外周血单核巨噬细胞免疫耐受障碍对脑内慢性炎症的影响及与帕金森病关系的研究

Neuroinflammation is an important pathogenesis of Parkinson's Disease (PD). Peripheral immune system used to exert significant impact on immune activities in the brain. The peripheral blood monocytes or macrophages (PBM) influence the inflammation within brain by transforming into microglia after passing through blood brain barrier or forming a special group of macrophages in brain such as perivascular macrophages. Immune tolerance is the refractoriness of immune system to certain stimulations that exist within body continuously or repeatedly to avoid over-activation of immune cells and unnecessary by-stander injury. The most important part of the immune tolerance is the macrophages tolerance, which featured of immune downregulation, and may lead to chronic inflammation in multiple condtions when impaired. The minor dose of LPS (lipopolysacchride)given peripherally has been demonstrated to be neuroprotective or attenuate the brain inflammation in various brain injuries.The minimal dose of LPS is able to induce the macrophages tolerance. Suitable LPS concentration for tolerance induction is approved to exist in peripheral blood in PD patients, while the peripheral immune cells in PD patients are still acitvated,combining with the evidence from our previous study that CD200R in PBM from PD patient is abnormally regulated and CD200R takes an active role in immune tolerance, we thus propose that there is an impaired PBM tolerance in PD patients, which leads to the failure of downregulation of the brain inflammation.We try in this proposal to explore the influence of activated or tolerated PBM on brain inflammation, see its effect on PD occurrence by manipulating PBM immune state and the specific roles of CD200/CD200R pathway in the whole process concomitantly.Hoping to get closer to the pathogenesis of PD.

小胶质细胞（MI）激活为核心的脑内过度炎症反应是帕金森病(PD)的重要病理特征，而外周免疫对中枢炎症影响深刻：一次大剂量LPS腹腔注射足以引起脑内持久的炎症反应，反之非甾体抗炎药物对外周免疫的抑制也能降低PD的发病率。外周血单核细胞（PBM）是外周影响中枢的重要途径，它能穿越血脑屏障入脑演变成MI直接或间接参与中枢炎症反应，而PBM在外周的免疫状态直接影响其入脑后对脑内炎症的干预方向。免疫耐受指抗原持续存在时发生的免疫下调或不应答，可以避免免疫系统的过度激活，是机体的一种自我保护机制。免疫耐受的PBM能够对中枢炎症施加影响，使其受限下调。有研究显示尽管PD患者的外周血中具备诱导免疫耐受的条件，但其外周免疫仍处于异常激活状态，据此我们提出外周PBM的免疫耐受障碍是PD脑内炎症不能及时下调的重要原因。本课题拟明确PBM免疫耐受对脑内炎症和PD发病的影响。为通过外周途径探讨PD提供思路。

外周血单核细胞（PBM）及中枢小胶质细胞（MI）在外周炎症诱发的中枢炎症及由脑内炎症介导的多巴胺能神经元损伤的进程中扮演着重要角色。免疫耐受亦被证实在多种炎症情况下起到机体自我保护作用。CD200-CD200R被认为是多种炎症、肿瘤条件下的重要通路。基于上述理论及研究基础，本课题重点研究了PBM、MI、CD200-CD200R通路三者在外周炎症、外周炎症诱导的中枢炎症、脑内炎症介导的多巴胺能神经元损伤等过程中的作用，外周血单核细胞免疫耐受的建立，外周血单核细胞免疫耐受对后续发生的外周炎症或中枢炎症的进程及转归的影响等。结果表明：PBM、MI及CD200-CD200R通路是外周炎症向中枢浸润的三大要素，耗竭PBM或MI、增加CD200-CD200R的表达均可以抑制外周炎症向中枢的浸润；外周血单核细胞免疫耐受可以通过重复小剂量脂多糖腹腔注射诱导建立；外周血单核细胞免疫耐受的建立既可以减轻后续的外周炎症及其诱发的中枢炎症，又可以减轻后续直接发生于脑内的炎症，并削弱由脑内炎症造成的多巴胺能神经元损伤，展现出外周免疫耐受的中枢神经元保护作用。本课题证实了外周炎症与中枢炎症之间的重要联系，亦强调了外周炎症在炎症诱导的中枢神经系统退行性疾病病程中的重要作用，并尝试通过外周血单核细胞免疫耐受的手段营造中枢神经元保护作用，以外周途径解决中枢问题。这将为炎症诱导的神经系统退行性疾病的治疗开辟新途径。