Complement in the Pathogenesis of Autoimmune Arthritis

补体系统是一条主要的促炎和免疫调节途径，发挥着核心作用。 在推动实验性人类类风湿关节炎小鼠模型发病机制中 (RA)。在这些小鼠模型中，针对自身组织的不适当的补体激活推动了最初的 细胞涌入关节以及滑膜炎症和骨侵蚀。然而，尽管有广泛的 对我们在这笔赠款的支持下开发的小鼠疾病的见解，包括激活 涉及的通路，如何克服对系统的控制，以及单个效应器通路如何促进 组织损伤，我们不知道补体系统是如何在RA患者中起致病作用的。 我们最近对人类疾病的研究发现，类风湿性关节炎存在较长的临床前阶段 以循环自身抗体和粘膜炎症的存在为特征的，这似乎推动了 最初打破对瓜氨酸自身抗原的耐受性。在无症状阶段之后，补体 激活存在于粘膜部位，但不是系统性的，很可能是补体激活和效应器 当疾病过渡到滑膜炎的非常早期阶段时，机制就变得尤为重要 针对瓜氨酸蛋白的循环自身抗体最初与抗原反应，这些抗原形成和 将显示在运动类型中。建立我们对人类疾病的理解，并将信息从 患者自身的疾病模型，这个相互竞争的更新提案的主要焦点是理解 补体系统在类风湿关节炎早期滑膜炎中的作用我们尤其处于有利地位， 实现这一重要目标，就像我们能够确定和跟踪主题的其他支持机制一样 从临床前期到第一次出现滑膜炎和类风湿关节炎的诊断。通过获得 滑膜活检，这是我们计划在过去3-4年里通过其他资金发展起来的一套技术，以及 患者血液样本的信息量在这一重要的过渡期，我们将努力确定其作用 补体激活及其调节和效应机制在慢性粒细胞白血病早期发展中的作用 炎症性关节炎和滑膜炎患者。此外，由于类风湿性关节炎有不同的亚型，指定为 具有预后重要性的致病类型，我们将确定补体激活过程 与个体致病类型相关的。最后，我们将特别关注一种主要的滑膜细胞类型 人类类风湿关节炎是高度炎性的成纤维细胞样滑膜细胞，其重要性日益增加 理解，并在无偏见组学研究中有报道的补体签名。我们将定义 补体与这种细胞类型相互作用的机制，既涉及补体如何 激活以及定义这些细胞在激活后的表型变化。其中的一个主要目标是 研究是利用获得的信息为当前和下一代补充疗法的使用提供信息 在这种重要的人类自身免疫性疾病中。

The complement system is a major pro-inflammatory and immunomodulatory pathway and plays a central role in the mechanisms that drive the pathogenesis of experimental murine models of human rheumatoid arthritis (RA). In these murine models, inappropriate complement activation that is directed to self-tissues drives initial cellular influx into the joint as well as synovial inflammation and bone erosions. However, despite the extensive insights into the murine disease that we have developed with support of this grant, including the activation pathways involved, how control of the system is overcome and how individual effector pathways promote tissue damage, we do not know how the complement system plays a pathogenic role in patients with RA. Recent findings in our studies of the human disease have identified a prolonged preclinical phase in RA characterized by the presence of circulating autoantibodies and mucosal inflammation that appears to drive the initial break in tolerance to citrullinated self-antigens. Following that asymptomatic phase, where complement activation is present in the mucosal site but not systemically, it is likely that complement activation and effector mechanisms are then especially important as the disease transitions to the very early phases of synovitis when circulating autoantibodies directed against citrullinated proteins initially react with antigens which develop and are displayed in the joint. To build our understanding of the human disease and translate information from models of disease to patients themselves, the major focus of this competing renewal proposal is to understand how the complement system is involved in the early synovitis in RA. We are especially well positioned to accomplish this important goal, as with other support mechanisms we are able to identify and follow subjects from the preclinical period into the very first appearance of synovitis and the diagnosis of RA. By obtaining synovial biopsies, a skill set also developed in our program in the last 3-4 years through other funding, and informative blood samples from patients in this important transition period, we will work to characterize the role of complement activation as well as its regulatory and effector mechanisms in the initial development of inflammatory arthritis and synovitis in patients. In addition, as there are distinct sub-types of RA, designated pathotypes, which have prognostic importance, we will determine what complement activation processes are associated with individual pathotypes. Finally, we will focus special attention on a major synovial cell type in human RA, which are highly inflammatory fibroblast-like synoviocytes, whose importance is increasingly understood and for which there are reported complement signatures in unbiased omics studies. We will define the mechanisms by which complement interacts with this cell type, both with regard to how complement is activated as well as defining the phenotypic changes in these cells following activation. A major goal in these studies is to use information gained to inform the use of current and next generation complement therapeutics in this important human autoimmune disease.