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: 9044728
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044728
• 关键词: Address; Affect; Alternative Complement Pathway; Anaphylatoxins; Animal Model; Antibodies; Antibody Activation; Antigen-Antibody Complex; Antigens; Arthritis; Autoantibodies; Autoimmune Diseases; Basic Science; Binding; Cartilage; Chronic; Cleaved cell; Collagen; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Factor D; Complement Factor H; Complement Membrane Attack Complex; Complex; Deposition; Development; Disease; Distal; Effector Cell; Exhibits; Fibroblasts; Funding; Genetic; Health; Human; Immune; In Vitro; Inflammatory; Inflammatory Arthritis; Injury; Joints; Knowledge; Lectin; Mannose Binding Lectin; Mannose-Binding Lectins; Mediating; Modeling; Molecular; Mus; Natural Immunity; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Play; Population; Process; Protein Biosynthesis; Protein Family; Proteins; Recombinant Proteins; Regulation; Rheumatoid Arthritis; Role; Serine Protease; Signal Transduction; Stress; Synovial Cell; Synovitis; Time; Tissue Fixation; Tissues; Work; autoimmune arthritis; base; bone erosion; collagen antibody induced arthritis; complement pathway; complement system; cost; disability; genetic regulatory protein; human disease; improved; in vivo; inhibitor/antagonist; injured; insight; joint injury; new therapeutic target; novel; pathogen; receptor; research study; tool

 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.

 描述（由申请人提供）：补体系统是先天免疫的主要组成部分，在驱动人类类风湿性关节炎（RA）发病机制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驱动细胞内流、滑膜炎症和骨侵蚀。最近的研究结果表明，这一致病过程可能是特别重要的疾病的早期阶段时，循环自身抗体最初与抗原的发展和显示在关节。我们已经使用了一个动物模型的RA指定胶原抗体诱导的关节炎（CAIA），以了解这些有害的补体作用的分子基础。拟议研究的一个主要重点将是补体如何通过凝集素途径的参与在关节内被受损组织激活，我们最近意外地发现凝集素途径在CAIA中起着重要作用。一旦激活，凝集素途径导致旁路途径扩增环的致病性接合。我们还将确定是否因子H（FH），一种可溶性蛋白质，我们已经表明在控制补体激活的脱细胞软骨和应激成纤维细胞样滑膜（FLS）细胞中起重要作用，本身是“去调节”的目标蛋白质从因子H相关（FHR）蛋白家族，调节其功能。最后，我们有了一个令人惊讶的发现，即由过敏毒素C5a和C3a受体结合引发的远端补体效应子途径放大了抗胶原抗体沉积和近端补体C3活化，导致关节损伤大大增加。我们打算表征这种远端扩增过程发生的分子机制，并确定什么效应细胞和危险信号介导这种效应。作为该努力的主要焦点，我们已经鉴定并将探索通过硬连线致病性天然抗体的参与的新损伤机制，所述抗体将损伤相关新表位识别为危险信号并进一步增加补体激活。通过这些努力，我们希望确定新的手段，我们可以有益地调节补体在治疗上有效的方式。