Complement in the Pathogenesis of Autoimmune Arthritis

补体在自身免疫性关节炎发病机制中的作用

• 批准号: 10255878
• 负责人: Vernon Michael Holers
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2021-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255878
• 关键词: Address; Adopted; Affect; Animal Model; Antibodies; Antigens; Appearance; Arthritis; Attention; Autoantibodies; Autoantigens; Autoimmune Diseases; Biological Markers; Biopsy; Blood; Blood specimen; Cells; Clinical Trials; Complement; Complement Activation; Complement Factor H; Development; Diagnosis; Disease; Disease model; Disease remission; Fibroblasts; Funding; Generations; Goals; Grant; Human; Immune; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Injury; Joints; Knowledge; Lectin; Lung; Mannose Binding Lectin; Mediator of activation protein; Medicine; Mucositis; Mus; Natural History; Natural Immunity; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Population; Positioning Attribute; Process; Proteins; Regulation; Reporting; Rheumatoid Arthritis; Role; Sampling; Serine Protease; Synovial Cell; Synovial Membrane; Synovitis; System; Systemic Lupus Erythematosus; Therapeutic; Tissues; Translating; Translational Research; United States National Institutes of Health; Work; autoimmune arthritis; bone erosion; cell type; citrullinated protein; complement pathway; complement system; disability; ficolin; human disease; human model; immunoregulation; improved; in vivo; information model; inhibitor/antagonist; insight; mouse model; mucosal site; natural antibodies; neoantigens; next generation; novel; pathogen; patient subsets; pre-clinical; prognostic; programs; skills; societal costs; targeted treatment; tissue injury

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.

补体系统是主要的促炎和免疫调节途径，并且起着核心作用 在驱动人类类风湿关节炎实验性鼠模型的发病机理的机制中 （RA）。在这些鼠模型中，针对自我组织的不适当补体激活驱动初始 细胞流入关节以及滑膜炎症和骨侵蚀。但是，尽管有广泛的 我们在支持这笔赠款的支持下对鼠类疾病的见解，包括激活 涉及的途径，如何克服系统的控制以及单个效应器途径如何促进 组织损伤，我们不知道补体系统如何在RA患者中起致病作用。 我们对人类疾病的研究的最新发现已经确定了RA的长时间临床前阶段 以循环自身抗体和粘膜炎症的存在为特征 对柑橘类自我抗原的耐受性的最初破裂。跟随无症状的阶段，其中补充 激活存在于粘膜部位，但在系统上不存在，很可能是补体激活和效应子 这样的机制尤其重要，因为疾病过渡到滑膜炎的早期阶段 针对瓜氨酸蛋白的循环自身抗体最初与发展和 显示在关节中。建立我们对人类疾病的理解并转化 对患者本身的疾病模型，该竞争性更新建议的主要重点是了解 补体系统如何参与RA的早期滑膜炎。我们特别好 实现这一重要目标，就像其他支持机制一样，我们能够识别并遵循主题 从临床前时期到滑膜炎的首次出现和RA的诊断。通过获得 滑动活检，这是在过去3 - 4年中通过其他资金在我们的计划中开发的技能，以及 在这个重要的过渡期内，患者的信息丰富的血液样本，我们将努力表征该角色 补体激活以及其初始发展中的调节和效应机制 患者的炎性关节炎和滑膜炎。另外，由于RA的不同子类型， 病态型具有预后重要性，我们将确定哪些补体激活过程是 与单个病原体相关。最后，我们将特别关注主要的滑细胞类型 人类RA，高度炎症成纤维细胞样的滑膜细胞，其重要性越来越多 理解并在其无偏的法学研究中有报道的补体特征。我们将定义 补体与这种细胞类型相互作用的机制，既与补体” 激活后激活并定义这些细胞的表型变化。这些主要目标 研究是使用获得的信息来告知当前和下一代补充治疗剂的使用 在这种重要的人类自身免疫性疾病中。