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 总血清IgE水平升高与冠状动脉疾病（CAD）有关。但是，因果角色 CAD中抗原特异性IgE的特异性IgE仍然很出乎意料。我们小组和其他人提供的最新工作 具有IgE对哺乳动物寡糖过敏原α-GAL敏感性的人的证据较大 与没有IgE相比 但是，IgE到α-GAL是否直接促进动脉粥样硬化斑块的发展和分子 介导IgE敏感性与动脉粥样硬化形成相关的α-GAL的细胞机制尚不清楚。 孤独的星形壁虱的叮咬引起IgE对α-GAL的敏感性，随后发生严重的过敏反应 该受试者会摄取含α-gal的食物，例如红肉。但是，绝大多数具有IGE的人 到α-gal不会出现延迟的过敏反应，并且经常没有外部识别符号。作为 这样，他们继续消费含α-gal的食品（肉类，乳制品等），这些食品有能力 继续刺激血管壁中的IgE反应和炎症。初步数据提供了第一个 IgE对α-GAL敏感的人的证据频率更高。 （SWM）B细胞。值得注意的是，与IgE敏感性与α-GAL和CAD的关联一致，量 SWM B细胞上的CCR6与CAD严重程度有关。转录组分析表明 与IgEα-相比 gal-。有趣的是，IL-4和STAT6对于B细胞类开关重组至IgE很重要，这表明 使IL-4的细胞在IgEα-GAL产生中可能很重要。研究IgE对α-gal的敏感性 像所有较低哺乳动物一样 人类表达酶半乳糖基转移酶，产生α-gal，并且不对α-产生IgE响应 gal。我们已经获得了一种新型的α-gal - / - 小鼠，该小鼠模仿了人类条件研究IgE的作用 在动脉粥样硬化中对α-gal的敏化。将α-gal - / - 小鼠与α-gal小鼠野生型（WT）进行比较，我们显示了一个 在暴露于α-gal的孤独星tick衍生的脂质的情况下，IgE对α-gal的显着诱导 - / - 但不是WT 老鼠。此外，来自NKT细胞缺乏小鼠的初步数据在调节中实现Inkt细胞 IgE抗体从孤独的星形滴答物中生产脂质。基于这些人类和鼠数据，总体 该提议的目的是研究这些因素和细胞在动脉粥样硬化中是否起因果作用 由于IgE对α-GAL的敏感性而引起的发展。我们将使用鼠的功能研究损失和获取 动脉粥样硬化模型定义了α-gal IgE产生的新机制以及tick诱导的α-的影响 GAL对饮食引起的动脉粥样硬化的敏感性，并测试与CAD的较大人群和 通过血管内超声虚拟组织学（IVUS-VH）进行定量，允许更强大的多变量 分析和更深入的审问，这些表型标志着那些处于最大风险的人。