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

IF 14.9 1区医学 Q1 NEUROSCIENCES Molecular Neurodegeneration Pub Date : 2024-08-01 DOI:10.1186/s13024-024-00748-2

Thanaphong Phongpreecha, Kavita Mathi, Brenna Cholerton, Eddie J Fox, Natalia Sigal, Camilo Espinosa, Momsen Reincke, Philip Chung, Ling-Jen Hwang, Chandresh R Gajera, Eloise Berson, Amalia Perna, Feng Xie, Chi-Hung Shu, Debapriya Hazra, Divya Channappa, Jeffrey E Dunn, Lucas B Kipp, Kathleen L Poston, Kathleen S Montine, Holden T Maecker, Nima Aghaeepour, Thomas J Montine

{"title":"Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort.","authors":"Thanaphong Phongpreecha, Kavita Mathi, Brenna Cholerton, Eddie J Fox, Natalia Sigal, Camilo Espinosa, Momsen Reincke, Philip Chung, Ling-Jen Hwang, Chandresh R Gajera, Eloise Berson, Amalia Perna, Feng Xie, Chi-Hung Shu, Debapriya Hazra, Divya Channappa, Jeffrey E Dunn, Lucas B Kipp, Kathleen L Poston, Kathleen S Montine, Holden T Maecker, Nima Aghaeepour, Thomas J Montine","doi":"10.1186/s13024-024-00748-2","DOIUrl":null,"url":null,"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.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"59"},"PeriodicalIF":14.9000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295553/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Neurodegeneration","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13024-024-00748-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

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.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

在多地点队列中对左旋体和帕金森病进行单细胞外周免疫分析。

背景：路易体病（LBD）是一种神经退行性疾病，包括无痴呆或伴痴呆的帕金森病（PD）和路易体痴呆（DLB）。然而，外周免疫反应对路易体痴呆症的潜在影响仍不清楚。本研究旨在以单细胞分辨率描述枸杞多糖症患者特有的外周免疫反应，以突出潜在的生物标记物，并增加对人类枸杞多糖症发病机制的机理认识：在一项病例对照研究中，研究人员的外周单核细胞（PBMC）样本从美国多个地点随机采样。诊断组包括健康对照组（HC，n = 159）、枸杞多糖症对照组（n = 110）、阿尔茨海默病痴呆症对照组（ADD，n = 97）、其他神经退行性疾病对照组（NDC，n = 19）和免疫性疾病对照组（IDC，n = 14）。用三种刺激物（LPS、IL-6 和 IFNa）激活或保持基础状态的 PBMC，用 13 种表面标记物和 7 种细胞内信号标记物染色，并用流式细胞术进行分析，选通后产生 1184 个免疫特征：该模型对LBD和HC进行分类的AUROC为0.87 ± 0.06，AUPRC为0.80 ± 0.06。在没有重新训练的情况下，同一模型能够将 LBD 与 ADD、NDC 和 IDC 区分开来。在特定激活条件下，来自特定细胞群的 pPLCγ2、p38 和 pSTAT5 信号驱动了模型预测。枸杞多糖症特有的免疫反应与其他与枸杞多糖症或痴呆症风险相关的常见疾病（如睡眠障碍、高血压或糖尿病）无关：对多地点研究参与者的白细胞介体免疫反应进行定量分析，发现了枸杞多糖症与高血压、多种相关神经退行性疾病和自身免疫性疾病相比的独特模式，从而突出了潜在的生物标志物和疾病机理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Molecular Neurodegeneration 医学-神经科学

CiteScore

23.00

自引率

4.60%

发文量

审稿时长

6-12 weeks

期刊介绍： Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.