高炎症倾向下恶性刺激对外周T细胞免疫、脑内炎症及帕金森发病机制的影响

The pathogenesis of Parkisnon’s Disease(PD) is closely related to the chronic neuroinflammation within the brain which is influenced by the overactivation of peripheral immune of PD patients. The genomic investigation of over a thousand sporadic PD patients revealed that over half of the high risk genes of PD are related to the regulation of immune responses, which suggested the high inflammation propensity genetic background of PD patients. Epidemic study reached the conclusion that the malignant tumor incidence was significantly lower in PD patients, while the key step to control and kill tumor cells within the body is the adequate activation of T cell immunity which is exactly the major part of peripheral inflammation in PD patient, additionally in both the patients’ brain and PD animal model’s brain, infiltrating activated T cells were identified and a close relation was found between the infiltrating T cells and disease severity, implying that activated peripheral T cells accelerate the occurrence of PD. On base of which we propose that T cell immunity is adequately activated to combat the tumor in an individual with high-inflammation propensity background, however even after the removal of malignancy threat the activated T cell immunity fail to resolute and continue to remain activated state, worsening the neuroinflammation within brain and precipitate the loss of dopamine neurons. During the whole procedure regulation of T cell immunity is the critical link. In this project we tried to modulate the T cell activation through the manipulation of CTLA-4/PD-1/CD28 molecules which are regulators of T cell activation , observing how a high inflammation genetic background mouse will react when facing the malignant stimulation, and how the peripheral immunity, brain immunity will response and how is the survival of dopaminergic neurons in this situation. Hoping to provide new clues to the neurimmune pathogenesis of PD.

外周免疫炎症深刻影响着脑内神经炎症的发生,后者与帕金森病（PD）的发病机制密切相关。对千余名散发PD患者基因组的研究发现一半以上的PD高危基因都与免疫调控有关,提示PD好发于高炎症倾向遗传背景的个体。有趣的是PD患者中各种癌症发病率显著下降,而降低癌症的关键是以外周T细胞为主的免疫监控的有效激活,提示:为控制肿瘤而激活的外周免疫既能抵抗恶变,也能恶化脑内炎症。据此我们提出高炎症倾向的个体受到恶变刺激后,原有的免疫稳态被打破,外周免疫充分激活,而恶变解除后外周过度炎症不能及时消退继续保持,并恶化了脑内炎症,最终导致PD的发生。其中个体高炎症倾向的遗传背景是外周免疫不能及时下调的内因基石。本课题以具有高炎症倾向的DBA/1鼠为研究主体，考察其受到恶性刺激时外周免疫、脑内炎症的变化及黑质神经元存亡，并通过CTLA-4/PD-1/CD28等免疫分子调控T细胞活化状态，考察对上述指标及PD发生的影响

外周免疫炎症深刻影响着脑内神经炎症的发生,后者与帕金森病（PD）的发病机制密切相关。对千余名散发PD患者基因组的研究发现一半以上的PD高危基因都与免疫调控有关 ,提示PD好发于高炎症倾向遗传背景的个体。有趣的是PD患者中各种癌症发病率显著下降, 而降低癌症的关键是以外周T细胞为主的免疫监控的有效激活,提示:为控制肿瘤而激活的 外周免疫既能抵抗恶变,也能恶化脑内炎症。据此我们提出高炎症倾向的个体受到恶变刺激后,原有的免疫稳态被打破,外周免疫充分激活,而恶变解除后外周过度炎症不能及时消 退继续保持,并恶化了脑内炎症,最终导致PD的发生。其中个体高炎症倾向的遗传背景是外周免疫不能及时下调的内因基石。本课题以具有高炎症倾向的DBA/1鼠为研究主体，考察其受到恶性刺激时外周免疫、脑内炎症的变化及黑质神经元存亡，并通过CTLA-4/PD-1/CD 28等免疫分子调控T细胞活化状态，考察对上述指标及PD发生的影响。结果：具有高炎症倾向的DBA/1小鼠在恶变诱导下，外周炎症持续增加，促进颅内炎症的发生，肿瘤发生率降低，神经变性增加。CD28和CTLA-4/PD-1降低了T细胞主导的炎症反应，降低了脑内炎症反应，保护了神经退行性变，增加了肿瘤的发病率。CTLA-4与PD-1阻断剂联合使用可过度激活T细胞，加重外周及颅内炎症，降低肿瘤发生率，损伤多巴胺神经元，促进神经退行性变的发生。结论:CD28和CTLA-4/PD-1失衡导致恶性刺激引起的高炎症倾向导致多巴胺神经元损伤。希望能够找到改善及延缓帕金森病的新方法。