Role of IgE in Atherosclerosis

描述（由申请人提供）：免疫球蛋白E（IgE）与过敏反应有关，但我们发现其血清水平在急性心肌梗死或不稳定型心绞痛患者中升高;它们几乎是稳定型心绞痛或无冠心病患者的两倍。IgE及其高亲和力受体Fc <$R1在人类动脉粥样硬化病变中高度表达，定位于富含巨噬细胞（M <$）的区域，并共定位于病变平滑肌细胞（SMC）和内皮细胞（EC）。初步实验表明，在缺乏Fc <$R1 <$-亚基的情况下，与Apoe-/-对照小鼠相比，易患动脉粥样硬化的载脂蛋白E缺陷（Apoe-/-）小鼠在胸腹主动脉中的脂质沉积减少了75%，主动脉弓中的动脉粥样硬化病变大小减少了50%以上。体外细胞培养研究表明，IgE诱导M ²、SMC和EC丝裂原活化蛋白激酶（MAPK）通路的激活，沿着增强炎症分子的产生和凋亡。令人惊讶的是，IgE刺激Fc <$R1 <$链和Toll样受体4（TLR 4）之间的复合物形成。Fc <$R1 <$-亚基和TLR 4对于IgE诱导的M <$细胞因子和趋化因子表达和细胞凋亡都是必需的。此外，IgE对M？的这些活性与Na+-H+交换器NHE 1的激活有关，随后是细胞外pH值的降低。这些新的初步发现与先前的观察结果一致，即在人类动脉粥样硬化病变中，凋亡细胞聚集在富含脂质的坏死核心周围，其中pH值（pH 7.15 <$0.01）显著低于相同病变的其他区域（pH 7.55 <$0.32，P=0.0001）。因此，我们假设IgE通过调节M ²、血管SMC和EC炎症和凋亡而促进动脉粥样硬化，并且这些过程依赖于Fc ² R1和TLR 4的相互作用以及NHE 1的激活。我们提出了两个具体的目标来检验这一假设：1）。研究IgE刺激M ²和血管SMC和EC炎症和凋亡的分子机制。2）。检测IgE或IgE受体Fc <$R1的抑制或缺乏是否减少动脉粥样硬化，并检测IgE介导的M <$活化在动脉粥样硬化形成中的重要性。我们预计，在这两个目标提出的实验将建立一个重要的和新的作用，IgE在M ²和血管细胞病理学，和直接参与动脉粥样硬化。

DESCRIPTION (provided by applicant): Immunoglobulin E (IgE) associates with allergic responses, but we found that its serum levels are enhanced in patients with acute myocardial infarction or unstable angina pectoris; they are nearly double those in patients with stable angina pectoris or without coronary heart disease. Both IgE and its high-affinity receptor Fc¿R1 were expressed highly in human atherosclerotic lesions, localized to areas rich in macrophages (M¿), and colocalized to lesion smooth-muscle cells (SMCs) and endothelial cells (ECs). Preliminary experiments showed that in the absence of Fc¿R1 ¿-subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice. In vitro cell culture studies demonstrated that IgE induced activation of M¿, SMC, and EC mitogen-activated protein kinase (MAPK) pathway, along with enhanced inflammatory molecule production and apoptosis. Surprisingly, IgE stimulated a complex formation between Fc¿R1 ¿-chain and Toll-like receptor 4 (TLR4). Both Fc¿R1 ¿-subunit and TLR4 are necessary for IgE-induced M¿ cytokine and chemokine expression and apoptosis. Furthermore, these activities of IgE on M¿ associate with activation of Na+-H+ exchanger NHE1, followed by extracellular pH reduction. These novel preliminary findings are consistent with prior observations that in human atherosclerotic lesions, apoptotic cells cluster around lipid-rich necrotic cores, where the pH values are significantly lower (pH 7.15¿0.01) than in other areas of the same lesions (pH 7.55¿0.32, P=0.0001). Therefore, we hypothesize that IgE contributes to atherosclerosis by regulating M¿, vascular SMC, and EC inflammation and apoptosis, and that these processes depend on Fc¿R1 and TLR4 interaction as well as on NHE1 activation. We propose two specific aims to test this hypothesis: 1). To examine the molecular mechanisms by which IgE stimulates M¿ and vascular SMC and EC inflammation and apoptosis. 2). To examine whether inhibition or deficiency of IgE or IgE receptor Fc¿R1 reduces atherosclerosis, and to test the importance of IgE-mediated M¿ activation in atherogenesis. We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M¿ and vascular cell pathobiology, and a direct participation of IgE in atherogenesis.