Complement in the Pathogenesis of Autoimmune Arthritis

 说明(申请人提供)：补体系统是先天免疫的主要组成部分，在推动人类类风湿性关节炎(RA)发病的促炎机制中发挥核心作用。在这个过程中，针对自身组织的不适当的补体激活会导致细胞涌入、滑膜炎症和骨侵蚀。最近的发现表明，在疾病的早期阶段，当循环自身抗体最初与形成并显示在关节中的抗原发生反应时，这种致病过程可能特别重要。我们使用了一种名为胶原抗体诱导性关节炎(CAIA)的类风湿关节炎动物模型，以了解补体这些损伤作用的分子基础。拟议研究的一个主要焦点将是损伤组织如何通过参与凝集素途径激活关节内的补体，我们最近意外地发现凝集素途径在CAIA中发挥重要作用。一旦被激活，凝集素途径就会导致替代途径扩增环的病理性参与。我们还将确定因子H(FH)本身是否是调节其功能的因子H相关(FHR)蛋白家族的“去调节”蛋白的靶标。我们已经证明，因子H(FH)在控制无细胞软骨和应激成纤维样滑膜(FLS)细胞上的补体激活方面起着至关重要的作用。最后，我们有一个令人惊讶的发现，由过敏性毒素C5a和C3a受体结合启动的远端补体效应通路放大了抗胶原抗体的沉积和近端补体C3的激活，导致关节损伤大大增加。我们打算描述这种远端扩增过程发生的分子机制，并确定是什么效应细胞和危险信号介导了这种效应。作为这项工作的一个主要焦点，我们已经确定并将探索一种新的损伤机制，通过接触硬连接的致病天然抗体，识别与损伤相关的新表位作为危险信号，并进一步增加补体的激活。通过这些努力，我们希望找到新的方法，通过这些方法，我们可以以治疗有效的方式有益地调节补体。

 DESCRIPTION (provided by applicant): The complement system is a major component of innate immunity and plays a central role in the pro-inflammatory mechanisms that drive the pathogenesis of human rheumatoid arthritis (RA). In this process, inappropriate complement activation that is directed to self-tissues drives cellular influx, synovial inflammation and bone erosions. Recent findings suggest that this pathogenic process is likely to be especially important in the early phases of disease when circulating autoantibodies initially react with antigens which develop and are displayed in the joint. We have used an animal model of RA designated collagen antibody-induced arthritis (CAIA) to understand the molecular basis for these injurious roles of complement. One major focus of the proposed studies will be on how complement is activated within the joint by injured tissues through the engagement of the lectin pathway, which we recently unexpectedly found to play a major role in CAIA. Once activated, the lectin pathway leads to pathogenic engagement of the alternative pathway amplification loop. We will also determine whether factor H (FH), a soluble protein that we have shown plays an essential role in controlling complement activation on the acellular cartilage and stressed fibroblast-like synovial (FLS) cells, is itself the target of "de-regulatory" proteins from the facor H related (FHR) protein family which modulate its function. Finally, we have made the surprising finding that distal complement effector pathways initiated by anaphylatoxin C5a and C3a receptor engagement amplifies anti-collagen antibody deposition and proximal complement C3 activation, resulting in greatly increased joint damage. We intend to characterize the molecular mechanisms by which this distal amplification process occurs and determine what effector cells and danger signals mediate this effect. As a major focus of this effort, we have identified and wil explore a new injury mechanism through the engagement of hard-wired pathogenic natural antibodies that recognize injury- associated neoepitopes as danger signals and further increase complement activation. Through these efforts we hope to identify novel means by which we can beneficially modulate complement in a therapeutically efficacious manner.