Pathogenesis of autoimmune valvular carditis

自身免疫性瓣膜性心脏病的发病机制

• 批准号: 9926159
• 负责人: Bryce Binstadt
• 金额: $ 37.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926159
• 关键词: Affect; Anti-Inflammatory Agents; Antiphospholipid Syndrome; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Award; Biophysics; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Carditis; Cause of Death; Cell Lineage; Cells; Cessation of life; Chronic; Data; Disease; Endothelial Cells; Endothelium; Fc Receptor; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic Transcription; Goals; Heart; Heart Valve Diseases; Heart Valves; Human; Immune; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-1; Interleukin-13; Interleukin-4; Knowledge; Lead; Left; Link; Lupus; Lymphoid Cell; Macrophage Activation; Mediating; Mediator of activation protein; Mesenchymal; Mind; Mitral Valve; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Myofibroblast; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Piezo 1 ion channel; Population; Process; Production; Research; Rheumatic Fever; Rheumatic Heart Disease; Rheumatism; Rheumatoid Arthritis; Role; Side; Study models; Sum; System; Therapeutic; Tissues; Tricuspid valve structure; atherosclerosis risk; autoimmune arthritis; cardiovascular disorder risk; cell type; cytokine; differential expression; disorder subtype; experimental study; high risk; improved; improved outcome; insight; interleukin-13 receptor; interstitial cell; macrophage; mechanotransduction; mitral cell; mortality; mouse model; novel; phase III trial; progenitor; programs; receptor; shear stress; success; transcriptome; virtual

Abstract Patients with chronic inflammatory/rheumatic diseases suffer increased cardiovascular morbidity and mortality. Improving outcomes requires understanding how chronic inflammation causes cardiovascular pathology. The focus of this proposal is on valvular carditis. The most common cause of valvular carditis is rheumatic heart disease (RHD), which affects >30 million people worldwide and causes >300,000 deaths annually. Valvular carditis also occurs in patients with lupus and the related antiphospholipid antibody syndrome. Our group has pioneered a mouse model of co-existing valvular carditis and inflammatory arthritis, with pathologic features recapitulating those in human patients. Our group was the first to show a critical role for myeloid cells in promoting valvular carditis. Specifically, we showed that autoantibodies engage particular Fc receptors on macrophages, leading to pro-inflammatory cytokine production and macrophage polarization, leading to chronic valve inflammation and fibrosis. We have identified the cytokine interleukin-13 (IL-13) as a key driver of this process. The current proposal builds on these findings and extends them. Here we will identify the cell type producing IL-13; preliminary data suggest type 2 innate lymphoid cells (ILC2s). We will also identify the pathways that lead to increased IL-13 production, focused on cytokines made by endothelial cells. Type 2 immune responses are known to promote tissue fibrosis, which occurs in the cardiac valves of patients with RHD and in our mouse model, characterized by the presence of myofibroblasts in the valves. The cell from which these myofibroblasts originate is not known. We propose sophisticated cell lineage tracing experiments to identify myofibroblast progenitors among valve interstitial cells (VICs) in valvular carditis. Understanding the origin of the myofibroblasts is critical to targeting them therapeutically. Finally, we are focused on the puzzling question of why valvular carditis preferentially affects the left-sided heart valves (mitral and aortic) and not the right-sided ones – this is true in both human patients and the mouse model. Many possibilities exist. Our preliminary data show that the expression of key genes and proteins involved in type 2 immunity or in sensing biophysical variables (e.g. oxygen tension and shear stress) differs between the left- and right-sided valves in normal mice. We therefore propose to perform comprehensive analysis of cardiac valve gene expression to identify molecular pathways that underlie this left-sided predilection. Guided by these data, we will interrogate the most promising of these pathways. In sum, we will define how discrete populations of immune cells interact with endothelial cells and VICs to cause chronic valve inflammation and fibrosis. Further, we will reveal why the milieu of the left side of the heart promotes inflammation and fibrosis. Although we are focused here on valvular carditis, we expect that our findings will be generalizable to other types of cardiovascular inflammation, including atherosclerosis.

摘要 患有慢性炎症性/风湿性疾病的患者心血管发病率和死亡率增加。 改善预后需要了解慢性炎症是如何导致心血管病理的。这个 这项提案的重点是瓣膜性心脏炎。瓣膜性心脏炎最常见的原因是风湿性心脏病 每年影响全球3000万人并导致30万人死亡的疾病(RHD)。瓣膜 狼疮和相关的抗磷脂抗体综合征患者也会发生心脏炎。我们的团队已经 首创具有病理学特征的瓣膜性心脏炎和炎症性关节炎共存的小鼠模型 在人类患者身上重述这些。我们小组是第一个显示髓系细胞在 促进瓣膜性心脏炎。具体地说，我们发现自身抗体与特定的Fc受体结合。 巨噬细胞，导致促炎细胞因子的产生和巨噬细胞极化，导致 慢性瓣膜炎症和纤维化。我们已经确定细胞因子白介素13(IL-13)是 这一过程。目前的提案建立在这些发现的基础上，并对其进行了扩展。在这里，我们将标识单元类型 产生IL-13；初步数据显示为2型先天淋巴样细胞(ILC2s)。我们还将确定 导致IL-13产生增加的途径集中在内皮细胞制造的细胞因子上。类型2 众所周知，免疫反应会促进组织纤维化，这种纤维化发生在心脏病患者的心脏瓣膜中。 风湿性心脏病和我们的小鼠模型中，特征是瓣膜中存在肌成纤维细胞。来自的单元格 这些肌成纤维细胞的来源尚不清楚。我们提出了复杂的细胞谱系追踪实验 目的：从瓣膜间质细胞(VIC)中鉴定心脏瓣膜炎肌成纤维细胞的来源。了解 肌成纤维细胞的来源是治疗靶向的关键。最后，我们关注的是令人费解的 为什么瓣膜性心脏炎优先影响左侧心脏瓣膜(二尖瓣和主动脉瓣)而不是 右侧--这在人类患者和小鼠模型中都是正确的。存在许多可能性。我们的 初步数据显示，参与2型免疫或感觉的关键基因和蛋白的表达 左侧和右侧瓣膜的生物物理变量(例如氧分压和剪应力)在以下方面有所不同 正常的小鼠。因此，我们建议对心脏瓣膜基因的表达进行全面分析，以 找出这种左倾倾向背后的分子途径。在这些数据的指引下，我们将对 这些途径中最有希望的。总而言之，我们将定义离散的免疫细胞群体如何相互作用 与血管内皮细胞和VICs一起引起慢性瓣膜炎症和纤维化。进一步，我们将揭示为什么 心脏左侧的环境会促进炎症和纤维化。尽管我们在这里关注的是 我们预计，我们的发现将推广到其他类型的心血管炎症， 包括动脉粥样硬化。