Role of lymphocytes for the progression of a genetically determined cardiomyopathy

最近的实验数据表明，心肌梗死后的慢性重构和病理性后负荷引起的肥厚性重构都是由自身反应性T细胞促进的。此外，有临床研究结果指出，在扩张性心肌病中存在适应性免疫应答，包括针对心肌表位的自身抗体。然而，淋巴细胞在遗传性心肌病进展中的作用尚未完全确定，我们自己的数据显示，在遗传性Duchenne心肌病（MDX）小鼠模型中，心肌炎症和抗心肌表位的自身抗体已经处于早期阶段，此时没有明显的心肌病理。在导致适应性免疫系统（SCID）中的广泛缺陷的遗传背景上的MDX小鼠显示出比野生型背景上的MDX小鼠显著更少的纤维化和心肌肥大。因此，在本项目中，我们想研究T和B淋巴细胞和自身抗体在MDX小鼠模型中心肌病进展中的作用。我们计划在MDX-SCID小鼠中进行骨髓重建实验，以解决各种淋巴细胞亚群的作用。我们进一步假设适应性免疫系统塑造心肌巨噬细胞的表型，从而促进疾病进展。因此，我们将对心肌中的白细胞进行流式细胞术分析。为了更广泛和更公正的方法，我们将表型心肌白细胞的一种新的单细胞蛋白质转录组学的方法。该研究项目将通过对内皮细胞、成纤维细胞和心肌细胞进行基于RNA测序的转录组分析，以更深入地了解心肌内白细胞和非白细胞的相互作用。该研究项目旨在更深入地了解适应性免疫系统在遗传性心肌病进展中的作用。我们希望，这里确定的机制适用于其他遗传性心肌病，因此，结果将有助于确定淋巴细胞亚群作为潜在的治疗靶点，以减缓遗传性心肌病的进展。

Recent experimental data indicate that both chronic remodeling after myocardial infarction and hypertrophic remodeling in response to pathological afterload are promoted by autoreactive T-cells. Moreover, there are clinical study results pointing to an adaptive immune response, including autoantibodies against myocardial epitopes, in dilative cardiomyopathies. However, the role of lymphocytes for the progression of genetic cardiomyopathies is not well established.Our own data showed myocardial inflammation and autoantibodies against myocardial epitopes in a mouse model of the inherited Duchenne cardiomyopathy (MDX) already at an early stage when there is no obvious myocardial pathology. MDX mice on a genetic background that leads to a broad defect in the adaptive immune system (SCID) show significantly less fibrosis and myocardial hypertrophy then MDX mice on a wildtype background. Therefore, in this project we want to study the role of T- and B-lymphocytes and autoantibodies for the progression of the cardiomyopathy in the MDX mouse model. We project to perform bone marrow reconstitution experiments in MDX-SCID mice to address the role of various lymphocyte subsets. We further hypothesize that the adaptive immune systems shapes the phenotype of myocardial macrophages and thereby promotes disease progression. Therefore, we will perform flow cytometric analyses of the leukocytes in the myocardium. For a broader and more unbiased approach we will phenotype myocardial leukocytes by a novel single cell proteo-transcriptomic approach. This will be accompanied by RNA-sequencing based transcriptome analyses of endothelial cells, fibroblasts, and cardiomyocytes to get deeper insights into the interaction of leukocytes and non-leukocytes within the myocardium.This research project aims to get a deeper understanding of the role of the adaptive immune system for the progression of an inherited cardiomyopathy. We expect that the mechanism identified here apply to other genetic cardiomyopathies and thus the results will help to identify lymphocyte subsets as potential therapeutic targets to decelerate the progression of inherited cardiomyopathies.