多中心队列中单细胞外周免疫谱分析路易体和帕金森病。

Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort.

机构信息

Department of Pathology, Stanford University, Stanford, CA, USA.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.

出版信息

Mol Neurodegener. 2024 Aug 1;19(1):59. doi: 10.1186/s13024-024-00748-2.

DOI:10.1186/s13024-024-00748-2

PMID:39090623

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11295553/

Abstract

BACKGROUND

Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.

METHODS

In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.

RESULTS

The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.

CONCLUSIONS AND RELEVANCE

Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

摘要

背景

多项证据表明，路易体病（LBD）的发病或进展涉及外周器官，LBD 是一系列神经退行性疾病的总称，包括无痴呆的帕金森病（PD）和痴呆伴路易体（DLB）。然而，外周免疫反应对 LBD 的潜在贡献仍不清楚。本研究旨在以单细胞分辨率描绘 LBD 患者特有的外周免疫反应，以突出潜在的生物标志物，并增加对人类 LBD 发病机制的机制理解。

方法

在病例对照研究中，来自美国多个地点的研究参与者的外周单核细胞（PBMC）样本被随机采样。诊断组包括健康对照（HC，n=159）、LBD（n=110）、阿尔茨海默病痴呆（ADD，n=97）、其他神经退行性疾病对照（NDC，n=19）和免疫性疾病对照（IDC，n=14）。用三种刺激物（LPS、IL-6 和 IFNa）或保持基础状态激活 PBMC，用 13 种表面标志物和 7 种细胞内信号标志物染色，用流式细胞术分析，门控后生成 1184 种免疫特征。

结果

该模型将 LBD 从 HC 中分类的 AUC 为 0.87±0.06，AUPRC 为 0.80±0.06。无需重新训练，同一模型能够区分 LBD 与 ADD、NDC 和 IDC。模型预测是由特定细胞群在特定激活下的 pPLCγ2、p38 和 pSTAT5 信号驱动的。与 LBD 相关的免疫反应特征与其他与 LBD 或痴呆风险相关的常见疾病无关，如睡眠障碍、高血压或糖尿病。