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 血清总IgE水平升高与冠状动脉疾病（CAD）相关。然而，因果作用 在CAD中抗原特异性IgE的表达在很大程度上尚未探索。我们小组和其他人最近的工作提供了 有证据表明，对哺乳动物寡糖过敏原α-gal有IgE致敏性的人， 冠状动脉斑块和不稳定斑块特征表明与无IgE的患者相比CAD增加 敬阿伽尽管有这些令人信服的人类关联发现，但迄今为止还没有研究调查了 作为CAD严重程度驱动因素的抗原特异性IgE以及介导IgE的分子和细胞机制 α-半乳糖致敏与动脉粥样硬化有关。我们最近报道了对α-半乳糖过敏的人， 具有更高频率的CCR 6+转换记忆（SWM）B细胞。值得注意的是， IgE对a-gal和CAD的敏感性、SWM B细胞上CCR 6的量与CAD的严重程度相关。 转录组学分析表明，受试者中CCR 6 + SWM B细胞表达较高的IL-4 R和STAT 6 与IgE a-gal-相比，IgE a-gal+。有趣的是，IL-4和STAT 6对于B细胞类别转换是重要的 这表明产生IL-4的细胞在IgE至α-gal的产生中可能是重要的。 使用NKT细胞缺陷的新型小鼠模型的初步数据显示，NKT细胞是IL-4的早期产生者， 结果表明，NKT细胞对α-gal的IgE水平的影响，并暗示不变的NKT细胞参与调节α-gal的IgE抗体产生。 基于这些人类和小鼠的数据，父母补助金的首要目标是调查是否 这些因子和细胞由于IgE对α-gal的敏感性而在动脉粥样硬化的发展中起因果作用。一 这些研究的主要组成部分是分析来源于第二代PBMC的单细胞团细胞计数数据， 具有对α-gal敏感的CAD的人的独立且较大的队列允许更稳健的多变量 分析和更深入的询问免疫细胞表型，标志着那些在最大的风险。总目标 本研究补充的一个目的是使大量细胞计数数据与相关的电子表格一起准备好， 细胞亚型注释、蛋白质类型和激活状态标记、群组统计、CAD严重性测量 以及其它相关的临床变量（例如，年龄、性别、吸烟状况等）。我们将准备过滤噪音， 用于AI应用的标准化、批次校正、细胞类型注释的CAD患者单细胞团细胞计数数据 并使用可解释的机器学习框架来预测CAD严重程度的测量并识别细胞类型 推动预测。AI就绪数据将被共享，并作为如何准备患者单细胞的模型 数据将为精准医疗和其他应用做好人工智能准备。