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: 10536408
• 负责人: Loren D Erickson
• 金额: $ 81.78万
• 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/10536408
• 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; 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; base; cohort; gain of function; galactosyl-(1-3)galactose; humanized mouse; 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 CAD 中抗原特异性 IgE 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 至α-gal。然而，IgE转α-gal是否直接促进动脉粥样硬化斑块的发展以及分子机制 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： 对象摄入含有α-gal的食物，例如红肉。然而，绝大多数患有 IgE 的人 α-gal 不表现为迟发性过敏反应，并且通常没有明显的外在症状。作为 因此，他们继续食用含有 α-gal 的食品（肉类、奶制品等），这些食品有能力 继续刺激 IgE 反应和血管壁炎症。初步数据提供了第一 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。值得注意的是，与 IgE 对 α-gal 和 CAD 致敏的关联一致， SWM B 细胞上 CCR6 的表达与 CAD 严重程度相关。转录组分析表明 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 加仑-。有趣的是，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 的细胞可能对 IgE α-gal 的产生很重要。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 加仑。我们获得了一种新型 α-gal-/- 小鼠，可以模仿人类状况来研究 IgE 的作用 动脉粥样硬化中对 α-gal 的敏感性。将 α-gal-/- 小鼠与野生型 (WT) 小鼠的 α-gal 进行比较，我们显示 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 老鼠。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 孤星蜱产生针对脂质的 IgE 抗体。根据这些人类和小鼠数据，总体 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。