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

基本信息

批准号：
10649670
负责人：
Loren D Erickson
金额：
$ 80.24万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10649670
关键词：
Address Allergens Ambylomma americanum Anaphylaxis Antibody Formation Antibody Response Antigens Arterial Fatty Streak Atherosclerosis Attenuated Automobile Driving B-Lymphocytes Bite Blood Vessels CCR6 gene Cells Consumption Coronary Angiography Coronary Arteriosclerosis Coronary artery Dairying Data Development Diet Enzymes Etiology Exposure to Food Fostering Frequencies Galactose Galactosyltransferases High Prevalence Histology Human Hypersensitivity IgE Immediate hypersensitivity Immune Immunoglobulin Class Switching Immunoglobulin Switch Recombination Individual Inflammation Ingestion Interleukin 4 Receptor Interleukin-4 Link Lipids Mammals Measures Meat Mediating Memory B-Lymphocyte Modeling Molecular Multivariate Analysis Mus Necrosis Oligosaccharides Peripheral Blood Mononuclear Cell Phenotype Play Population Pre-Clinical Model Production Reaction Regulation Research Risk Role STAT6 gene Serum Severity of illness Structure of germinal center of lymph node Symptoms Testing Ticks Wild Type Mouse Work allergic response alpha-gal syndrome cohort comparison control gain of function galactosyl-(1-3)galactose humanized mouse hypercholesterolemia loss of function mouse model multiple omics novel response single cell analysis transcriptomics ultrasound vascular inflammation virtual

项目摘要

PROJECT ABSTRACT 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 α-gal have larger coronary artery plaques and unstable plaque features signifying increased CAD compared to those without IgE to α-gal. Yet, whether IgE to α-gal directly promotes atherosclerotic plaque development and the molecular and cellular mechanisms mediating IgE sensitization to α-gal linked to atherosclerosis formation are unknown. Bites from the lone star tick induce IgE sensitization to α-gal and a subsequent severe allergic response when the subject ingests α-gal-containing foods such as red meat. However, the vast majority of individuals with IgE to α-gal do not manifest with delayed anaphylaxis and frequently have no outward identifying symptoms. As such, they continue to consume α-gal-containing food products (meat, dairy, etc.) which have the capacity to continue to stimulate IgE responses and inflammation in the vessel wall. Preliminary data provide the first evidence that humans with IgE sensitization to α-gal had a higher frequency of CCR6+ switched memory (SWM) B cells. Notably, consistent with the association of the IgE sensitization to α-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 α-gal+ compared to IgE α- 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 α-gal production. Studying IgE sensitization to α-gal in conventional murine models of atherosclerosis is not feasible as mice, like all lower mammals but unlike humans, express the enzyme galactosyltransferase, produce α-gal and do not develop an IgE response to α- gal. We have obtained a novel α-gal-/- mouse that mimics the human condition to study the role of IgE sensitization to α-gal in atherosclerosis. Comparing α-gal-/- mice to mice wildtype (WT) for α-gal, we show a significant induction of IgE to α-gal after exposure to lone star tick-derived lipids in the α-gal-/- but not the WT mouse. Moreover, preliminary data from mice deficient in NKT cells implicates iNKT cells in the regulation of IgE antibody production to lipids from lone star ticks. Based on these human and murine data, the overarching objective of this proposal is to investigate whether these factors and cells play a causal role in atherosclerosis development due to IgE sensitization to α-gal. We will use loss and gain of function studies in murine atherosclerosis models to define novel mechanisms of α-gal IgE production and the impact of tick-induced α- gal sensitization on diet-induced atherosclerosis, and test a larger cohort of humans with CAD qualitatively and quantitatively by intravascular ultrasound virtual histology (IVUS-VH), allowing for more robust multivariate analysis and deeper interrogation of immune cell phenotypes that mark those at greatest risk.

项目摘要然而，血清总 IgE 水平升高与冠状动脉疾病 (CAD) 相关。我们小组和其他人最近的工作表明，CAD 中抗原特异性 IgE 的作用在很大程度上尚未得到探索。有证据表明，对哺乳动物寡糖过敏原 α-gal 具有 IgE 敏感性的人类具有更大的与无 IgE 的患者相比，冠状动脉斑块和不稳定斑块特征表明 CAD 增加然而，IgE 至 α-gal 是否直接促进动脉粥样硬化斑块的发展及其分子机制。介导 IgE 对与动脉粥样硬化形成相关的 α-gal 敏感的细胞机制尚不清楚。孤星蜱的叮咬会诱导 IgE 对 α-gal 过敏，并在以下情况下引起严重的过敏反应：受试者摄入含有 α-gal 的食物，例如红肉。然而，绝大多数个体患有 IgE。 α-gal 不表现出迟发性过敏反应，并且通常没有明显的明显症状。因此，他们继续食用含有 α-gal 的食品（肉类、乳制品等），这些食品有能力继续刺激 IgE 反应和血管壁炎症提供了第一个初步数据。有证据表明，对 α-gal 具有 IgE 敏感性的人类具有更高的 CCR6+ 记忆切换频率 (SWM) B 细胞，与 IgE 对 α-gal 和 CAD 致敏的关联一致。 SWM B 细胞上的 CCR6 与 CAD 严重程度相关。与 IgE α- 相比，IgE α-gal+ 受试者中的 CCR6+ SWM B 细胞表达更高的 IL-4R 和 STAT6 gal-表明，IL-4 和 STAT6 对于 B 细胞类别转换重组为 IgE 很重要，这表明产生 IL-4 的细胞可能在 IgE α-gal 产生中发挥重要作用，研究 IgE 对 α-gal 的敏感性。与所有低等哺乳动物一样，传统的动脉粥样硬化小鼠模型并不可行，但与小鼠不同人类表达半乳糖基转移酶，产生 α-gal 并且不会对 α- 产生 IgE 反应我们获得了一种模仿人类状况的新型 α-gal-/- 小鼠，用于研究 IgE 的作用动脉粥样硬化中对 α-gal 的敏感性比较 α-gal-/- 小鼠与野生型 (WT) 小鼠的 α-gal，我们显示了在 α-gal-/- 中暴露于孤星蜱衍生的脂质后，IgE 显着诱导为 α-gal，但在 WT 中则不然此外，来自缺乏 NKT 细胞的小鼠的初步数据表明 iNKT 细胞参与调节孤星蜱产生的 IgE 抗体基于这些人类和鼠类数据。该提案的目的是调查这些因素和细胞是否在动脉粥样硬化中发挥因果作用由于 IgE 对 α-gal 敏感而导致的发育我们将使用小鼠的功能丧失和获得研究。动脉粥样硬化模型定义 α-gal IgE 产生的新机制以及蜱诱导的 α-的影响 gal 对饮食引起的动脉粥样硬化的敏感性，并对更大的 CAD 人群进行定性和测试通过血管内超声虚拟组织学 (IVUS-VH) 进行定量分析，从而实现更稳健的多变量分析对标记风险最大的免疫细胞表型进行分析和更深入的询问。