Characterization of a new mouse model of autoimmune cardiac valve disease

描述（由申请人提供）：内皮活化发生在许多系统性自身免疫性风湿病中，包括类风湿关节炎、系统性红斑狼疮、抗磷脂抗体综合征和风湿热。这种内皮活化可能导致冠状动脉疾病、血栓形成或心脏瓣膜炎症，所有这些都增加了这些患者的死亡风险。因此，了解自身免疫性疾病导致内皮病理的基本机制对于减轻此类疾病的负担至关重要。关节炎小鼠K/BxN模型为研究全身自身免疫与内皮病理之间的相互作用提供了一个新的系统。在这个模型中，关节炎发生的机制被很好地理解，包括针对普遍表达的抗原的自身抗体的形成，免疫复合物的形成和在滑膜表面的沉积，炎症细胞的募集和补体激活。虽然该模型中的炎症攻击被认为仅限于关节，但本文提出的初步数据显示，K/BxN小鼠的心脏瓣膜也会炎症和增厚。这是第一个自发性心脏瓣膜炎症的动物模型。瓣膜疾病发生在已建立的小鼠关节炎模型中，这一事实提供了一个独特的机会来剖析全身自身免疫引起心脏内皮损伤的机制。这种自身免疫性心炎的新模型将通过三个特定目标来表征，包括(1)描述K/BxN模型中炎症性瓣膜性心炎的组织病理学和免疫病理学特征，(2)确定B细胞和免疫球蛋白在瓣膜病理产生中的作用，(3)确定补体系统调节瓣膜病理的机制。根据初步观察，补体成分C1q的遗传缺乏会加重心炎的严重程度。预计通过研究这种新的自身免疫性心脏瓣膜疾病动物模型所获得的知识将为研究系统性自身免疫性疾病的内皮病理机制开辟进一步的途径，并为此类疾病患者带来创新的治疗方法。

DESCRIPTION (provided by applicant): Endothelial activation occurs in many of the systemic autoimmune rheumatologic disorders, including rheumatoid arthritis, systemic lupus erythematosus, the antiphospholipid antibody syndrome, and rheumatic fever. This endothelial activation may lead to coronary artery disease, thrombosis, or cardiac valve inflammation, all of which contribute to the increased mortality risk these patients incur. Understanding the basic mechanisms by which autoimmune diseases lead to endothelial pathology is therefore essential to reduce the burden of such diseases. The K/BxN murine model of arthritis provides a novel system in which to study the interplay between systemic autoimmunity and endothelial pathology. The mechanisms of arthritogenesis in this model are well understood, and include autoantibody formation against a ubiquitously expressed antigen, immune complex formation and deposition on synovial surfaces, recruitment of inflammatory cells and complement activation. Although the inflammatory attack in this model was thought to be restricted to the joints, preliminary data presented herein show that the cardiac valves of K/BxN mice are also inflamed and thickened. This is the first animal model of spontaneous cardiac valve inflammation. The fact that the valve disease occurs in an established murine model of arthritis affords a unique opportunity to dissect the mechanisms by which systemic autoimmunity provokes endothelial injury in the heart. This new model of autoimmune carditis will be characterized via three specific aims, including (1) describing the histopathologic and immunopathologic features of the inflammatory valvular carditis in the K/BxN model, (2) determining the role that B cells and immunoglobulins play in generation of the valve pathology and (3) determining the mechanism(s) by which the complement system regulates the valve pathology, based on the preliminary observation that genetic deficiency of complement component C1q exacerbates carditis severity. It is expected that the knowledge gained by studying this new animal model of autoimmune cardiac valve disease will open further avenues for investigating the mechanisms of endothelial pathology in systemic autoimmune conditions and also lead to innovative therapeutic approaches for patients with such disorders.