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

描述(申请人提供)：许多全身性自身免疫性疾病同时影响滑膜关节和心血管系统。例如，类风湿性关节炎或系统性红斑狼疮(SLE)患者患冠状动脉疾病的风险增加。特别是，风湿热(风湿性心脏炎)和系统性红斑狼疮(SLE)以及相关的抗磷脂综合征(Libman-Sack心内膜炎)会导致心脏瓣膜发炎。在这些人类全身性自身免疫性疾病中，引发滑膜关节和心脏瓣膜相伴炎症的免疫机制仍不清楚。我们最近在一种经过充分研究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)。这一模型提供了独特的机会来剖析介导关节与心脏瓣膜自身免疫攻击的免疫机制。本文提供的初步数据表明，心内膜炎和关节炎依赖于相同的适应性免疫系统元素，导致免疫耐受最初被打破，从而导致自身抗体的产生。相反，关键的先天免疫系统效应器通路在两个靶组织之间是不同的。在这个小鼠模型中，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。与以中性粒细胞为主的关节浸润液不同，这些小鼠的心脏瓣膜浸润液由T细胞和巨噬细胞组成，它们携带22个整合素黏附受体，并上调这些受体的内皮配体。目前的提案调查了两个天然免疫受体家族，Fc受体和22整合素，如何在自身免疫性心内膜炎的发展中起作用。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，我们将通过研究特定的22整合素缺乏对这两个组织的疾病进展的影响，来研究22整合素受体家族成员在关节炎和心内膜炎的发展中起不同作用的可能性。人们希望这些研究将为进一步研究单一系统性、自身抗体相关的自身免疫性疾病不同地与先天性免疫系统接触以在离散的靶组织中引发损害的机制提供重要的基础。了解这些差异可能有助于开发更有针对性的治疗系统性自身免疫性疾病的方法，这是基于单个患者的器官系统所涉及的。 与公共卫生相关：在风湿热和系统性红斑狼疮等疾病中，心脏瓣膜可能会被免疫系统破坏。我们的研究项目使用小鼠模型来深入研究免疫系统破坏心脏瓣膜的机制。我们希望我们的发现最终将导致风湿热、狼疮和相关自身免疫性疾病患者的新疗法的开发。

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.