胶质细胞免疫功能研究建立SD大鼠慢性高眼压模型,免疫组织化学方法观察高眼压过程中视网膜专职抗原提呈细胞-视网膜小胶质细胞的功能特征。
四、Nogo-66蛋白对慢性高眼压SD大鼠视网膜RGCs保护作用的研究按照皮下接种Nogo-66蛋白后时间-效应关系,进行眼玻璃体内追加免疫,检测慢性高眼压SD大鼠的视网膜免疫特征改变。并通过四甲基葡聚糖罗丹明标记计数视网膜神经节细胞及视觉诱发电位检测视觉功能,分析判断Nogo-66蛋白的对慢性高眼压SD大鼠视网膜的免疫保护作用。
主要结果及结论如下:
一、Nogo-66蛋白对视网膜小胶质细胞具有免疫原性经视网膜小胶质细胞培养证明;Nogo-66蛋白能够激活视网膜小胶质细胞使体积增大,当Nogo-66蛋白浓度至2000ng/ml出现巨噬细胞样改变。并刺激视网膜小胶质细胞表达表面黏附分子OX40L,Nogo-66蛋白质对视网膜小胶质细胞具有的免疫原性。
二、Nogo-66蛋白能够促进SD大鼠特异性免疫反应Nogo-66蛋白接种SD大鼠后,采用流式细胞术分析SD大鼠脾淋巴细胞的细胞周期,结果显示:Nogo-66蛋白能够刺激大鼠产生致敏T淋巴细胞,提高血清Nogo-66蛋白特异性IgG抗体浓度。另外,在有效浓度刺激下,正常SD大鼠大脑、小脑、脊髓及各实质脏器均未发生实验性自身免疫性脑脊髓炎(xperimental autoimmune encephalomyelitis,EAE)特征性改变、视网膜无实验性变应性色素层炎(experimental allergic uveitis,EAU)发生。
三、慢性高眼压激活视网膜小胶质细胞吞噬功能,损伤抗原提呈功能。在慢性高眼压损害下大鼠视网膜内颗粒层和内丛状层小胶质细胞表达表面黏附分子CD11b,证明吞噬功能被激活。小胶质细胞在慢性高眼压的过程中始终不表达抗原提呈分子MHC-Ⅱ,因此认为,慢性高眼压损伤产生的自身抗原不能激活小胶质细胞的抗原提呈功能,可能是CNS免疫赦免所致。
四、Nogo-66蛋白对慢性高眼压SD大鼠视网膜RGCs有免疫保护作用在激光造模时对慢性高眼压大鼠皮下接种Nogo-66,100μg,7天时玻璃体内注射0.005% Nogo-66蛋白溶液2μL,1月时再次玻璃体内接种Nogo-66后,检测视网膜小胶质细胞发现CD11b主要表达在神经纤维层,MHC-Ⅱ在神经纤维层少量表达。6月时,通过四甲基葡聚糖罗丹明标记RGCs,450nm绿色光激发下拍照计数视网膜RGCs发现:Nogo-66接种组SD大鼠视网膜中央区和周边区RGCs存活率分别为80.79%±2.34% 86.00%±6.79%,较对照组提高5.89%±3.04%～10.98%±4.36%,统计学分析二者有显著差异。F-VEP结果证实:Nogo-66接种组P波峰值提高及N1波潜时缩短,与对照组相比有显著差异(P<0.05)。实验组RGCs得到保护,视网膜功能损害减小。
The character of damage in glaucoma show strong resemblance to degenerated central nervous system (CNS). Just a few damaged retinal ganglion cells(RGCs) will trigger the self-propagating chain of hazard events and lead to the injury of vicinity nerve cells.
As the immune privilege of CNS, the primary degeneration will result in cytotoxicity of internal environment. It is mean, the degenerated nerve cells initiate a series of secondary degeneration (SD) and the latter trigger more wider-bound and deeper layer injury. So it seems that the SD means the injuryed nerve cells intiate the autoimmune response and the autoimmune response intiate turn into futhermore injury. Even if the classic ways in clinical, we have no other achievement but remove the intraocular hypertension of glaucoma ,it still on its way of SD ahead come from the degeneration of RGCs leads to special cytotoxicity microenvironment.
Bakalash(2003)found that immunized Rats with high IOP-induced RGC loss was reduced by vaccination with R16(a peptide derived from interphotoreceptor retinoid-binding protein) and the benefit of protection against IOP-induced RGC loss outweighed the cost of the monophasic experimental autoimmune uveitis (EAU) that transiently developed in a susceptible rat strain.
There are lots of factors act in the secondary degeneration coming from nervous degeneration . the most significance one is myelin inhibitor Nogo which express Nogo-A, Nogo-B and Nogo-C whose common Nogo-66 topology outside cellular membrane. In CNS post-trauma, Nogo-66 present and bind NgR leading to inhibiting result in nerve cells’survival. It has been named as self-propagating chain( SPC) . As a immune privilege apparatus, the CNS can not identify Nogo-66 as a damaging antigen which result in antigenic specificity T lymph cell keep unreactiveness. No available intervention is practiced to break the SPC which lead a infernal circle between secondary damage and damaging antigen.
Our study on immunoprotection in nervous damage has discovered that Nogo was widely expressed during chronic ocular hypertension in retina and according to the level of ocular hypertension. Accordingly to these results, we designed to immune the injuried RGCs with exogenous Nogo-66 that we got by genetic recombination owing the same amino acid array with the endogenous ones. So we get the Nogo-66 special T lymph cells activation and T cell mediated autoimmune responce that break the injuring SPC and achieve effective immunoprotection to damaged RGCs.
We have got T lymph cell epitope in Nogo-66 through ProPred MHC Class-II Binding Peptide Prediction Server software by ProPred web interface procedure. Coming from achieved work, What we do in this study lately as follow: 1. Characterizated the OX40L expressing on microglia and the volume of every group cells under the in different level of protein Nogo-66 with immunocytochemistry (ICC),contrasting with the normal and the different strength of protein Nogo-66 cell culture fluid by different density. 2. To study the influence of Nogo-66 to the retinal immunologic character of SD rats by immunising the experimental animals by Nogo-66 protein and detect IgG in blood serum for verifying the change in humoral-mediated immunity,detecting the percentage of T cell in S and G2/M stage to know the change about potential improving of cell mediated immunity at the pre-immunse and post-immunised different time points. While the experimental autoimmune encephalomyelitis( EAE) and experimental autoimmune uveitis( EAU) was detected post the vaccinated with Nogo-66 of different level of density. 3. The study about the character of immune in retinal microglia during chronic ocular hypertension in SD rats:Building the animal model of chronic ocular hypertension by 532-laser light coaglation and detected the CD11b and MHC-Ⅱexpression in the retinal’s microglia by immuno- histochemistry , Dextran Tetramethyl Rhodamine (DTR ) labeled the RGCs and amounted them to comparison the experiment and control groups. 4. The study on the immune character of retinal microglia and immunoprotection to RGCs in SD rats with chronic ocular hypertension. Based on those immune character of Protein Nogo-66, injection were acted to the chronic intraocular hypertension SD rats as animal model by 532-laser. Then we detected the CD11b expression in the retinal’s microglia by immunohistochemistry , Dextran Tetramethyl Rhodamine (DTR ) labeled the RGCs and amounted them. To contrasted the amount of microglia cell for phagocytose and the residual RGCs between control and experiment group.
The main results and conclusions are as follows:
1. Comparing with the control group, retinal microglia expressing more significant level charged by protein Nogo-66. the activated microglia showed bigger volume and less cell process ,contrasting the different experiment groups. The megalophage( MP) like cells appeared when concentration of Nogo-66 arrived 2000ng/ml. meanwhile, retinal microglia could be activated by protein Nogo-66 and expressing higher level OX40L,maybe contribution on the immune situation.
2. The immunition of Nogo-66 protein improving both the humoral- mediated immunity and cell-mediated immunity be proved by in vivo. The immuned SD rats IgG show higher concentration in serum and T cells of S stage in splenic lymphocyte ( SPL) than control groups. Meanwhile, under the different concentration of Nogo-66, no experimental autoimmune encephalomyelitis( EAE) or experimental autoimmune uveitis( EAU) occurrenced.
3. Retinal microglia get actived function of swallow while lost the function of antigen presention under the chronic ocular hypertension. As ocular hypertension continuing, retinal microglia expressed adhesion molecule CD11b showing phagocytosis action. Whilemean, through the process of ocular hypertension, retinal microglia expressed no MHC-Ⅱthat maybe come from immune privilege CNS.
4. The immunoprotection of Nogo-66 to RGCs in SD rats with chronic ocular hypertension. Vaccinating the Nogo-66 to SD rats 7d before the ocular hypertension( OHT), and strengthen it 1m after the OHT by 100μg,We got retinal microglia charactered with expressed MHC-Ⅱand less expressed CD11b in internal granular layer(IGL) and inner plexiform layer(IPL), as the stronger expressed CD11b in the nerve fiber layer (NFL). The vaccination show immunoprotection to RGCs , which verified by the amount of RGCs and LP1 as well as AP1 of FVEP 2m after OHT.
引文
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