Autoimmune Mechanisms in the Progression of CVD in Type 1 Diabetes

描述（由申请人提供）：众所周知，1型糖尿病（T1D）患者在心肌梗死（Ml）后发病率和死亡率过高。然而，潜在的机制尚不清楚，也不能用经典的危险因素来解释。我们最近发现，在非肥胖糖尿病（NOD）小鼠（人类T1D模型）中实验诱导Ml，引发梗死后自身免疫（PIA）综合征的发展，产生高滴度IgG自身抗体和T细胞对心肌凝蛋白的反应，以及心肌中破坏性的淋巴细胞浸润。在同样梗死的对照C57BL/6小鼠中不发生PIA。有趣的是，我们之前的研究表明，表达T1 d相关的人MHC II类分子HLA-DQ8的转基因NOD小鼠也会发生自身免疫性心脏病，其特征类似于高滴度IgG心肌肌球蛋白自身抗体、T细胞对心肌肌球蛋白的反应和心肌的淋巴细胞浸润。这些发现提高了一部分人11D患者在急性Ml后也发生PIA的可能性。本研究的具体目的是：1)确定PIA是否会改变心室重塑并恶化心功能，以及高血糖的存在是否与PIA相互作用而不成比例地恶化心脏结局；2)确定PIA的主要免疫效应机制，评估PIA的易感性是否受糖尿病相关MHC II类基因控制；3)定义PIA启动的机制。该项目代表了研究T1D和自身免疫性心脏病的免疫学家Myra Lipes博士和在实验性小鼠Ml和心脏重塑方面拥有丰富专业知识的心脏病专家Richard Lee博士之间的持续合作努力。这些研究结果为了解T1D患者CVD并发症的病因打开了一扇新的窗口，为今后的临床研究提供了重要的基础。

DESCRIPTION (provided by applicant): It is well established that patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality following myocardial infarction (Ml). However, the underlying mechanisms are poorly understood and are not explained by classical risk factors. We have recently discovered that the experimental induction of Ml in nonobese diabetic (NOD) mice, a model of human T1D, triggers the development of a post-infarct autoimmunity (PIA) syndrome with the production of high-titer IgG autoantibodies and T cell reactivity against cardiac rnyosin as well as destructive lymphocytic infiltrates in the myocardium. PIA does not develop in similarly infarcted control C57BL/6 mice. Interestingly, our previous studies have shown that transgenic NOD mice expressing the T1 D-associated human MHC class II molecule, HLA-DQ8, also developed autoimmune heart disease that was similarly characterized by high-titer IgG cardiac myosin autoantibodies, T cell responses against cardiac myosin and lymphocytic infiltrates in the myocardium. These findings raise the likelihood that a subset of human 11D patients also develop PIA after acute Ml. The specific aims of this study are: 1) To determine whether PIA alters ventricular remodeling and worsens cardiac function and whether the presence of hyperglycemia interacts with PIA to disproportionately worsen cardiac outcome; 2) To identify the primary immunological effector mechanisms in PIA and assess whether susceptibility to PIA is controlled by diabetes-associated MHC class II genes; and 3) To define the mechanisms underlying the initiation of PIA. This project represents a continued collaborative effort between Dr. Myra Lipes, an immunologist who studies T1D and autoimmune heart disease and Dr. Richard Lee, a cardiologist with extensive expertise in experimental mouse Ml and cardiac remodeling . The results of these studies could open up a new window into the etiology of CVD complications in T1D and provide an important foundation for future clinical studies.