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水平升高与冠心病(CAD)相关。然而，因果关系的作用 抗原特异性IgE在冠心病中的作用在很大程度上仍未被探索。我们小组和其他人最近的工作提供了 有证据表明，对哺乳动物低聚糖变应原α-Gal有IgE敏感性的人有更大的 冠状动脉斑块和不稳定斑块特征表明与没有IgE的人相比，冠心病增加 对一个女孩来说。尽管有这些令人信服的人类关联性发现，但到目前为止还没有研究调查 抗原特异性IgE是冠心病严重程度的驱动因素及其分子和细胞机制 与动脉粥样硬化有关的对α-半乳糖的敏化。我们最近报道了免疫球蛋白E对α-半乳糖敏感的人 有较高频率的CCR6+开关记忆(SWM)B细胞。值得注意的是，与 IgE对α-Gal和CAD的增敏作用、SWM B细胞表面CCR6的数量与冠心病的严重程度相关。 转录分析显示CCR6+SWM B细胞表达较高的IL-4R和STAT6 与Ig E-A-Gal-相比，它们是Ig E-a-ga+。有趣的是，IL-4和STAT6对B细胞类开关很重要 重组为IgE，提示产生IL-4的细胞可能在IgE中对α-半乳糖的产生起重要作用。 使用一种新型小鼠模型的初步数据显示，早期产生IL-4的NKT细胞缺陷的小鼠细胞数量减少 α-Gal的IgE水平和不变的NKT细胞参与调节α-Gal的IgE抗体的产生。 基于这些人类和老鼠的数据，父母赠款的首要目标是调查 这些因素和细胞在动脉粥样硬化的发展中起着因果作用，这是由于IgE对α-半乳糖的敏感性所致。一个 这些研究的主要组成部分是分析从一秒的PBMC中获得的单细胞质量细胞术数据， 对α-GAL敏感的独立和更大的CAD人群队列允许更强大的多变量 分析和更深入地询问免疫细胞表型，这些表型标志着那些风险最高的人。总目标 这项研究的补充是使大量细胞分析数据人工智能做好准备，并提供包含以下内容的相关数据表 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(如年龄、性别、吸烟状况等)。我们会准备好噪音过滤， 用于人工智能应用的归一化、批次校正、细胞类型注释的CAD患者单细胞质量细胞术数据 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 推动了预测。将共享人工智能就绪数据，并作为如何准备患者单细胞的模型 数据将为人工智能做好准备，用于精准医疗和其他应用。