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. 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. 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. 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.

中文翻译：

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多位点队列中路易体和帕金森病的单细胞外周免疫分析


多种证据支持外周器官参与路易体病 (LBD) 的发生或进展，路易体病 (LBD) 是一系列神经退行性诊断，包括不伴或伴痴呆 (PDD) 的帕金森病 (PD) 和伴路易体痴呆 (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表征 LBD 参与者独特的外周免疫反应，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。在一项病例对照研究中，研究参与者的外周单核细胞 (PBMC) 样本是从美国多个地点随机抽取的。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）和免疫疾病对照（IDC） ，n = 14)。 PBMC 用三种刺激剂（LPS、IL-6 和 IFNa）激活或保持在基础状态，用 13 个表面标记物和 7 个细胞内信号标记物进行染色，并通过流式细胞术进行分析，在门控后生成 1,184 个免疫特征。该模型将 LBD 与 HC 进行分类，AUROC 为 0.87 ± 0.06，AUPRC 为 0.80 ± 0.06。无需重新训练，同一模型就能够区分 LBD 与 ADD、NDC 和 IDC。模型预测由特定激活下特定细胞群的 pPLCγ2、p38 和 pSTAT5 信号驱动。 LBD 的免疫反应特征与其他与 LBD 或痴呆风险相关的常见疾病（如睡眠障碍、高血压或糖尿病）无关。 对多中心研究参与者的 PBMC 免疫反应进行量化，得出了与 HC、多种相关神经退行性疾病和自身免疫性疾病相比，LBD 的独特模式，从而突出了潜在的生物标志物和疾病机制。