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: 10851057
• 负责人: Loren D Erickson
• 金额: $ 28.66万
• 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/10851057
• 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敏感者有更大的 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 致α-Gal。然而，α-Gal是否直接促进动脉粥样硬化斑块的发展和分子水平 而介导α-GAL对Ig E增敏与动脉粥样硬化形成相关的细胞机制尚不清楚。 当α-GAL出现严重的过敏反应时，来自孤星的扁虱的叮咬会导致Ig E致敏 受试者摄入含有α-Gal的食物，如红肉。然而，绝大多数IgE携带者 对于α-GAL，没有表现出迟发性过敏反应，而且经常没有外在的识别症状。AS 这样，他们继续食用含有α-GAL的食品(肉类、乳制品等)。它们有能力 继续刺激血管壁上的IgE反应和炎症。初步数据提供了第一个 有证据表明，对α-Gal敏感的人有更高的CCR6+开关记忆频率 (Swm)B细胞。值得注意的是，与α-GAL和冠心病的免疫球蛋白致敏的关联一致， SWM B细胞CCR6的表达与冠脉病变严重程度相关。转录分析表明， 与α-α-相比，CcR6+SWMB细胞表达IL-4R和STAT6的水平更高。 加里-。有趣的是，IL-4和STAT6对于B细胞类到IgE的转换重组是重要的，这表明 产生IL-4的细胞可能在免疫球蛋白α-Gal的产生中起重要作用。免疫球蛋白E对α-GAL增敏作用的研究 与所有低等哺乳动物一样，常规的小鼠动脉粥样硬化模型是不可行的，但不同于 人类表达半乳糖基转移酶，产生α-Gal，对α-Gal不产生免疫反应 盖尔。我们已经获得了一种新型的模拟人类条件的α-Gal-/-小鼠来研究IgE的作用 动脉粥样硬化对α-Gal的增敏作用。比较α-GAL-/-小鼠和野生型(WT)小鼠的α-GAL，我们发现 α-GAL-/-但WT-GAL-/-α-GAL-/-在暴露于单星硬虱来源的脂类后显著诱生IgE-GAL 老鼠。此外，来自NKT细胞缺陷小鼠的初步数据表明，iNKT细胞参与调节 独星硬蜱产生抗脂的IgE抗体。基于这些人类和老鼠的数据，最重要的是 这项建议的目的是调查这些因素和细胞是否在动脉粥样硬化中起因果作用。 α-Gal致Ig E致敏的进展。我们将使用小鼠的功能损失和获得研究 动脉粥样硬化模型，以确定α-Gal Ig E产生的新机制以及扁虱诱导的α-1的影响 Gal对饮食诱导的动脉粥样硬化的增敏作用，并对更多的冠心病患者进行定性和 通过血管内超声虚拟组织学(IVUS-VH)定量，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。