抗磷脂抗体对Th细胞亚型影响的研究
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摘要
第一部分不同浓度抗磷脂抗体对外周血单个核细胞中Th细胞亚型表达的调节
目的：探讨不同浓度aPL抗体对外周血中Th1、Th2、Th17、Treg细胞调节作用。
方法：分离健康人外周血单个核细胞,与不同浓度的抗磷脂抗体共同培养孵育48小时后,检测外周血单个核细胞中Th1、Th2、Th17、 Treg四种亚型的表达。我们采用流式细胞检测技术直接从数量上检测抗磷脂抗体干预后的Th1、Th2、Th17、Treg四种亚型细胞分化情况,并通过实时定量PCR检测转录因子的表达,从Th细胞分化的上游过程中探讨抗磷脂抗体干预后的Th1、Th2、Th17、Treg四种亚型细胞分化状态。
结果：本研究发现aPL干预后Th1细胞及其T-bet mRNA表达均出现下调；Th2细胞及其GATA3mRNA表达上调,Th1/Th2比值下降,平衡向Th2偏移；Th17细胞及其ROR-γ t mRNA表达上调,Treg细胞及其Foxp3mRNA表达下调,Th17/Treg失衡。且本实验发现Th细胞亚型变化与aPL抗体浓度相关,高浓度的aPL抗体导致Th细胞亚型分化的紊乱。
结论：
1.aPL导致PBMCs中Th1、Th2、Th17、Treg细胞表达发生改变,导致Th1/Th2失衡,Th17/Treg失衡,导致免疫紊乱,可能参与aPL介导的组织损伤。
2.Th细胞亚型变化与aPL浓度存在剂量关系。
第二部分探讨抗磷脂抗体对外周血单个核细胞表达协同刺激分子PD-L1的影响
目的：探讨不同浓度抗磷脂抗体对协同刺激分子PD-L1表达的调节作用以及PD-L1在aPL导致Th细胞亚型分化紊乱中的作用。
方法：分离健康人外周血单个核细胞,与不同浓度的抗磷脂抗体共同培养孵育48小时后,检测采用流式细胞技术检测外周血单个核细胞中PD-L1蛋白表达强度,并通过实时定量PCR检测PD-L1mRNA转录因子的表达。同时分析PD-L1表达与Th细胞分化的相关情况。观察并比较经PD-L1-Ig预处理后,致病浓度的aPL抗体对Th1、Th2、 Th17、Treg四种Th亚型细胞分化的影响。
结果：本研究发现aPL干预后PD-L1蛋白及mRNA表达均呈上调趋势,各组间表达有统计学差异(F=9.391,p=0.000；F=15.344,p=0.000),且上调与抗体浓度显著正相关(r=0.713,p=0.000；r=0.756,p=0.000)。PD-L1蛋白表达与Th1细胞,Treg细胞以及Thl/Th2比例负相关,而与Th2细胞及Th17细胞表达无相关性。而PD-L1mRNA表达与T-bet mRNA, Foxp3mRNA以及T-bet/GATA3比例显著负相关,与GATA3mRNA及ROR-γ t mRNA表达显著正相关。但是给予PD-L1-Ig阻断协同刺激信号通路后,研究发现高浓度的aPL组与阻断抗体组Th细胞亚型变化无显著差异(p>0.05)。
结论：
1.aPL可导致PD-L1表达上调,且与抗体浓度正相关。协同刺激分子PD-L1可能在APS发病中发挥作用。
2.协同刺激分子PD-L1可能在aPL导致的Th细胞分化紊乱中发挥作用。
3.抑制PD-L1协同刺激信号通路对Th亚型分化无明显影响。
第三部分卡介菌多糖核酸对aPL干预后的PBMGs中Th细胞亚型的影响
目的：探讨卡介菌多糖核酸治疗APS的可能机制
方法：分离健康人外周血单个核细胞,与致病浓度的抗磷脂抗体、治疗浓度的卡介菌多糖核酸溶液共同培养孵育48小时后,采用流式细胞技术检测外周血单个核细胞中Th1、Th2、Th17、Treg四种Th亚型细胞表达情况,并通过实时定量PCR检测Th1、Th2、Th17、Treg四种Th亚型细胞mRNA表达的变化情况。
结果：本研究发现卡介菌多糖核酸溶液干预后Thl细胞及其T-bet mRNA表达均出现显著上调(p=0.000；p=0.000)；Th2细胞及其GATA3mRNA表达变化无统计学差异(p>0.05)；Th1/Th2比值上调,平衡向Th1偏移。Treg细胞及其Foxp3mRNA表达上调,均有统计学差异(p=0.016；p=0.024)；而Th17细胞及其ROR-γt mRNA表达无统计学差异(p>0.05)。
结论：卡介菌多糖核酸溶液可以有效逆转Th细胞的分化,卡介菌多糖核酸溶液可能在临床治疗APS中发挥作用。
Chapter One The expression of Th cell subtypes in cultured PBMCs with different concentrations of aPL
Objective:To evaluate the Thl/Th2/Th17/Treg cells expression in APS, and whether they are related to the aPL titers.
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with different titers of aPL. After incubated48hours, PBMCs were collected, and the Th cell subsets were detected by Flow Cytometry and the transcription factors were detected by Real-time PCR.
Results:It was showed that after incubated with aPL, there was a significant decrease in Thl frequencies and T-bet mRNA, a significant increase in Th2frequencies and GATA3mRNA. Th1/Th2ratio was decreased. The Th17frequencies and ROR-yt mRNA was increased, but Treg frequencies and Foxp3mRNA was decreased. And also we found the Th subsets expression were positively correlated with the antibodies titers, especially at higher concentrations.
Conclusion:
1. aPL may change Thl/Th2/Thl7/Treg expression, result Thl/Th2and Th17/Treg imbalance, and result immune disorders. All these may participate in the aPL mediated tissue damage.
2. The expression of Th cell subsets were correlated with the aPL titers.
Chapter Two The expression of costimulatory molecules PD-L1in cultured PBMCs with aPL
Objective:To evaluated the costimulatory molecules PD-L1expression with different titers of aPL, and to explore the possible mechanisms about Th cell differentiation disorder with PD-L1.
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with different titers of aPL. After incubated48hours, PBMCs were collected, and the PD-L1was detected by Flow Cytometry and Real-time PCR. And we analysed the relationships between PD-L1expression and Th cells differentiation. We also compared the Th1/Th2/Th17/Treg cells expression with PD-L1-Ig pretreated or not by Flow Cytometry and Real-Time PCR.
Results:It was showed that incubated with aPL can induce significant increase in PD-L1proten and mRNA expression (F=9.391, p=0.000; F=15.344,p=0.000), and were positively correlated with the antibodies titers (r=0.713,p=0.000; r=0.756, p=0.000).PD-L1protein expression has negative correlation with Thl frequencies, Treg frequencies and Th1/Th2proportion, but had no correlation with Th2frequencies and Th17frequencies. In the same, PD-Ll mRNA expression has negative correlation with T-bet mRNA, Foxp3mRNA and T-bet/GATA3proportion, but had positive correlation with GATA3mRNA and ROR-yt mRNA. However pretreated with PD-L1-Ig had no function in Th differentiation (p>0.05).
Conclusion:
1. aPL may result PD-L1upregulated, and were positive correlated with the aPL titers. The costimulatory molecules PD-L1may be play a role in the development of APS.
2. The costimulatory molecules PD-L1may participate in Th cell differentiation disorder in APS.
3. Block the costimulatory pathway of PD-L1had no function in Th differentiation.
Chapter Three The expression of Th cell subtypes in incubated PBMCs with with aPL treated by Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin
Objective:To evaluate the positive mechanism of Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin in treating APS
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with high titers of aPL and Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin. After incubated48hours, PBMCs were collected, and the Th cell subsets were detected by Flow Cytometry and the transcription factors were detected by Real-time PCR.
Results:It was showed that after treated with Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin, there was significant increase in Th1frequencies and T-bet mRNA (p=0.000; p=0.000); but no different in Th2frequencies and GATA3mRNA (p>0.05); Th1/Th2ratio was significant increased; Treg frequencies and Foxp3mRNA was significant increased (p=0.016; p=0.024), but no different in Th17frequencies and ROR-yt mRNA (p>0.05).
Conclusion:
Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin can effectively reversed Th cells differentiation, it could be make sense in treating APS.
目的：探讨不同浓度aPL抗体对外周血中Th1、Th2、Th17、Treg细胞调节作用。
方法：分离健康人外周血单个核细胞,与不同浓度的抗磷脂抗体共同培养孵育48小时后,检测外周血单个核细胞中Th1、Th2、Th17、 Treg四种亚型的表达。我们采用流式细胞检测技术直接从数量上检测抗磷脂抗体干预后的Th1、Th2、Th17、Treg四种亚型细胞分化情况,并通过实时定量PCR检测转录因子的表达,从Th细胞分化的上游过程中探讨抗磷脂抗体干预后的Th1、Th2、Th17、Treg四种亚型细胞分化状态。
结果：本研究发现aPL干预后Th1细胞及其T-bet mRNA表达均出现下调；Th2细胞及其GATA3mRNA表达上调,Th1/Th2比值下降,平衡向Th2偏移；Th17细胞及其ROR-γ t mRNA表达上调,Treg细胞及其Foxp3mRNA表达下调,Th17/Treg失衡。且本实验发现Th细胞亚型变化与aPL抗体浓度相关,高浓度的aPL抗体导致Th细胞亚型分化的紊乱。
结论：
1.aPL导致PBMCs中Th1、Th2、Th17、Treg细胞表达发生改变,导致Th1/Th2失衡,Th17/Treg失衡,导致免疫紊乱,可能参与aPL介导的组织损伤。
2.Th细胞亚型变化与aPL浓度存在剂量关系。
第二部分探讨抗磷脂抗体对外周血单个核细胞表达协同刺激分子PD-L1的影响
目的：探讨不同浓度抗磷脂抗体对协同刺激分子PD-L1表达的调节作用以及PD-L1在aPL导致Th细胞亚型分化紊乱中的作用。
方法：分离健康人外周血单个核细胞,与不同浓度的抗磷脂抗体共同培养孵育48小时后,检测采用流式细胞技术检测外周血单个核细胞中PD-L1蛋白表达强度,并通过实时定量PCR检测PD-L1mRNA转录因子的表达。同时分析PD-L1表达与Th细胞分化的相关情况。观察并比较经PD-L1-Ig预处理后,致病浓度的aPL抗体对Th1、Th2、 Th17、Treg四种Th亚型细胞分化的影响。
结果：本研究发现aPL干预后PD-L1蛋白及mRNA表达均呈上调趋势,各组间表达有统计学差异(F=9.391,p=0.000；F=15.344,p=0.000),且上调与抗体浓度显著正相关(r=0.713,p=0.000；r=0.756,p=0.000)。PD-L1蛋白表达与Th1细胞,Treg细胞以及Thl/Th2比例负相关,而与Th2细胞及Th17细胞表达无相关性。而PD-L1mRNA表达与T-bet mRNA, Foxp3mRNA以及T-bet/GATA3比例显著负相关,与GATA3mRNA及ROR-γ t mRNA表达显著正相关。但是给予PD-L1-Ig阻断协同刺激信号通路后,研究发现高浓度的aPL组与阻断抗体组Th细胞亚型变化无显著差异(p>0.05)。
结论：
1.aPL可导致PD-L1表达上调,且与抗体浓度正相关。协同刺激分子PD-L1可能在APS发病中发挥作用。
2.协同刺激分子PD-L1可能在aPL导致的Th细胞分化紊乱中发挥作用。
3.抑制PD-L1协同刺激信号通路对Th亚型分化无明显影响。
第三部分卡介菌多糖核酸对aPL干预后的PBMGs中Th细胞亚型的影响
目的：探讨卡介菌多糖核酸治疗APS的可能机制
方法：分离健康人外周血单个核细胞,与致病浓度的抗磷脂抗体、治疗浓度的卡介菌多糖核酸溶液共同培养孵育48小时后,采用流式细胞技术检测外周血单个核细胞中Th1、Th2、Th17、Treg四种Th亚型细胞表达情况,并通过实时定量PCR检测Th1、Th2、Th17、Treg四种Th亚型细胞mRNA表达的变化情况。
结果：本研究发现卡介菌多糖核酸溶液干预后Thl细胞及其T-bet mRNA表达均出现显著上调(p=0.000；p=0.000)；Th2细胞及其GATA3mRNA表达变化无统计学差异(p>0.05)；Th1/Th2比值上调,平衡向Th1偏移。Treg细胞及其Foxp3mRNA表达上调,均有统计学差异(p=0.016；p=0.024)；而Th17细胞及其ROR-γt mRNA表达无统计学差异(p>0.05)。
结论：卡介菌多糖核酸溶液可以有效逆转Th细胞的分化,卡介菌多糖核酸溶液可能在临床治疗APS中发挥作用。
Chapter One The expression of Th cell subtypes in cultured PBMCs with different concentrations of aPL
Objective:To evaluate the Thl/Th2/Th17/Treg cells expression in APS, and whether they are related to the aPL titers.
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with different titers of aPL. After incubated48hours, PBMCs were collected, and the Th cell subsets were detected by Flow Cytometry and the transcription factors were detected by Real-time PCR.
Results:It was showed that after incubated with aPL, there was a significant decrease in Thl frequencies and T-bet mRNA, a significant increase in Th2frequencies and GATA3mRNA. Th1/Th2ratio was decreased. The Th17frequencies and ROR-yt mRNA was increased, but Treg frequencies and Foxp3mRNA was decreased. And also we found the Th subsets expression were positively correlated with the antibodies titers, especially at higher concentrations.
Conclusion:
1. aPL may change Thl/Th2/Thl7/Treg expression, result Thl/Th2and Th17/Treg imbalance, and result immune disorders. All these may participate in the aPL mediated tissue damage.
2. The expression of Th cell subsets were correlated with the aPL titers.
Chapter Two The expression of costimulatory molecules PD-L1in cultured PBMCs with aPL
Objective:To evaluated the costimulatory molecules PD-L1expression with different titers of aPL, and to explore the possible mechanisms about Th cell differentiation disorder with PD-L1.
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with different titers of aPL. After incubated48hours, PBMCs were collected, and the PD-L1was detected by Flow Cytometry and Real-time PCR. And we analysed the relationships between PD-L1expression and Th cells differentiation. We also compared the Th1/Th2/Th17/Treg cells expression with PD-L1-Ig pretreated or not by Flow Cytometry and Real-Time PCR.
Results:It was showed that incubated with aPL can induce significant increase in PD-L1proten and mRNA expression (F=9.391, p=0.000; F=15.344,p=0.000), and were positively correlated with the antibodies titers (r=0.713,p=0.000; r=0.756, p=0.000).PD-L1protein expression has negative correlation with Thl frequencies, Treg frequencies and Th1/Th2proportion, but had no correlation with Th2frequencies and Th17frequencies. In the same, PD-Ll mRNA expression has negative correlation with T-bet mRNA, Foxp3mRNA and T-bet/GATA3proportion, but had positive correlation with GATA3mRNA and ROR-yt mRNA. However pretreated with PD-L1-Ig had no function in Th differentiation (p>0.05).
Conclusion:
1. aPL may result PD-L1upregulated, and were positive correlated with the aPL titers. The costimulatory molecules PD-L1may be play a role in the development of APS.
2. The costimulatory molecules PD-L1may participate in Th cell differentiation disorder in APS.
3. Block the costimulatory pathway of PD-L1had no function in Th differentiation.
Chapter Three The expression of Th cell subtypes in incubated PBMCs with with aPL treated by Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin
Objective:To evaluate the positive mechanism of Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin in treating APS
Method:Peripheral mononuclear cells (PBMCs) were isolated from health doners, and incubated with high titers of aPL and Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin. After incubated48hours, PBMCs were collected, and the Th cell subsets were detected by Flow Cytometry and the transcription factors were detected by Real-time PCR.
Results:It was showed that after treated with Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin, there was significant increase in Th1frequencies and T-bet mRNA (p=0.000; p=0.000); but no different in Th2frequencies and GATA3mRNA (p>0.05); Th1/Th2ratio was significant increased; Treg frequencies and Foxp3mRNA was significant increased (p=0.016; p=0.024), but no different in Th17frequencies and ROR-yt mRNA (p>0.05).
Conclusion:
Polysaccharide nucleic acid fraction of Bacillus Calmette Guerin can effectively reversed Th cells differentiation, it could be make sense in treating APS.
引文
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