Autoimmune Mechanisms /Progression of CVD in Type 1 Diab

描述（由申请人提供）：众所周知，1型糖尿病（T1 D）患者在心肌梗死（MI）后发病率和死亡率过高。然而，其潜在机制知之甚少，经典的风险因素无法解释。我们最近发现，在非肥胖糖尿病（NOD）小鼠（一种人T1 D模型）中实验性诱导M1触发了梗塞后自身免疫（PIA）综合征的发展，其产生高滴度IgG自身抗体和针对心肌肌球蛋白的T细胞反应性以及心肌中的破坏性淋巴细胞浸润。在类似的梗塞对照C57 BL/6小鼠中不发生PIA。有趣的是，我们先前的研究已经表明，表达TlD相关的人MHC II类分子HLA-DQ 8的转基因NOD小鼠也发展出自身免疫性心脏病，其类似地特征在于高滴度IgG心肌肌球蛋白自身抗体、针对心肌肌球蛋白的T细胞应答和心肌中的淋巴细胞浸润。这些发现提高了人类11 D患者的子集在急性MI后也发展PIA的可能性。本研究的具体目的是：1）确定PIA是否改变心室重构和心脏功能，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，并评估PIA的易感性是否受糖尿病相关的MHC II类基因控制;（3）明确PIA的发生机制。该项目代表了研究T1 D和自身免疫性心脏病的免疫学家Myra Lipes博士和在实验小鼠MI和心脏重塑方面具有广泛专业知识的心脏病学家Richard Lee博士之间的持续合作努力。这些研究结果可能为T1 D CVD并发症的病因学开辟新的窗口，并为未来的临床研究提供重要基础。

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.