帕金森病的外周-中枢免疫串扰及其与临床严重程度的关系

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-04-23 DOI:10.1016/j.bbi.2025.04.028

Julia C. Greenland , Jonathan Holbrook , Lakmini Kahanawita , Marta Camacho , Tim D. Fryer , Young T. Hong , Caroline H. Williams-Gray

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引用次数: 0

摘要

免疫系统在帕金森病（PD）的病因和进展中的作用越来越大。免疫激活在外周血中可见，有促炎倾向，在脑脊液和脑实质中可见，中枢神经系统中有小胶质细胞激活和免疫细胞数量增加。然而，这种外周和中枢免疫特征之间的关系，以及与疾病严重程度的临床测量的关系尚不清楚。方法61例PD患者，诊断3年内无免疫合并症，51例匹配对照，使用流式细胞术面板进行详细的血液免疫表型分析，标记适应性和先天免疫人群。在PD队列中，35人还进行了脑脊液（CSF）免疫细胞分析，31人进行了正电子发射断层扫描（PET）脑成像，使用放射配体[11C]-PK11195来评估小胶质细胞的激活。PD参与者用运动障碍学会统一帕金森病评定量表（MDS-UPDRS）和阿登布鲁克认知检查（ACE-III）进行评估。比较PD组和对照组的免疫特征。在PD组中，采用多元线性回归探索性分析研究外周和脑脊液免疫细胞群、[11C]-PK11195结合和临床措施之间的关系。结果与对照组相比，PD参与者的血液中有促炎特征，全身炎症指数（SII）升高（p = 0.049），经典单核细胞比例更高（p = 0.046）， T调节细胞（FoxP3 （p = 0.030）和Helios (p = 0.015)）和B调节细胞（CD1d (p = 0.031)）的功能标志物表达降低。血液和脑脊液中CD8+细胞（rho = 0.42, p = 0.011）、CD16+ NK细胞（rho = 0.49, p = 0.004）和经典单核细胞（rho = - 0.38, p = 0.028）的免疫细胞亚群数量相关。脑脊液免疫群体也与[11C]-PK11195在疾病相关区域的结合相关。一些血液和脑脊液免疫细胞亚群和区域[11C]-PK11195结合与运动和认知评分相关，促炎标志物与更严重的疾病表型相关的趋势一致。脑脊液经典单核细胞中toll样受体2表达增加和黑质中[11C]-PK11195结合独立预测运动评分（MDS-UPDRS-III）。结论本探索性研究提示PD患者外周和中枢免疫变化密切相关，且与临床疾病严重程度相关。这些发现值得进一步验证和探索，以确定与疾病状态相关的免疫生物标志物，以及候选治疗靶点。

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Peripheral-central immune crosstalk in Parkinson’s disease and its association with clinical severity

Background

Increasingly, the immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Immune activation is seen both peripherally in the blood, with a tendency towards a pro-inflammatory profile, and centrally in the cerebrospinal fluid and brain parenchyma, with microglial activation and increased numbers of immune cells in the central nervous system. However, the relationship between this peripheral and central immune profile, as well as the association with clinical measures of disease severity is not clear.

Methods

61 people with PD, within three years of diagnosis and no immune comorbidities, and 51 matched controls underwent detailed blood immunophenotyping using a flow cytometry panel with markers to characterise adaptive and innate immune populations. In the PD cohort, 35 also had cerebrospinal fluid (CSF) immune cell analysis and 31 underwent positron emission tomography (PET) brain imaging with the radioligand [¹¹C]-PK11195 to assess microglial activation. PD participants were assessed with the Movement Disorder Society-Unified Parkinson’s disease rating Scale (MDS-UPDRS) and the Addenbrooke’s Cognitive Examination (ACE-III). The immune profiles of PD and control participants were compared. In the PD group, relationships between peripheral and CSF immune cell populations, [¹¹C]-PK11195 binding, and clinical measures were investigated in exploratory analyses using multiple linear regression.

Results

Compared to controls, PD participants had a pro-inflammatory profile in the blood with an elevated Systemic Inflammatory Index (SII) (p = 0.049), a higher percentage of classical monocytes (p = 0.046), and decreased expression of functional markers of T regulatory cells (FoxP3 (p = 0.030) and Helios (p = 0.015)) and B regulatory cells (CD1d (p = 0.031)).

Immune cell subset numbers in blood and CSF were correlated for CD8+ cells (rho = 0.42, p = 0.011), CD16+ NK cells (rho = 0.49, p = 0.004) and classical monocytes (rho = −0.38, p = 0.028). CSF immune populations were also correlated with [¹¹C]-PK11195 binding in disease-relevant regions of interest.

Several blood and CSF immune cell subsets and regional [¹¹C]-PK11195 binding showed relationships with motor and cognitive scores, with a consistent trend of pro-inflammatory markers being related to a more severe disease phenotype. Increased Toll-like receptor 2 expression on classical monocytes in the CSF and [¹¹C]-PK11195 binding in the substantia nigra independently predicted motor score (MDS-UPDRS-III).

Conclusion

This exploratory study suggests that peripheral and central immune changes are closely linked in PD, and relevant to clinical disease severity. These findings warrant further validation and exploration to identify immune biomarkers linked to disease state, as well as candidate therapeutic targets.

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.