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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：完成系统是先天免疫的主要组成部分，并且在促进人类类风湿关节炎（RA）发病机理的促炎机制中起着核心作用。在此过程中，针对自我组织的不当完成激活驱动细胞影响，滑膜感染和骨侵蚀。最近的发现表明，当循环自身抗体与最初与抗原发生反应的抗原时，这种致病过程在疾病的早期阶段尤为重要。我们已经使用了RA设计的胶原蛋白抗体诱导的关节炎（CAIA）的动物模型来了解这些受伤的完成作用的分子基础。拟议的研究的一个主要重点将是通过讲座途径通过受伤组织在关节内如何激活完成的重点，我们最近意外地发现这在凯亚（CAIA）中起着重要作用。一旦激活，讲座途径就会导致替代途径放大环的致病性参与。我们还将确定因子H（FH）是一种固体蛋白，我们在控制细胞软骨上的完成激活中表现出至关重要的作用，而应力的成纤维细胞样滑膜（FLS）细胞本身是从Faceer H相关（FHR）蛋白（FHR）蛋白（调节其功能）的“去调节性”蛋白的靶标。最后，我们提出了一个令人惊讶的发现，远端补体效应子途径由过敏毒素C5A和C3A受体参与放大器抗胶原抗体沉积和近端完成C3激活，从而大大增加关节损伤。我们打算表征这种远端放大器过程发生的分子机制，并确定效应细胞和危险信号介导这种效果。作为这项工作的主要重点，我们通过参与硬连线的致病天然抗体来探索并探索一种新的伤害机制，这些抗体识别损伤与造成的Neoeppitopes是危险信号并进一步增加完成激活。通过这些努力，我们希望确定我们可以以治疗效率进行有益地调节完成的新颖手段。