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: 10818690
• 负责人: Loren D Erickson
• 金额: $ 11.22万
• 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/10818690
• 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

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 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致敏反应的人， 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 到α-gal。然而，α-gal的IgE是否直接促进动脉粥样硬化斑块的发展， 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。 当发生以下情况时，被孤独星星蜱叮咬可诱导IgE对α-gal致敏，随后发生严重过敏反应： 受试者摄取含α-半乳糖的食物如红肉。然而，绝大多数IgE患者 对α-半乳糖不表现为迟发性过敏反应，并且通常没有外部识别症状。作为 因此，他们继续食用含α-半乳糖的食品（肉类、乳制品等）。它们有能力 继续刺激血管壁中的IgE反应和炎症。初步数据显示， 有证据表明，IgE对α-gal敏感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，与IgE对α-gal的致敏性和CAD的相关性一致， SWM B细胞上CCR 6的表达与CAD的严重程度相关。转录组学分析表明， 在IgE α-gal+受试者中，CCR 6 + SWM B细胞表达的IL-4 R和STAT 6高于IgE α-gal+受试者。 gal-.有趣的是，IL-4和STAT 6对于B细胞类别转换重组为IgE是重要的，这表明 产生IL-4的细胞在IgE α-gal的产生中可能是重要的。研究IgE对α-gal的致敏作用， 传统的动脉粥样硬化小鼠模型不适合作为小鼠，像所有的低等哺乳动物，但不像 人类表达半乳糖基转移酶，产生α-gal，对α-gal不产生IgE反应。 加我们已经获得了一种新型的α-gal-/-小鼠，它模拟了人类的状况，以研究IgE的作用。 动脉粥样硬化中对α-gal的增敏作用。比较α-gal-/-小鼠和野生型小鼠（WT）的α-gal，我们发现， 在α-gal-/-中暴露于单独的星星蜱衍生的脂质后，α-gal的IgE显着诱导，但在WT中则不然 老鼠.此外，来自NKT细胞缺陷小鼠的初步数据表明iNKT细胞参与了细胞周期的调节。 来自孤星星蜱的对脂质的IgE抗体产生。基于这些人类和鼠的数据， 本计划的目的是研究这些因子和细胞是否在动脉粥样硬化中起因果作用 由于IgE对α-gal的致敏作用，我们将在小鼠中使用功能丧失和获得的研究， 动脉粥样硬化模型，以确定α-gal IgE产生的新机制和蜱诱导的α-gal IgE的影响。 半乳糖致敏饮食诱导的动脉粥样硬化，并测试了一个更大的人群与CAD定性和 通过血管内超声虚拟组织学（IVUS-VH）定量，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。