Genetic mechanisms of autoimmune myocarditis

描述(申请人提供)：心肌炎是40岁以下人群猝死的主要原因，其中许多病例与自身免疫过程有关[1，2]。与其他自身免疫性疾病一样，心肌炎的根本原因和发病机制尚不清楚。为了研究自身免疫性心肌炎和自身免疫性疾病的一般机制，我们建立了心肌肌球蛋白诱导的实验性自身免疫性心肌炎(EAM)的小鼠模型[3]。该模型表明心肌炎的易感性有很强的遗传影响，为理解这种自身免疫性疾病的发病机制提供了一条新的途径[8]。与其他自身免疫性疾病模型相比，EAM模型是独一无二的，值得研究，因为它显示了更大的非H-2基因影响，并显示了一种不同寻常的男性影响。在初步工作中，我们已经证明了小鼠6号染色体上的基因座以及可能的1和4号染色体上的基因座与易感性有关。其中两个基因座(Chr.相互作用并与其他自身免疫性疾病有关，如糖尿病[7]。此外，还研究了Cr.1位点包括CTLA-4，这是一个免疫学上重要的基因，我们先前已经证明它调节心肌炎的发病机制。该基因主要在男性中起作用，与在胸腺细胞稳态和凋亡中起重要作用的基因座重叠[5]。我们建议最终确定将作为未来位置克隆的基础的遗传学发现，并对CTLA-4基因的多态性进行功能研究，这可能导致心肌炎的不同易感性。初步实验还表明，这些遗传位点通过造血组织发挥作用。我们建议巩固这些发现，并调查这些遗传位点通过免疫系统中哪些特定的细胞类型起作用。我们以我们的初步数据为基础，提出假设驱动的目标，以确定控制自身免疫性心肌炎小鼠模型中易感性的宿主基因，并描述其作用机制。

DESCRIPTION (provided by applicant): Myocarditis is a major cause of sudden death in people under 40 years of age, and many of these cases are associated with an autoimmune process[1, 2]. Like other autoimmune diseases, the fundamental causes and mechanisms of pathogenesis of myocarditis are not understood. To study the mechanisms of autoimmune myocarditis and autoimmune diseases in general we have developed a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin [3]. This model demonstrates that there are strong genetic influences to susceptibility to myocarditis, offering a fresh avenue into understanding the pathogenesis of this autoimmune disease [8]. The EAM model is unique and worthy of study apart from other autoimmune disease models because it shows greater influence of non H-2 genes, and shows an unusual male influence. In preliminary work we have demonstrated that loci on murine chromosomes 6 and possibly 1 and 4 are involved in susceptibility. Two of these loci (Chr. 1, Chr.6) interact and are also implicated in other autoimmune disease such as diabetes [7]. Furthermore, the Chr. 1 locus includes CTLA-4, an immunologically important gene, which we have previously demonstrated to regulate the pathogenesis of imyocarditis. The Chr.6 locus, which functions primarily in males, overlaps with loci that are important in thymocyte homeostasis and apoptosis [5]. We propose to conclusively establish the genetic findings which will be the foundation of future positional cloning and perform functional studies of polymorphisms in CTLA-4 which may lead to differential susceptibility to myocarditis. Preliminary experiments also indicate that these genetic loci act through hematopoietic tissues. We propose to solidify these findings and investigate through which specific cell types in the immune system these genetic loci operate. We build on our preliminary data to propose hypothesis-driven aims to identify host genes that control susceptibility and characterize their mechanisms of action in a murine model of autoimmune myocarditis.