Pathogenesis of autoimmune endocarditis: roles for Fc receptors and integrins?

描述（由申请人提供）：许多系统性自身免疫性疾病影响滑膜关节和心血管系统。例如，类风湿关节炎或系统性红斑狼疮（SLE）患者发生冠状动脉疾病的风险增加。特别是，心脏瓣膜的炎症发生在风湿热（风湿性心炎）和SLE及相关的抗磷脂综合征（Libman-Sacks心内膜炎）。在这些人类系统性自身免疫性疾病中，引起滑膜关节和心脏瓣膜伴随炎症的免疫机制仍然不清楚。我们最近在一个研究充分的自身抗体相关性关节炎模型中发现了自发性心脏瓣膜炎症（心内膜炎）。这个模型提供了独特的机会来解剖免疫机制介导自身免疫攻击的关节和心脏瓣膜。本文提出的初步数据表明，心内膜炎和关节炎依赖于相同的适应性免疫系统元素，导致免疫耐受的初始破坏，从而产生自身抗体。相反，关键的先天免疫系统效应途径在两种靶组织之间不同。该小鼠模型中的关节炎主要依赖于补体C5而不是Fc受体；相反，心内膜炎主要依赖于Fc受体，而不是C5。与中性粒细胞为主的关节浸润相反，这些小鼠的心脏瓣膜浸润包括携带22个整合素粘附受体的T细胞和巨噬细胞，以及这些受体的内皮配体的上调。目前的提案研究了两个先天免疫受体家族，Fc受体和22整合素，如何促进自身免疫性心内膜炎的发展。我们将确定哪些细胞类型必须表达Fc受体，以及哪种特定的Fc受体对心内膜炎的发展至关重要。此外，我们将研究22整合素受体家族成员在关节炎和心内膜炎发生过程中的差异，通过研究特定22整合素缺乏对这两种组织疾病进展的影响。希望这些研究将为进一步研究单个系统性自身抗体相关自身免疫性疾病以不同方式参与先天免疫系统以引起离散靶组织损伤的机制提供重要的基础。了解这些差异可能有助于开发针对系统性自身免疫性疾病的更有针对性的治疗方法，这些治疗方法是基于个体患者所涉及的器官系统。

DESCRIPTION (provided by applicant): Many systemic autoimmune diseases affect both the synovial joints and the cardiovascular system. For example, patients with rheumatoid arthritis or systemic lupus erythematosus (SLE) are at increased risk for developing coronary artery disease. In particular, inflammation of the cardiac valves occurs in rheumatic fever (rheumatic carditis) and in SLE and the related antiphospholipid syndrome (Libman-Sacks endocarditis). The immune mechanisms that provoke concomitant inflammation of synovial joints and cardiac valves in these human systemic autoimmune disorders remain poorly defined. We have recently discovered spontaneous cardiac valve inflammation (endocarditis) in a well-studied model of autoantibody-associated arthritis. This model affords the unique opportunity to dissect the immune mechanisms mediating autoimmune attack on the joints versus the heart valves. The preliminary data presented herein demonstrate that endocarditis and arthritis depend on the same adaptive immune system elements for the initial breach of immunologic tolerance leading to autoantibody production. In contrast, the key innate immune system effector pathways differ between the two target tissues. Arthritis in this mouse model depends primarily on complement C5 and not Fc receptors; conversely, endocarditis depends essentially on Fc receptors and not C5. In contrast to the neutrophil-predominated joint infiltrate, the cardiac valve infiltrate in these mice comprises T cells and macrophages bearing 22 integrin adhesion receptors, as well as up-regulation of the endothelial ligands for these receptors. The current proposal investigates how two families of innate immune receptors, Fc receptors and 22 integrins, contribute to the development of autoimmune endocarditis. We will determine what cell types must express Fc receptors and which particular Fc receptor is critical for the development of endocarditis. In addition, we will investigate the possibility that members of the 22 integrin receptor family contribute differentially to the development of arthritis and endocarditis by studying the effects that deficiencies of specific 22 integrins have on the progression of disease in both tissues. It is hoped that these studies will provide important groundwork for additional research into the mechanisms by which a single systemic, autoantibody-associated autoimmune disease differentially engages the innate immune system to provoke damage in discrete target tissues. Understanding these differences may allow the development of more targeted therapies for systemic autoimmune diseases, based on which organ systems are involved in an individual patient. PUBLIC HEALTH RELEVANCE: The valves of the heart can be damaged by the immune system in diseases such as rheumatic fever and systemic lupus erythematosus. Our research program uses a mouse model to study in depth the mechanisms by which the immune system damages the heart valves. We expect that our findings will lead eventually to the development of new therapies for patients with rheumatic fever, lupus, and related autoimmune diseases.