IgE antibody responses to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) in murine and human atherosclerosis

IgE 抗体对小鼠和人类动脉粥样硬化中寡糖半乳糖-α-1,3-半乳糖 (α-gal) 的反应

• 批准号: 10842540
• 负责人: Loren D Erickson
• 金额: $ 32.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10842540
• 关键词: Age; Allergens; Antibody Formation; Antibody Response; Antigens; Arterial Fatty Streak; Artificial Intelligence platform; Atherosclerosis; Automobile Driving; B-Lymphocytes; Benchmarking; Blood; CCR6 gene; CXCR4 gene; Cells; Classification; Clinical; Clinical Data; Communities; Computer software; Coronary Arteriosclerosis; Coronary artery; Custom; Cytometry; Data; Data Set; Dendritic Cells; Development; Disease; Disease Outcome; Frequencies; Galactose; Goals; Histology; Human; IgE; Immune; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Instruction; Interleukin-4; Label; Linear Regressions; Link; Machine Learning; Measures; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Multivariate Analysis; Mus; NF-kappa B; Neural Network Simulation; Noise; Oligosaccharides; Outcome; Patients; Performance; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Phosphotransferases; Play; Production; Proteins; Regulation; Reporting; Research; Risk; Role; Running; STAT1 gene; STAT6 gene; Sampling; Serum; Severity of illness; Signal Transduction; Signaling Protein; Smoking Status; T-Lymphocyte; Testing; Training; Work; cell type; clinically relevant; cohort; deep neural network; design; file format; galactosyl-(1-3)galactose; high dimensionality; machine learning framework; monocyte; mouse model; novel; p38 Mitogen Activated Protein Kinase; parent grant; precision medicine; protein expression; sex; single-cell RNA sequencing; statistics; transcription factor; transcriptomics; ultrasound; virtual

Project Summary Increased total serum IgE levels are associated with coronary artery disease (CAD). However, the causal role of antigen-specific IgE in CAD remains largely unexplored. Recent work from our group and others provide evidence that humans with IgE sensitization to the mammalian oligosaccharide allergen a-gal have larger coronary artery plaques and unstable plaque features signifying increased CAD compared to those without IgE to a-gal. Despite these compelling human associative findings, no study to date has investigated the role of antigen-specific IgE as a driver of CAD severity and the molecular and cellular mechanisms mediating IgE sensitization to a-gal linked to atherosclerosis. We recently reported that humans with IgE sensitization to a-gal had a higher frequency of CCR6+ switched memory (SWM) B cells. Notably, consistent with the association of the IgE sensitization to a-gal and CAD, the amount of CCR6 on SWM B cells was associated with CAD severity. Transcriptomic analysis demonstrated that CCR6+ SWM B cells expressed higher IL-4R and STAT6 in subjects that were IgE a-gal+ compared to IgE a-gal-. Interestingly, IL-4 and STAT6 are important for B cell class switch recombination to IgE, suggesting that cells that make IL-4 may be important in IgE to a-gal production. Preliminary data using a novel mouse model deficient in NKT cells that are early producers of IL-4 show reduced levels of IgE to a-gal and implicates invariant NKT cells in the regulation of IgE antibody production to a-gal. Based on these human and murine data, the overarching objective of the parent grant is to investigate whether these factors and cells play a causal role in atherosclerosis development due to IgE sensitization to a-gal. A major component of these studies is to analyze single cell mass cytometry data derived from PBMCs of a second, independent and larger cohort of humans with CAD sensitized to a-gal allowing for more robust multivariate analysis and deeper interrogation of immune cell phenotypes that mark those at greatest risk. The overall goal of this research supplement is to make the mass cytometry data AI-ready with associated datasheets that contain the cell subtype annotations, protein type and activation state markers, cohort statistics, CAD severity measures and other relevant clinical variables (e.g., age, sex, smoking status, etc.). We will prepare noise filtered, normalized, batch corrected, cell type annotated CAD patient single cell mass cytometry data for AI applications and use an explainable machine learning framework to predict measures of CAD severity and identify cell types driving the predictions. AI-ready data will be shared and serve as a model of how to prepare patient single cell data to be AI-ready for precision medicine and other applications.

项目摘要 总血清IgE水平升高与冠状动脉疾病（CAD）有关。但是，因果角色 CAD中抗原特异性IgE的特异性IgE仍未得到探索。我们小组和其他人提供的最新工作 具有IgE敏化对哺乳动物寡糖过敏原A-GAL的人类具有更大的证据 与没有IgE相比 到a-gal。尽管这些令人信服的人类联想发现，但迄今为止，尚未研究 抗原特异性IgE作为CAD严重程度的驱动力以及介导IgE的分子和细胞机制 与动脉粥样硬化有关的A-GAL的敏化。我们最近报告说，人类对a-gal具有敏感性 CCR6+开关内存（SWM）B单元的频率更高。值得注意的是，与 IgE对A-GAL和CAD的敏化，SWM B细胞上的CCR6量与CAD严重程度有关。 转录组分析表明，CCR6+ SWM B细胞在受试者中表达较高的IL-4R和STAT6 与IgE a-gal-相比，是IgE A-GAL+。有趣的是，IL-4和STAT6对于B细胞类开关很重要 重组IgE，表明使IL-4的细胞对IgE对A-GAL产生很重要。 使用缺乏IL-4早期生产者的NKT细胞中缺乏的新型小鼠模型显示的初步数据显示降低 IgE至a-gal的水平，并暗示不变的NKT细胞在调节A-GAL的IgE抗体产生中。 基于这些人类和鼠的数据，父母赠款的总体目标是调查是否是否 这些因素和细胞在动脉粥样硬化的发展中起因素作用，这是由于IgE对A-GAL的敏感性。一个 这些研究的主要组成部分是分析来自pbmcs的单细胞质量细胞仪数据， 具有CAD对A-GAL敏化的独立人群和更大的人群，使多变量更强大 分析和对标志着最大风险的免疫细胞表型的更深入询问。总体目标 本研究补充是用包含的相关数据表的质量细胞仪数据AI-Ready准备 细胞亚型注释，蛋白质类型和激活状态标记，队列统计，CAD严重程度测量 以及其他相关的临床变量（例如年龄，性别，吸烟状况等）。我们将准备噪音过滤， 标准化，批准，细胞类型注释的CAD患者单细胞质量细胞仪数据，用于AI应用 并使用可解释的机器学习框架来预测CAD严重性的度量并识别单元格类型 推动预测。 AI-Ready数据将被共享，并作为如何准备患者单细胞的模型 可以使用精密医学和其他应用的数据。