MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN DIABETES

糖尿病中的修饰低密度脂蛋白、自身免疫和血管疾病

• 批准号: 6658432
• 负责人: MARIA F LOPES-VIRELLA
• 金额: $ 7.35万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6658432
• 关键词: autoimmune disorder; bacterial antigens; blood glucose; blood lipoprotein metabolism; cardiovascular disorder epidemiology; cell adhesion molecules; chlamydial disease; cholesterol; clinical research; diabetic angiopathy; human subject; immune complex; inflammation; lipopolysaccharides; low density lipoprotein; macrophage; noninsulin dependent diabetes mellitus; oxidized lipid; vascular endothelium

DESCRIPTION: (provided by applicant) High levels of immune complexes (IC) containing oxLDL predict the development of macrovascular complications in type 1 diabetes (DM) and are associated with coronary artery disease (CAD) in type 2 DM. Data obtained during the on-going funding period shows that the levels of oxLDL-IC are significantly associated with internal carotid intima-medial thickness (p<0.001, n=853) and are significantly increased in type 1 DM with micro/macroalbuminuria and moderate/severe retinopathy, compared with levels of LDL-IC in patients with normalalbuminuria or mild retinopathy (p<0.013 and 0.0006, respectively). The levels of LDL-IC are strongly correlated with serum Apo B levels, serum Lp(a) levels and serum triglycerides (p<0.0001, n=853) and have also a significant direct correlation (p<0.0001, n=854) with C-reactive protein and with soluble ICAM-1 (p<0.02, n=455). LDL-IC correlate as well with Hb A1c (p<0.005, n=888), suggesting that glycemic control will impact the formation of LDL-IC. We have also demonstrated in patients with micro or macroalbuminuria that antibodies (Ab) against ox-LDL isolated from oxLDL-IC have a higher affinity than the free Ab present in sera of the same patients. This suggests that one critical factor determining the pathogenicity of oxLDL-IC is the synthesis of oxLDL Ab of moderate affinity, able to form stable IC with pro-inflammatory potential. Because Chlamydia pneumonia has been shown to have a strong epidemiological correlation with CAD and one of its major antigens is a cell wall lipopolysaccharide (LPS), that when released into circulation is transported by lipoproteins, we plan to investigate whether chlamydia LPS is present in IC purified from sera of diabetic patients. The main goal of this proposal is to compare the levels of soluble adhesion molecules (sCAM) and the levels and characteristics of LDL-IC isolated from the sera of a type 2 DM cohort (Prospective VA Cooperative Trial) under intensive or standard glycemic control. We hypothesize that, similarly to type 1 DM, LDL-IC in type 2 DM have pro-inflammatory characteristics and are associated with micro and macrovascular complications. We further hypothesize that intensive glycemic control will impact the formation of IC and the release of CAMs into the circulation. We also propose to determine whether or not patients from the DCCT/EDIC cohort (type 1 DM) and VA cohort 2 (type 2 DM) that develop macrovascular disease, retinopathy and micro/macro-albuminuria have a higher incidence of chronic C. pneumoniae infection and to characterize the IC present in the serum of patients from both cohort 1 and 2 that develop macrovascular disease/nephropathy/retinopathy for oxLDL, oxLDL-Lp(a), AGE-LDL, Chlamdial-LPS or DNA, as well as Ab against these antigens. We will also determine the affinity and isotype distribution of Ab isolated from IC, to evaluate their pro-inflammatory potential. Finally, we will assess possible pathogenic mechanisms triggered by these IC by investigating their ability to induce accumulation of cholesterol in macrophages, kidney mesangial cells and retinal pericytes and to activate these cells leading to the expression of cytokines, sCAM and metalloproteinases. Incorporation of our study into the Program allows us to compare LDL-IC levels with the inflammatory markers and endothelial cell dysfunction markers measured in other projects and that will result in a better understanding of the significance of auto-immune responses to modified forms of LDL to the pathogenesis of atherosclerosis in diabetes.

描述：（申请人提供） 高水平的免疫复合物（IC）含有OXLDL预测发育 1型糖尿病（DM）中的大血管并发症 2型DM中的冠状动脉疾病（CAD）。在进行的过程中获得的数据 资金期表明OXLDL-IC的水平显着相关 内部颈动脉内膜厚度（p <0.001，n = 853），为 1型DM的显着增加，微藻尿症和 与患有LDL-IC的水平相比，中度/严重的视网膜病变 正常白蛋白尿或轻度视网膜病（分别为p <0.013和0.0006）。这 LDL-IC的水平与血清​​APO B水平，血清LP（A）密切相关 水平和血清甘油三酸酯（p <0.0001，n = 853），也有显着的 直接相关（p <0.0001，n = 854）与C反应蛋白和可溶性 ICAM-1（p <0.02，n = 455）。 LDL-IC也与HB A1C相关（P <0.005， n = 888），表明血糖控制会影响LDL-IC的形成。 我们还在微藻或大藻尿症患者中证明了 针对从OXLDL-IC分离的OX-LDL的抗体（AB）具有较高的亲和力 比同一患者的血清中存在的免费AB。这表明一个 确定oxLDL-IC致病性的关键因素是合成 中等亲和力的OXLDL AB，能够用促炎性形成稳定的IC 潜在的。因为肺炎已显示出强大 与CAD及其主要抗原之一的流行病学相关性是细胞 壁脂多糖（LPS），当释放到循环中是 通过脂蛋白运输，我们计划调查衣原体LPS是否是 从糖尿病患者血清中纯化的IC中存在。 该提议的主要目标是比较可溶性附着的水平 分子（骗局）以及从从中分离出的LDL-IC的水平和特征 2型DM队列的血清（前瞻性VA合作试验） 密集或标准血糖控制。我们假设这与 1型DM，2型DM中的LDL-IC具有促炎的特征，是 与微血管并发症有关。我们进一步假设 强化血糖控制将影响IC和IC的形成 将凸轮释放到循环中。我们还建议确定是否或 不是来自DCCT/EDIC队列（1型DM）和VA队列2（2型DM）的患者 患有大血管疾病，视网膜病和微/宏 - 珠蛋白尿 具有较高的慢性肺炎肺炎感染的发生率，并表征 来自队列1和2的患者血清中的IC存在 大血管疾病/肾病/肾病/视网膜病，用于OXLDL，OXLDL-LP（A），年龄-LDL， CHLAMDIAL-LPS或DNA，以及针对这些抗原的AB。我们也会 确定从IC分离到的AB的亲和力和同种型分布 评估其促炎潜力。最后，我们将评估可能 这些IC触发的致病机制通过研究了它们的能力 诱导巨噬细胞，肾脏肾小球细胞和 视网膜周细胞并激活这些细胞，导致表达 细胞因子，骗局和金属蛋白酶。 将我们的研究纳入计划使我们可以比较LDL-IC级别 带有炎症标记和内皮细胞功能障碍标记 在其他项目中衡量，这将使人们更好地理解 自动免疫反应对修饰形式的LDL对 糖尿病动脉粥样硬化的发病机理。