Center of Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100, Varese, VA, Italy.
Movement Disorders Centre, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
J Neuroinflammation. 2018 Jul 12;15(1):205. doi: 10.1186/s12974-018-1248-8.
Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue.
We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency.
PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity.
The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.
帕金森病（PD）影响全球约 700 至 1000 万人，目前仅提供对症治疗以缓解大脑多巴胺能神经元丧失的后果。PD 中的神经元退化是神经炎症的结果，反过来又受到外周适应性免疫的影响，CD4+T 淋巴细胞起着关键作用。然而，CD4+T 细胞可能获得促炎表型，如辅助性 T（Th）1 和 Th17，以及抗炎表型，如 Th2 和调节性 T（Treg），并且不同的 CD4+T 细胞亚群在 PD 中失衡到何种程度以及它们的功能失调在很大程度上仍然是一个未解决的问题。
我们在接受抗帕金森病药物治疗和未接受药物治疗的 PD 患者以及年龄和性别匹配的健康对照者中进行了两项横断面研究。在第一项研究中，我们检查了循环 Th1、Th2、Th17，在第二项研究中检查了循环 Treg。通过流式细胞术评估外周血中 CD4+T 细胞亚群的数量和频率，并在体外试验中研究其功能。在两项研究中，我们独立评估了完整的临床评估、血液计数和 CD4+T 细胞中谱系特异性转录因子的 mRNA 水平，然后比较了它们的一致性。
PD 患者的循环 CD4+T 淋巴细胞减少，这是由于 Th2、Th17 和 Treg 减少所致。PD 患者外周血中的幼稚 CD4+T 细胞优先向 Th1 谱系分化。PD 患者 CD4+T 细胞产生的干扰素-γ和肿瘤坏死因子-α增加，并在同源 Treg 存在的情况下保持增加。这种 Th1 偏向的免疫特征发生在未经药物治疗的患者和接受多巴胺能药物治疗的患者中，表明目前的抗帕金森病药物不会影响外周适应性免疫。
PD 患者 CD4+T 细胞亚群的复杂表型和功能特征增强了外周适应性免疫参与 PD 的证据，并代表了对新型免疫调节治疗的临床前和临床评估的目标。
